Science.gov

Sample records for background genetic susceptibility

  1. Genetic background affects susceptibility to tumoral stem cell reprogramming

    PubMed Central

    García-Ramírez, Idoia; Ruiz-Roca, Lucía; Martín-Lorenzo, Alberto; Blanco, Óscar; García-Cenador, María Begoña; García-Criado, Francisco Javier; Vicente-Dueñas, Carolina; Sánchez-García, Isidro

    2013-01-01

    The latest studies of the interactions between oncogenes and its target cell have shown that certain oncogenes may act as passengers to reprogram tissue-specific stem/progenitor cell into a malignant cancer stem cell state. In this study, we show that the genetic background influences this tumoral stem cell reprogramming capacity of the oncogenes using as a model the Sca1-BCRABLp210 mice, where the type of tumor they develop, chronic myeloid leukemia (CML), is a function of tumoral stem cell reprogramming. Sca1-BCRABLp210 mice containing FVB genetic components were significantly more resistant to CML. However, pure Sca1-BCRABLp210 FVB mice developed thymomas that were not seen in the Sca1-BCRABLp210 mice into the B6 background. Collectively, our results demonstrate for the first time that tumoral stem cell reprogramming fate is subject to polymorphic genetic control. PMID:23839033

  2. Mitochondrial Genetic Background Modulates Bioenergetics and Susceptibility to Acute Cardiac Volume – Overload

    PubMed Central

    Fetterman, Jessica L.; Zelickson, Blake R.; Johnson, Larry W.; Moellering, Douglas R.; Westbrook, David G.; Pompilius, Melissa; Sammy, Melissa J.; Johnson, Michelle; Dunham-Snary, Kimberly J.; Cao, Xuemei; Bradley, Wayne E.; Zhang, Jinju; Wei, Chih-Chang; Chacko, Balu; Schurr, Theodore G.; Kesterson, Robert A.; Dell’Italia, Louis J.; Darley-Usmar, Victor M.; Welch, Danny R.; Ballinger, Scott W.

    2013-01-01

    Synopsis Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mitochondrial DNA (mtDNA) sequence variation contributes to disease susceptibility. In this study we present a novel animal model of mtDNA polymorphisms, the mitochondrial nuclear exchange mouse (MNX), in which the mtDNA from C3H/HeN mouse has been inserted onto the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harboring the C57/BL6J mtDNA generate more reactive oxygen species (ROS) and have a higher mitochondrial membrane potential relative to those having the C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the “mitochondrial paradigm” for the development of disease susceptibility, and show that the mtDNA modulates, cellular bioenergetics, mitochondrial reactive oxygen species generation and susceptibility to cardiac stress. PMID:23924350

  3. Genetic aspects of susceptibility to air pollution.

    PubMed

    Kleeberger, S R

    2003-05-01

    Inter-individual variation in human responses to air pollutants suggests that some subpopulations are at increased risk, and it is increasingly clear that genetic background is an important susceptibility factor. Genetically standardised animal models provide useful investigative tools. Linkage analyses using inbred mice identified chromosomal segments (quantitative trait loci (QTL)), with genes controlling susceptibility to the lung inflammatory (chromosome 17), injury (chromosome 11), and hyperpermeability (chromosome 4) responses to ozone (O3) exposure. An immune dysfunction response induced by exposure to sulphate-associated particles is linked to the identical chromosome 17 and 11 QTLs described for O3 susceptibility, thus similar genetic mechanisms may be controlling pulmonary responses to these pollutants. Candidate genes within the QTLs on chromosomes 4 and 17 include the toll-like receptor 4 and the pro-inflammatory cytokine, tumour necrosis factor-alpha, respectively. Functional analyses strongly support a role for these candidate genes in determining susceptibility to O3 and particulates. Because striking linkage homology exists between the human and mouse genomes, candidate susceptibility genes identified in the mouse are likely to aid research aimed at understanding human genetic factors that contribute to differential susceptibility. To date, no studies have examined the interaction between age and genetic background in the development of air pollution-induced lung disease. However, investigations have suggested an influence of age on genetic susceptibility to lung cancer and other diseases, which indicate that an interaction between age and genetic background may be important in air pollution disease pathogenesis. PMID:12762575

  4. Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line

    PubMed Central

    Krentz, Anthony D.; Murphy, Mark W.; Zhang, Teng; Sarver, Aaron L.; Jain, Sanjay; Griswold, Michael D.; Bardwell, Vivian J.; Zarkower, David

    2013-01-01

    Dmrt1(doublesex and mab-3 related transcription factor 1) is a regulator of testis development in vertebrates that has been implicated in testicular germ cell tumors of mouse and human. In the fetal mouse testis Dmrt1 regulates germ cell pluripotency in a strain-dependent manner. Loss of Dmrt1 in 129Sv strain mice results in a >90% incidence of testicular teratomas, tumors consisting cells of multiple germ layers; by contrast, these tumors have never been observed in Dmrt1 mutants of C57BL/6J (B6) or mixed genetic backgrounds. To further investigate the interaction between Dmrt1 and genetic background we compared mRNA expression in wild type and Dmrt1 mutant fetal testes of 129Sv and B6 mice at embryonic day 15.5 (E15.5), prior to overt tumorigenesis. Loss of Dmrt1 caused misexpression of overlapping but distinct sets of mRNAs in the two strains. The mRNAs that were selectively affected included some that changed expression only in one strain or the other and some that changed in both strains but to a greater degree in one versus the other. In particular, loss of Dmrt1 in 129Sv testes caused a more severe failure to silence regulators of pluripotency than in B6 testes. A number of genes misregulated in 129Sv mutant testes also are misregulated in human testicular germ cell tumors (TGCTs), suggesting similar etiology between germ cell tumors in mouse and man. Expression profiling showed that DMRT1 also regulates pluripotency genes in the fetal ovary, although Dmrt1 mutant females do not develop teratomas. Pathway analysis indicated disruption of several signaling pathways in Dmrt1 mutant fetal testes, including Nodal, Notch, and GDNF. We used a Nanos3-cre knock-in allele to perform conditional gene targeting, testing the GDNF coreceptors Gfra1 and Ret for effects on teratoma susceptibility. Conditional deletion of Gfra1 but not Ret in fetal germ cells of animals outcrossed to 129Sv caused a modest but significant elevation in tumor incidence. Despite some variability in genetic background in these crosses, this result is consistent with previous genetic mapping of teratoma susceptibility loci to the region containing Gfra1. Using Nanos3-cre we also uncovered a strong genetic interaction between Dmrt1 and Nanos3, suggesting parallel functions for these two genes in fetal germ cells. Finally, we used chromatin immunoprecipitation (ChIP-seq) analysis to identify a number of potentially direct DMRT1 targets. This analysis suggested that DMRT1 controls pluripotency via transcriptional repression of Esrrb, Nr5a2/Lrh1, and Sox2. Given the strong evidence for involvement of DMRT1 in human TGCT, the downstream genes and pathways identified in this study provide potentially useful candidates for roles in the human disease. PMID:23473982

  5. Genetic background of febrile seizures.

    PubMed

    Saghazadeh, Amene; Mastrangelo, Mario; Rezaei, Nima

    2014-01-01

    Febrile seizures (FSs) occur in children older than 1 month and without prior afebrile seizures in the absence of a central nervous system infection or acute electrolyte imbalance. Their pathogenesis is multifactorial. The most relevant familial studies evidence an occurrence rate ranging from 10% to 46% and median recurrence rate of 36% in children with positive familial history for FS. The main twin studies demonstrated a higher concordance rate in monozygotic twins with FS than in dizygotic ones. Linkage studies have proposed 11 chromosomal locations responsible to FS attributed to FEB1 to FEB11. Population-based association studies have shown at least one positive association for 14 of 41 investigated genes with FS. The proinflammatory cytokine interleukin 1β (IL-1β) was the most investigated and also gene associated with susceptibility to FS. A possible role in the overlapping of epilepsy and FS was found for 16 of 36 investigated genes. SCN1A, IL-1β, CHRNA4, and GABRG2 were the most commonly involved genes in this context. The genetic background of FS involves the regulation of different processes, including individual and familial susceptibility, modulation of immune response, and neuronal excitability and interactions with exogenous agents such as viruses. PMID:24399675

  6. Genetics and gastric cancer susceptibility

    PubMed Central

    Lu, Yan; Lu, Fang; Zeng, Sha; Sun, Suqing; Lu, Li; Liu, Lifeng

    2015-01-01

    Gastric cancer has high morbidity and mortality in China. It is ranked first in malignant tumors of the digestive system. Its etiology and pathogenesis are still unclear, but they may be associated with a variety of factors. Genetic susceptibility genes have become a research hotspot in China. Elucidating the genetic mechanisms of gastric cancer can facilitate achieving individualized prevention and developing more effective methods to reduce clinical adverse consequences, which has important clinical significance. Genetic susceptibility results from the influence of genetic factors or specific genetic defects that endow an individual’s offspring with certain physiological and metabolic features that are prone to certain diseases. Currently, studies on the genetic susceptibility genes of gastric cancer have become a hotspot. The purpose is to screen for the etiology of gastric cancer, search for gene therapy methods, and ultimately provide a scientific basis for the prevention and control of gastric cancer. This article reviews the current progress of studies on genetic susceptibility genes for gastric cancer. PMID:26309491

  7. Genetic susceptibility to breast cancer.

    PubMed

    Bradbury, Angela R; Olopade, Olufunmilayo I

    2007-09-01

    Deleterious mutations in two breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2 have been identified in breast and ovarian cancer families. Women with a BRCA1 or BRCA2 mutation are candidates for additional risk reduction measures such as intensive screening, prophylactic surgery or chemoprevention. Additional susceptibility genes have been identified, including PTEN, ATM, TP53, CHEK2, CASP8, PBRL and BRIP1. Yet, many women with a personal or family history suggestive of a hereditary susceptibility to breast cancer undergo genetic testing and no significant genetic alteration is found. Thus, there are other susceptibility genes that have not been identified, and it is likely that the remaining familial contribution to breast cancer will be explained by the presence of multiple low penetrance alleles that coexist to confer high penetrance risks (a polygenic model). The American Cancer Society has identified cancer prevention as a key component of cancer management and there is interest in developing individualized cancer prevention focused on identifying high risk individuals who are most likely to benefit from more aggressive risk reduction measures. Breast cancer risk assessment and genetic counseling are currently provided by genetic counselors, oncology nurse specialist, geneticists, medical and surgical oncologists, gynecologists and other health care professionals, often working within a multidisciplinary clinical setting. Current methods for risk assessment and predictive genetic testing have limitations and improvements in molecular testing and risk assessment tools is necessary to maximize individual breast cancer risk assessment and to fulfill the promise of cancer prevention. PMID:17508290

  8. Bringing genetic background into focus.

    PubMed

    Chow, Clement Y

    2016-02-01

    Researchers should embrace differences in genetic background to build richer disease models that more accurately reflect the level of variation in the human population, posits Clement Chow. PMID:26659016

  9. Genetic Susceptibility to Rhodococcus equi.

    PubMed

    McQueen, C M; Dindot, S V; Foster, M J; Cohen, N D

    2015-01-01

    Rhodococcus equi pneumonia is a major cause of morbidity and mortality in neonatal foals. Much effort has been made to identify preventative measures and new treatments for R.equi with limited success. With a growing focus in the medical community on understanding the genetic basis of disease susceptibility, investigators have begun to evaluate the interaction of the genetics of the foal with R.equi. This review describes past efforts to understand the genetic basis underlying R.equi susceptibility and tolerance. It also highlights the genetic technology available to study horses and describes the use of this technology in investigating R.equi. This review provides readers with a foundational understanding of candidate gene approaches, single nucleotide polymorphism-based, and copy number variant-based genome-wide association studies, and next generation sequencing (both DNA and RNA). PMID:26340305

  10. Genetic susceptibility to radiation

    NASA Astrophysics Data System (ADS)

    Hall, E. J.; Brenner, D. J.; Worgul, B.; Smilenov, L.

    In the context of space radiation, it is important to know whether the human population includes genetically predisposed radiosensitive subsets. One possibility is that haploinsufficiency for ATM confers radiosensitivity, and this defect involves 1-3% of the population. Using knock-out mice we chose to study cataractogenesis in the lens and oncogenic transformation in mouse embryo fibroblasts to assay for effects of ATM deficiency. Radiation induced cataracts appeared earlier in the heterozygous versus wild-type animals following exposure to either gamma rays or 1 GeV/nucleon iron ions. In addition, it was found that embryo fibroblasts of Atm heterozygotes showed an increased incidence of oncogenic transformation compared with their normal litter-matched counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally-significant radiosensitive subpopulation.

  11. Genetic susceptibility to radiation

    NASA Astrophysics Data System (ADS)

    Hall, E. J.; Brenner, D. J.; Worgul, B.; Smilenov, L.

    In the context of space radiation, it is important to know whether the human population includes genetically predisposed radiosensitive subsets. One possibility is that haploinsufficiency for ATM confers radiosensitivity, and this defect involves 1 3% of the population. Using knock-out mice we chose to study cataractogenesis in the lens and oncogenic transformation in mouse embryo fibroblasts to assay for effects of ATM deficiency. Radiation induced cataracts appeared earlier in the heterozygous versus wild-type animals following exposure to either gamma rays or 1 GeV/nucleon iron ions. In addition, it was found that embryo fibroblasts of Atm heterozygotes showed an increased incidence of oncogenic transformation compared with their normal litter-matched counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally significant radiosensitive subpopulation. Knock-out mice are now available for other genes including BRCA1 and 2, and Mrad9. An exciting possibility is the creation of double heterozygotes for pairs of mutated genes that function in the same signal transduction pathway, and consequently confer even greater radiosensitivity.

  12. Exploring Genetic Susceptibility to Fibromyalgia

    PubMed Central

    Park, Dong-Jin; Kang, Ji-Hyoun; Yim, Yi-Rang; Kim, Ji-Eun; Lee, Jeong-Won; Lee, Kyung-Eun; Wen, Lihui; Kim, Tae-Jong; Park, Yong-Wook

    2015-01-01

    Fibromyalgia (FM) affects 1% to 5% of the population, and approximately 90% of the affected individuals are women. FM patients experience impaired quality of life and the disorder places a considerable economic burden on the medical care system. With the recognition of FM as a major health problem, many recent studies have evaluated the pathophysiology of FM. Although the etiology of FM remains unknown, it is thought to involve some combination of genetic susceptibility and environmental exposure that triggers further alterations in gene expression. Because FM shows marked familial aggregation, most previous research has focused on genetic predisposition to FM and has revealed associations between genetic factors and the development of FM, including specific gene polymorphisms involved in the serotonergic, dopaminergic, and catecholaminergic pathways. The aim of this review was to discuss the current evidence regarding genetic factors that may play a role in the development and symptom severity of FM. PMID:26306300

  13. The ontology of genetic susceptibility factors (OGSF) and its application in modeling genetic susceptibility to vaccine adverse events

    PubMed Central

    2014-01-01

    Background Due to human variations in genetic susceptibility, vaccination often triggers adverse events in a small population of vaccinees. Based on our previous work on ontological modeling of genetic susceptibility to disease, we developed an Ontology of Genetic Susceptibility Factors (OGSF), a biomedical ontology in the domain of genetic susceptibility and genetic susceptibility factors. The OGSF framework was then applied in the area of vaccine adverse events (VAEs). Results OGSF aligns with the Basic Formal Ontology (BFO). OGSF defines ‘genetic susceptibility’ as a subclass of BFO:disposition and has a material basis ‘genetic susceptibility factor’. The ‘genetic susceptibility to pathological bodily process’ is a subclasses of ‘genetic susceptibility’. A VAE is a type of pathological bodily process. OGSF represents different types of genetic susceptibility factors including various susceptibility alleles (e.g., SNP and gene). A general OGSF design pattern was developed to represent genetic susceptibility to VAE and associated genetic susceptibility factors using experimental results in genetic association studies. To test and validate the design pattern, two case studies were populated in OGSF. In the first case study, human gene allele DBR*15:01 is susceptible to influenza vaccine Pandemrix-induced Multiple Sclerosis. The second case study reports genetic susceptibility polymorphisms associated with systemic smallpox VAEs. After the data of the Case Study 2 were represented using OGSF-based axioms, SPARQL was successfully developed to retrieve the susceptibility factors stored in the populated OGSF. A network of data from the Case Study 2 was constructed by using ontology terms and individuals as nodes and ontology relations as edges. Different social network analys is (SNA) methods were then applied to verify core OGSF terms. Interestingly, a SNA hub analysis verified all susceptibility alleles of SNPs and a SNA closeness analysis verified the susceptibility genes in Case Study 2. These results validated the proper OGSF structure identified different ontology aspects with SNA methods. Conclusions OGSF provides a verified and robust framework for representing various genetic susceptibility types and genetic susceptibility factors annotated from experimental VAE genetic association studies. The RDF/OWL formulated ontology data can be queried using SPARQL and analyzed using centrality-based network analysis methods. PMID:24963371

  14. The genetic background of inflammatory bowel disease.

    PubMed

    Yang, H; Rotter, J I

    2000-01-01

    Available evidence indicates that genetic factors are essential in providing the susceptibility to the majority of the various forms of inflammatory bowel disease occurring in man. It is also clear that the genetic susceptibility to these diseases is complex, and that more than one gene may predispose (the concept of multilocus/oligogenic inheritance), and likely in different etiologic combinations (the concept of genetic heterogeneity). Paradigms are now available that should lead to the identification of a number of these predisposing genes. These paradigms include the candidate gene approach, systematic genome wide scans, and mouse human synteny. While genome wide scans are currently limited to multiplex family linkage studies, both candidate genes and mouse human synteny can be approached in either linkage or association paradigms. Eventually whole genome association studies will be available as well. Identification of inflammatory bowel disease predisposing genes should lead to their incorporation in studies of natural history, investigation of environmental risk factors, and especially utilization of genetic markers in clinical trials. This will allow us to identify the best therapy available for the individual patient based on their unique genetic constitution. With advances in molecular technology, the search for genes influencing traits and diseases with a complex genetic background, such as the inflammatory bowel diseases, has become a realistic task. Although exogenous or infectious agents may contribute to the pathogenesis or may trigger the onset of disease, and the immune system almost certainly mediates the tissue damage, it is clear from available data that genetic factors determine the susceptibility of a given individual to inflammatory bowel disease (reviewed below). Thus, genetic studies are essential for the delineation of the basic etiologies of the various forms of inflammatory bowel disease and thus can aid in the development of radically new and specific therapies. In this review, we will discuss the importance and complexity of genetic factors in inflammatory bowel disease, methods and problems in the genetic dissection of complex traits, and future directions of genetic studies in inflammatory bowel disease. PMID:10690581

  15. Genetic Variants Associated with Colorectal Adenoma Susceptibility

    PubMed Central

    Abulí, Anna; Castells, Antoni; Bujanda, Luis; Lozano, Juan José; Bessa, Xavier; Hernández, Cristina; Álvarez-Urturi, Cristina; Pellisé, Maria; Esteban-Jurado, Clara; Hijona, Elizabeth; Burón, Andrea; Macià, Francesc; Grau, Jaume; Guayta, Rafael

    2016-01-01

    Background Common low-penetrance genetic variants have been consistently associated with colorectal cancer risk. Aim To determine if these genetic variants are associated also with adenoma susceptibility and may improve selection of patients with increased risk for advanced adenomas and/or multiplicity (≥ 3 adenomas). Methods We selected 1,326 patients with increased risk for advanced adenomas and/or multiplicity and 1,252 controls with normal colonoscopy from population-based colorectal cancer screening programs. We conducted a case-control association study analyzing 30 colorectal cancer susceptibility variants in order to investigate the contribution of these variants to the development of subsequent advanced neoplasia and/or multiplicity. Results We found that 14 of the analyzed genetic variants showed a statistically significant association with advanced adenomas and/or multiplicity: the probability of developing these lesions increased with the number of risk alleles reaching a 2.3-fold risk increment in individuals with ≥ 17 risk alleles. Conclusions Nearly half of the genetic variants associated with colorectal cancer risk are also related to advanced adenoma and/or multiplicity predisposition. Assessing the number of risk alleles in individuals within colorectal cancer screening programs may help to identify better a subgroup with increased risk for advanced neoplasia and/or multiplicity in the general population. PMID:27078840

  16. Genetic background of supernumerary teeth.

    PubMed

    Subasioglu, Asli; Savas, Selcuk; Kucukyilmaz, Ebru; Kesim, Servet; Yagci, Ahmet; Dundar, Munis

    2015-01-01

    Supernumerary teeth (ST) are odontostomatologic anomaly characterized by as the existence excessive number of teeth in relation to the normal dental formula. This condition is commonly seen with several congenital genetic disorders such as Gardner's syndrome, cleidocranial dysostosis and cleft lip and palate. Less common syndromes that are associated with ST are; Fabry Disease, Ellis-van Creveld syndrome, Nance-Horan syndrome, Rubinstein-Taybi Syndrome and Trico-Rhino-Phalangeal syndrome. ST can be an important component of a distinctive disorder and an important clue for early diagnosis. Certainly early detecting the abnormalities gives us to make correct management of the patient and also it is important for making well-informed decisions about long-term medical care and treatment. In this review, the genetic syndromes that are related with ST were discussed. PMID:25713500

  17. Genetic background of supernumerary teeth

    PubMed Central

    Subasioglu, Asli; Savas, Selcuk; Kucukyilmaz, Ebru; Kesim, Servet; Yagci, Ahmet; Dundar, Munis

    2015-01-01

    Supernumerary teeth (ST) are odontostomatologic anomaly characterized by as the existence excessive number of teeth in relation to the normal dental formula. This condition is commonly seen with several congenital genetic disorders such as Gardner's syndrome, cleidocranial dysostosis and cleft lip and palate. Less common syndromes that are associated with ST are; Fabry Disease, Ellis-van Creveld syndrome, Nance-Horan syndrome, Rubinstein-Taybi Syndrome and Trico–Rhino–Phalangeal syndrome. ST can be an important component of a distinctive disorder and an important clue for early diagnosis. Certainly early detecting the abnormalities gives us to make correct management of the patient and also it is important for making well-informed decisions about long-term medical care and treatment. In this review, the genetic syndromes that are related with ST were discussed. PMID:25713500

  18. Awareness of Cancer Susceptibility Genetic Testing

    PubMed Central

    Mai, Phuong L.; Vadaparampil, Susan Thomas; Breen, Nancy; McNeel, Timothy S.; Wideroff, Louise; Graubard, Barry I.

    2014-01-01

    Background Genetic testing for several cancer susceptibility syndromes is clinically available; however, existing data suggest limited population awareness of such tests. Purpose To examine awareness regarding cancer genetic testing in the U.S. population aged ≥25 years in the 2000, 2005, and 2010 National Health Interview Surveys. Methods The weighted percentages of respondents aware of cancer genetic tests, and percent changes from 2000–2005 and 2005–2010, overall and by demographic, family history, and healthcare factors were calculated. Interactions were used to evaluate the patterns of change in awareness between 2005 and 2010 among subgroups within each factor. To evaluate associations with awareness in 2005 and 2010, percentages were adjusted for covariates using multiple logistic regression. The analysis was performed in 2012. Results Awareness decreased from 44.4% to 41.5% (p<0.001) between 2000 and 2005, and increased to 47.0% (p<0.001) in 2010. Awareness increased between 2005 and 2010 in most subgroups, particularly among individuals in the South (p-interaction=0.03) or with a usual place of care (p-interaction=0.01). In 2005 and 2010, awareness was positively associated with personal or family cancer history and high perceived cancer risk, and inversely associated with racial/ethnic minorities, age 25–39 or ≥60 years, male gender, lower education and income levels, public or no health insurance, and no provider contact in 12 months. Conclusions Despite improvement from 2005 to 2010, ≤50% of the U.S. adult population was aware of cancer genetic testing in 2010. Notably, disparities persist for racial/ethnic minorities and individuals with limited health care access or income. PMID:24745633

  19. Update in genetic susceptibility in melanoma

    PubMed Central

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep

    2015-01-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual. PMID:26488006

  20. Genetic susceptibility to ischemic stroke

    PubMed Central

    Meschia, James F.; Worrall, Bradford B.; Rich, Stephen S.

    2014-01-01

    Clinicians who treat patients with stroke need to be aware of several single-gene disorders that have ischemic stroke as a major feature, including sickle cell disease, Fabry disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and retinal vasculopathy with cerebral leukodystrophy. The reported genome-wide association studies of ischemic stroke and several related phenotypes (for example, ischemic white matter disease) have shown that no single common genetic variant imparts major risk. Larger studies with samples numbering in the thousands are ongoing to identify common variants with smaller effects on risk. Pharmacogenomic studies have uncovered genetic determinants of response to warfarin, statins and clopidogrel. Despite increasing knowledge of stroke genetics, incorporating this new knowledge into clinical practice remains a challenge. The goals of this article are to review common single-gene disorders relevant to ischemic stroke, summarize the status of candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors, and to briefly discuss pharmacogenomics related to stroke treatment. PMID:21629240

  1. Genetic susceptibility variants in parkinsonism.

    PubMed

    Soto-Ortolaza, Alexandra I; Ross, Owen A

    2016-01-01

    Parkinsonism is an umbrella term for a group of disorders characterized by the clinical signs of tremor, bradykinesia, rigidity, and postural instability. On neuropathologic examination parkinsonism can display alternate protein pathologies (e.g. ?-synucleinopathy or tauopathy) but the degeneration of nigral neurons is consistent. The main forms of parkinsonism are, Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Genetic studies from candidate gene, to unbiased genome-wide approaches including association and next-generation sequencing have nominated a number of disease determinants. Within this review we will highlight the genetic loci that are associated with disease and discuss the implications and importance for a better understanding of the genes involved and thus the underlying pathophysiology of these disorders. PMID:26414118

  2. Population screening for genetic susceptibility to disease.

    PubMed Central

    Clarke, A.

    1995-01-01

    Genetic screening for susceptibility to common diseases, such as the common cancers, cardiovascular disease, and diabetes, may soon be technically feasible. Commercial interests should not be allowed to introduce such screening before proper evaluation or without adequate counselling and support. The evaluation of such testing should include psychosocial and medical outcomes and outcomes for those given low risks as well as high risks. These tests may distract attention away from environmental factors contributing to disease, for which social and political measures may be more appropriate than individualised susceptibility screening and lifestyle modification. PMID:7613325

  3. Genetic Susceptibility to Non-Necrotizing Erysipelas/Cellulitis

    PubMed Central

    Hannula-Jouppi, Katariina; Massinen, Satu; Siljander, Tuula; Mäkelä, Siru; Kivinen, Katja; Leinonen, Rasko; Jiao, Hong; Aitos, Päivi; Karppelin, Matti; Vuopio, Jaana; Syrjänen, Jaana; Kere, Juha

    2013-01-01

    Background Bacterial non-necrotizing erysipelas and cellulitis are often recurring, diffusely spreading infections of the skin and subcutaneous tissues caused most commonly by streptococci. Host genetic factors influence infection susceptibility but no extensive studies on the genetic determinants of human erysipelas exist. Methods We performed genome-wide linkage with the 10,000 variant Human Mapping Array (HMA10K) array on 52 Finnish families with multiple erysipelas cases followed by microsatellite fine mapping of suggestive linkage peaks. A scan with the HMA250K array was subsequently performed with a subset of cases and controls. Results Significant linkage was found at 9q34 (nonparametric multipoint linkage score (NPLall) 3.84, p = 0.026), which is syntenic to a quantitative trait locus for susceptibility to group A streptococci infections on chromosome 2 in mouse. Sequencing of candidate genes in the 9q34 region did not conclusively associate any to erysipelas/cellulitis susceptibility. Suggestive linkage (NPLall>3.0) was found at three loci: 3q22-24, 21q22, and 22q13. A subsequent denser genome scan with the HMA250K array supported the 3q22 locus, in which several SNPs in the promoter of AGTR1 (Angiotensin II receptor type I) suggestively associated with erysipelas/cellulitis susceptibility. Conclusions Specific host genetic factors may cause erysipelas/cellulitis susceptibility in humans. PMID:23437094

  4. A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis.

    PubMed

    Yu, Haiyang; Artomov, Mykyta; Brähler, Sebastian; Stander, M Christine; Shamsan, Ghaidan; Sampson, Matthew G; White, J Michael; Kretzler, Matthias; Miner, Jeffrey H; Jain, Sanjay; Winkler, Cheryl A; Mitra, Robi D; Kopp, Jeffrey B; Daly, Mark J; Shaw, Andrey S

    2016-03-01

    Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes. PMID:26901816

  5. Genetic factors affecting susceptibility to udder pathogens.

    PubMed

    Detilleux, J C

    2009-02-16

    Many studies have identified genetic factors underlying resistance or susceptibility to mastitis in dairy cows and heifers. Some authors focused on polygenic variation while others searched for genes and/or quantitative trait loci with major effects on mastitis. Classical traits related to mastitis include somatic cell counts, electrical conductivity and clinical cases of the disease. With the development of automatic milking devices and '-omics' technologies, new traits are considered, such as acute phase proteins, immunological assays, and milk flow patterns, and new biological pathways are discovered, for example the role of mammary epithelium and the nervous system. The usefulness of these traits for the identification of resistant cows is discussed in relation to the biological mechanisms underlying the development of the disease. In addition, the utility of these traits for genetic improvement is reviewed. Finally, the problem of durability in resistance is addressed, including co-evolution and the cost of resistance. PMID:18930606

  6. Inherited genetic susceptibility to multiple myeloma.

    PubMed

    Morgan, G J; Johnson, D C; Weinhold, N; Goldschmidt, H; Landgren, O; Lynch, H T; Hemminki, K; Houlston, R S

    2014-03-01

    Although the familial clustering of multiple myeloma (MM) supports the role of inherited susceptibility, only recently has direct evidence for genetic predisposition been demonstrated. A meta-analysis of two genome-wide association (GWA) studies has identified single-nucleotide polymorphisms (SNPs) localising to a number of genomic regions that are robustly associated with MM risk. In this review, we provide an overview of the evidence supporting a genetic contribution to the predisposition to MM and MGUS (monoclonal gammopathy of unknown significance), and the insight this gives into the biological basis of disease aetiology. We also highlight the promise of future approaches to identify further specific risk factors and their potential clinical utility. PMID:24247655

  7. Role of genetic background in induced instability

    NASA Technical Reports Server (NTRS)

    Kadhim, Munira A.; Nelson, G. A. (Principal Investigator)

    2003-01-01

    Genomic instability is effectively induced by ionizing radiation. Recently, evidence has accumulated supporting a relationship between genetic background and the radiation-induced genomic instability phenotype. This is possibly due to alterations in proteins responsible for maintenance of genomic integrity or altered oxidative metabolism. Studies in human cell lines, human primary cells, and mouse models have been performed predominantly using high linear energy transfer (LET) radiation, or high doses of low LET radiation. The interplay between genetics, radiation response, and genomic instability has not been fully determined at low doses of low LET radiation. However, recent studies using low doses of low LET radiation suggest that the relationship between genetic background and radiation-induced genomic instability may be more complicated than these same relationships at high LET or high doses of low LET radiation. The complexity of this relationship at low doses of low LET radiation suggests that more of the population may be at risk than previously recognized and may have implications for radiation risk assessment.

  8. Cancer Genetic Markers of Susceptibility | Office of Cancer Genomics

    Cancer.gov

    The Cancer Genetic Markers of Susceptibility (CGEMS) project began in 2005 as a 3-year pilot study to identify inherited genetic susceptibility to prostate and breast cancer. CGEMS has developed into a successful research program of genome-wide association studies (GWAS) to identify genetic variants that affect a persons risk of developing cancer.

  9. Genetic susceptibility and gastric cancer risk.

    PubMed

    González, Carlos A; Sala, Núria; Capellá, Gabriel

    2002-07-20

    The aim of the present paper is to review and evaluate, in a comprehensive manner, the most recent published evidence on the contribution of genetic susceptibility to gastric cancer risk in humans. We have identified all studies available in MEDLINE published up to October 2001. Only studies carried out in humans and comparing gastric cancer cases with at least 1 standard control group were included in the analysis. We were able to find 31 articles based on 25 case-control studies carried out in Caucasian, Asian and African populations. Most of the studies assess the effect of genes involved in detoxifying pathways (n = 12) and inflammatory responses (n = 7). The most widely studied is the GSTM1 null polymorphism. Only a very few studies have evaluated the risk of gastric cancer associated with genes acting on mucosa protection, oxidative damage and DNA repair. The most consistent results are the increased gastric cancer risk associated with IL1B and NAT1 variants, which may account for up to 48% of attributable risk of gastric cancer. Only polymorphisms at HLA-DQ, TNF and CYP2E genes may confer some protective effect against gastric cancer. The most important limitations that preclude definitive conclusions are (i) the lack of appropriate control of potential sources of bias (only 5 population-based studies have been published so far); (ii) the low number of cases analyzed (14 studies included fewer than 99 cases); and (iii) the low number of studies (n = 3) offering concomitant analysis of genetic susceptibility and exposure to relevant cofactors (Helicobacter pylori infection, diet and smoking). We conclude that the scientific data on the role of genetic factors in gastric cancer risk are promising. The lack of association reported so far should be considered with caution due to significant limitations in study design. Cohort studies taking into account simultaneously the different genetic and environmental factors potentially involved in gastric tumorigenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contribution of their putative interactions. PMID:12115538

  10. Genetic Association Between PER3 Genetic Polymorphisms and Cancer Susceptibility

    PubMed Central

    Geng, Peiliang; Ou, Juanjuan; Li, Jianjun; Wang, Ning; Xie, Ganfeng; Sa, Rina; Liu, Chen; Xiang, Lisha; Liang, Houjie

    2015-01-01

    Abstract The genes along the circadian pathways control and modulate circadian rhythms essential for the maintenance of physiological homeostasis through self-sustained transcription-translation feedback loops. PER3 (period 3) is a circadian pathway gene and its variants (rs1012477, 4/5-repeat) have frequently been associated with human cancer. The mixed findings, however, make the role of the 2 variants in cancer susceptibility elusive. We aimed in this article to clarify the association of PER3 variants with cancer. We collected genetic data from 8 studies, providing 6149 individuals for rs1012477 and 5241 individuals for 4/5-repeat. Based on the genotype and allele frequency, we chose the fixed-effects model to estimate risk of cancer. Overall analysis did not suggest a global role of rs1012477 in cancer susceptibility. For PER3 4/5-repeat variant, we found a moderate increase in risk of cancer among individuals with the 5-allele compared to individuals with the 4-allele, although this association was not statistically significant (homozygous model: odds ratio [OR] 1.17, 95% confidence interval [CI] 0.81–1.67; recessive model: OR 1.17, 95% CI 0.82–1.67). No substantial heterogeneity was revealed in this analysis. Our meta-analysis provides no evidence supporting a global association of PER3 genetic variants with the incidence of cancer. PMID:25837749

  11. Genetic background in nonalcoholic fatty liver disease: A comprehensive review

    PubMed Central

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-01-01

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

  12. Genetic background in nonalcoholic fatty liver disease: A comprehensive review.

    PubMed

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-10-21

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

  13. Genetic polymorphisms and associated susceptibility to asthma.

    PubMed

    March, Michael E; Sleiman, Patrick Ma; Hakonarson, Hakon

    2013-01-01

    As complex common diseases, asthma and allergic diseases are caused by the interaction of multiple genetic variants with a variety of environmental factors. Candidate-gene studies have examined the involvement of a very large list of genes in asthma and allergy, demonstrating a role for more than 100 loci. These studies have elucidated several themes in the biology and pathogenesis of these diseases. A small number of genes have been associated with asthma or allergy through traditional linkage analyses. The publication of the first asthma-focused genome-wide association (GWA) study in 2007 has been followed by nearly 30 reports of GWA studies targeting asthma, allergy, or associated phenotypes and quantitative traits. GWA studies have confirmed several candidate genes and have identified new, unsuspected, and occasionally uncharacterized genes as asthma susceptibility loci. Issues of results replication persist, complicating interpretation and making conclusions difficult to draw, and much of the heritability of these diseases remains undiscovered. In the coming years studies of complex diseases like asthma and allergy will probably involve the use of high-throughput next-generation sequencing, which will bring a tremendous influx of new information as well as new problems in dealing with vast datasets. PMID:23637549

  14. Genetic susceptibility in ecosystems: the challenge for ecotoxicology.

    PubMed Central

    Evenden, A J; Depledge, M H

    1997-01-01

    Environmental management is inevitably complicated by the large variation in susceptibility to chemical toxicity exhibited by the living components of ecosystems, a significant proportion of which is determined by genetic factors. This paper examines the concept of genetic susceptibility in ecosystems and suggests the existence of two distinct forms reflecting genetic changes at the level of the individual and at the level of population and community. The influence of genetic susceptibility on exposure-response curves is discussed and the consequent accuracy of data used for toxicity test-based risk assessments examined. The paper concludes by describing a possible biomarker-based approach to future studies of susceptibility in ecosystems, suggesting the use of modern molecular genetic methods. PMID:9255571

  15. Phenotypic variability and genetic susceptibility to genomic disorders

    PubMed Central

    Girirajan, Santhosh; Eichler, Evan E.

    2010-01-01

    The duplication architecture of the human genome predisposes our species to recurrent copy number variation and disease. Emerging data suggest that this mechanism of mutation contributes to both common and rare diseases. Two features regarding this form of mutation have emerged. First, common structural polymorphisms create susceptible and protective chromosomal architectures. These structural polymorphisms occur at varying frequencies in populations, leading to different susceptibility and ethnic predilection. Second, a subset of rearrangements shows extreme variability in expressivity. We propose that two types of genomic disorders may be distinguished: syndromic forms where the phenotypic features are largely invariant and those where the same molecular lesion associates with a diverse set of diagnoses including epilepsy, schizophrenia, autism, intellectual disability and congenital malformations. Copy number variation analyses of patient genomes reveal that disease type and severity may be explained by the occurrence of additional rare events and their inheritance within families. We propose that the overall burden of copy number variants creates differing sensitized backgrounds during development leading to different thresholds and disease outcomes. We suggest that the accumulation of multiple high-penetrant alleles of low frequency may serve as a more general model for complex genetic diseases, posing a significant challenge for diagnostics and disease management. PMID:20807775

  16. Genetic Ancestry Influences Asthma Susceptibility and Lung Function Among Latinos

    PubMed Central

    Pino-Yanes, Maria; Thakur, Neeta; Gignoux, Christopher R.; Galanter, Joshua M.; Roth, Lindsey A.; Eng, Celeste; Nishimura, Katherine K.; Oh, Sam S.; Vora, Hita; Huntsman, Scott; Nguyen, Elizabeth A.; Hu, Donglei; Drake, Katherine A.; Conti, David V.; Moreno-Estrada, Andres; Sandoval, Karla; Winkler, Cheryl A.; Borrell, Luisa N.; Lurmann, Fred; Islam, Talat S.; Davis, Adam; Farber, Harold J.; Meade, Kelley; Avila, Pedro C.; Serebrisky, Denise; Bibbins-Domingo, Kirsten; Lenoir, Michael A.; Ford, Jean G.; Brigino-Buenaventura, Emerita; Rodriguez-Cintron, William; Thyne, Shannon M.; Sen, Saunak; Rodriguez-Santana, Jose R.; Bustamante, Carlos D.; Williams, L. Keoki; Gilliland, Frank D.; Gauderman, W. James; Kumar, Rajesh; Torgerson, Dara G.; Burchard, Esteban G.

    2014-01-01

    Background Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. Objective To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. Methods We analyzed 5,493 Latinos with and without asthma from three independent studies. For each participant we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. Results Native American ancestry was associated with lower odds of asthma (OR=0.72, 95% confidence interval [CI]: 0.66–0.78, p=8.0×10−15), while African ancestry was associated with higher odds of asthma (OR=1.40, 95%CI: 1.14–1.72, p=0.001). These associations were robust to adjustment for covariates related to early life exposures, air pollution and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of forced expiratory volume in the first second (−77±19 ml, p=5.8×10−5 and −83±19 ml, p=1.1×10−5, respectively) and forced vital capacity (−100±21 ml, p=2.7×10−6 and −107±22 ml, p=1.0×10−6, respectively). Conclusion Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos. PMID:25301036

  17. [Genetic background of human prion diseases].

    PubMed

    Kovács, Gábor Géza

    2007-11-30

    Human prion diseases may be sporadic, genetic, or acquired. The human prion protein gene (PRNP) is located to chromosome 20 (20p12-ter). Mutations and polymorphisms in the PRNP are associated with prion disease. Genetic prion diseases are inherited in an autosomal dominant trait, examination of the penetrance is restricted to mutation E200K (59-89%). Mutations can be substitutions or insertions. Genetic prion diseases are classified according to the clinicopathological phenotype and comprise genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia. Base pair insertions may resemble Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker disease phenotypes, however, their unique clinicopathological presentations are also emphasized. Among the polymorphisms of the PRNP, the one at codon 129 is the most important, where methionine or valine may be encoded. This polymorphism is known to influence the phenotype of disease forms. Molecular classification of sporadic Creutzfeldt-Jakob disease also depends on the codon 129 polymorphisms in addition to the Western blot pattern of the protease resistant prion protein. According to this at least six well characterised forms of sporadic Creutzfeldt-Jakob disease are known. Influence of other genes were also investigated. Contrasting results are reported regarding the role of apolipoprotein E allele epsilon4, but presence of allele epsilon2 seems to influence the prognosis. Polymorphisms in the doppel gene or ADAM10 could not be clearly associated with Creutzfeldt-Jakob disease. Polymorphisms in the upstream and intronic regulatory region of the PRNP gene may be a risk factor for Creutzfeldt-Jakob disease. The PRNP codon 129 polymorphism was examined in non-prion diseases. Some studies suggest that this polymorphism may have influence on the cognitive decline and early onset Alzheimer's disease. PMID:18198790

  18. Population genetic testing for cancer susceptibility: founder mutations to genomes.

    PubMed

    Foulkes, William D; Knoppers, Bartha Maria; Turnbull, Clare

    2016-01-01

    The current standard model for identifying carriers of high-risk mutations in cancer-susceptibility genes (CSGs) generally involves a process that is not amenable to population-based testing: access to genetic tests is typically regulated by health-care providers on the basis of a labour-intensive assessment of an individual's personal and family history of cancer, with face-to-face genetic counselling performed before mutation testing. Several studies have shown that application of these selection criteria results in a substantial proportion of mutation carriers being missed. Population-based genetic testing has been proposed as an alternative approach to determining cancer susceptibility, and aims for a more-comprehensive detection of mutation carriers. Herein, we review the existing data on population-based genetic testing, and consider some of the barriers, pitfalls, and challenges related to the possible expansion of this approach. We consider mechanisms by which population-based genetic testing for cancer susceptibility could be delivered, and suggest how such genetic testing might be integrated into existing and emerging health-care structures. The existing models of genetic testing (including issues relating to informed consent) will very likely require considerable alteration if the potential benefits of population-based genetic testing are to be fully realized. PMID:26483301

  19. Genetic Susceptibility to Fungal Infections in Humans

    PubMed Central

    Lionakis, Michail S.

    2012-01-01

    Most fungal infections in humans occur in the setting of iatrogenic immunosuppression or HIV infection. In the absence of these factors, fungi cause mild, self-limited infections that typically involve mucocutaneous surfaces. Hence, when persistent or recurrent mucocutaneous infections (chronic mucocutaneous candidiasis [CMC]) or invasive fungal infections (IFIs) develop in a “normal” host, they are indicative of genetic defects causing innate or adaptive immune dysfunction. In this review, recent developments concerning genetic and immunologic factors that affect the risk for IFIs and CMC are critically discussed. PMID:23087779

  20. Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma

    SciTech Connect

    Lacko, Martin; Braakhuis, Boudewijn J.M.; Sturgis, Erich M.; Boedeker, Carsten C.; Suárez, Carlos; Rinaldo, Alessandra; Ferlito, Alfio; Takes, Robert P.

    2014-05-01

    Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives of research on genetic susceptibility in HNSCC are discussed.

  1. Genetic control of susceptibility to osteoporosis.

    PubMed

    Ralston, Stuart H

    2002-06-01

    Osteoporosis is a common disease with a strong genetic component. Twin studies have shown that genetic factors play an important role in regulating bone mineral density (BMD), ultrasound properties of bone, skeletal geometry, and bone turnover as well as contributing to the pathogenesis of osteoporotic fracture itself. These phenotypes are determined by the combined effects of several genes and environmental influences, but occasionally, osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, caused by inactivating mutations in the lipoprotein receptor-related protein 5 gene and the high bone mass syndrome, caused by activating mutations of the same gene. Genome-wide linkage studies in man have identified loci on chromosomes 1p36, 1q21, 2p21, 5q33-35, 6p11-12, and 11q12-13 that show definite or probable linkage to BMD, but so far, the causative genes remain to be identified. Linkage studies in mice have similarly identified several loci that regulate BMD, and a future challenge will be to investigate the syntenic loci in humans. A great deal of research has been done on candidate genes; among the best studied are the vitamin D receptor and the collagen type I alpha 1 gene. Polymorphisms of vitamin D receptor have been associated with bone mass in several studies, and there is evidence to suggest that this association may be modified by dietary calcium and vitamin D intake. A functional polymorphism affecting an Sp1 binding site has been identified in the collagen type I alpha 1 gene that predicts osteoporotic fractures independently of bone mass by influencing collagen gene regulation and bone quality. An important problem with most candidate gene studies is small sample size, and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis to try and address this issue and gain an accurate estimate of effect size for different polymorphisms in relation to relevant clinical endpoints, such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important, because they offer the prospect of developing genetic markers for the assessment of fracture risk and the opportunity to identify molecules that will be used as targets for the design of new drugs for the prevention and treatment of bone disease. PMID:12050200

  2. Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise

    PubMed Central

    Kapplinger, Jamie D.; Landstrom, Andrew P.; Bos, J. Martijn; Salisbury, Benjamin A.; Callis, Thomas E.; Ackerman, Michael J.

    2014-01-01

    Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the Hypertrophic Cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the “Gold Standard” Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly over-represented in disease, a background rate as high as ~5% among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test. PMID:24510615

  3. Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes and mapping of Rapop1, a novel susceptibility gene

    SciTech Connect

    Mori, Nobuko; Okumoto, Masaaki; Esaki, Kozaburo

    1995-02-10

    Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes was performed by counting dead cells in histologically processed thymuses after 0.5 Gy of whole-body X-irradiation, using recombinant congenic (CcS/Dem) strains derived from inbred mouse strains BALB/cHeA (susceptible) and STS/A (resistant). A high (8/20) number of strains with lower dead cell scores than BALB/cHeA among CcS/Dem recombinant congenic strains (RCS), which contain 12.5% of STS/A genome in the genetic background of BALB/cHeA strain, indicates that the difference between BALB/cHeA and STS/A is caused by several genes and that susceptibility probably requires BALB/ cHeA alleles at more than one locus. Similar results were obtained with CXS/Hg recombinant inbred (CXS/ Hg) strains. Analysis of F{sub 2} hybrids between BALB/ cHeA and CcS-7, one of the CcS/Dem strains that showed lower dead cell scores than BALB/cHeA, demonstrated that a novel gene (Rapop1, radiation-induced apoptosis 1) controlling susceptibility to radiation-induced apoptosis in the thymus is located in the proximal region of mouse chromosome 16. 40 refs., 2 figs., 2 tabs.

  4. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    PubMed Central

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  5. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci.

    PubMed

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  6. GENETIC SUSCEPTIBILITY AND EXPERIMENTAL INDUCTION OF PULMONARY DISEASE

    EPA Science Inventory

    Genetic Susceptibility and Experimental Induction of Pulmonary Disease. UP Kodavanti, MC Schladweiler, AD Ledbetter, PS Gilmour, P Evansky, KR Smith*, WP Watkinson, DL Costa, KE Pinkerton*. ETD, NHEERL, ORD, US EPA, RTP, NC; *Univ California, Davis, CA, USA.
    Conventional la...

  7. Genetic susceptibility to the endemic form of NPC.

    PubMed

    Bei, Jin-Xin; Zuo, Xiao-Yu; Liu, Wen-Sheng; Guo, Yun-Miao; Zeng, Yi-Xin

    2016-04-01

    Nasopharyngeal carcinoma (NPC) is a malignancy with remarkably high prevalence in East Asia. Lines of evidence have suggested the involvement of genetic lesions in the etiology of NPC, together with the contributions of Epstein-Barr virus infection and environmental exposures. Linkage and association studies, either based on candidate genes or genome-wide levels, have been conducted to dissect the genetic variants that contribute to NPC risk. This review summarizes the current findings of genetic susceptibility to NPC, and points out some future challenges on discovery of other risk variants to explain the missing heritability of NPC. PMID:27121875

  8. Genetic susceptibility testing for neurodegenerative diseases: Ethical and practice issues

    PubMed Central

    Roberts, J. Scott; Uhlmann, Wendy R.

    2013-01-01

    As the genetics of neurodegenerative disease become better understood, opportunities for genetic susceptibility testing for at-risk individuals will increase. Such testing raises important ethical and practice issues related to test access, informed consent, risk estimation and communication, return of results, and policies to prevent genetic discrimination. The advent of direct-to-consumer genetic susceptibility testing for various neurodegenerative disorders (including Alzheimer’s disease, Parkinson’s disease, and certain prion diseases) means that ethical and practical challenges must be faced not only in traditional research and clinical settings, but also in broader society. This review addresses several topics relevant to the development and implementation of genetic susceptibility tests across research, clinical, and consumer settings; these include appropriate indications for testing, the implications of different methods for disclosing test results, clinical versus personal utility of risk information, psychological and behavioral responses to test results, testing of minors, genetic discrimination, and ethical dilemmas posed by whole-genome sequencing. We also identify future areas of likely growth in the field, including pharmacogenomics and genetic screening for individuals considering or engaged in activities that pose elevated risk of brain injury (e.g., football players, military personnel). APOE gene testing for risk of Alzheimer’s disease is used throughout as an instructive case example, drawing upon the authors’ experience as investigators in a series of multisite randomized clinical trials that have examined the impact of disclosing APOE genotype status to interested individuals (e.g., first-degree relatives, persons with mild cognitive impairment). PMID:23583530

  9. Human genetic susceptibility and infection with Leishmania peruviana.

    PubMed Central

    Shaw, M A; Davies, C R; Llanos-Cuentas, E A; Collins, A

    1995-01-01

    Racial differences, familial clustering, and murine studies are suggestive of host genetic control of Leishmania infections. Complex segregation analysis has been carried out by use of the programs POINTER and COMDS and data from a total population survey, comprising 636 nuclear families, from an L. peruviana endemic area. The data support genetic components controlling susceptibility to clinical leishmaniasis, influencing severity of disease and resistance to disease among healthy individuals. A multifactorial model is favored over a sporadic model. Two-locus models provided the best fit to the data, the optimal model being a recessive gene (frequency .57) plus a modifier locus. Individuals infected at an early age and with recurrent lesions are genetically more susceptible than those infected with a single episode of disease at a later age. Among people with no lesions, those with a positive skin-test response are genetically less susceptible than those with a negative response. The possibility of the involvement of more than one gene together with environmental effects has implications for the design of future linkage studies. PMID:7485168

  10. Human genetic susceptibility and infection with Leishmania peruviana

    SciTech Connect

    Shaw, M.A.; Davis, C.R.; Collins, A.

    1995-11-01

    Racial differences, familial clustering, and murine studies are suggestive of host genetic control of Leishmania infections. Complex segregation analysis has been carried out by use of the programs POINTER and COMDS and data from a total population survey, comprising 636 nuclear families, from an L. perurviana endemic area. The data support genetic components controlling susceptibility to clinical leishmaniasis, influencing severity of disease and resistance to disease among healthy individuals. A multifactorial model is favored over a sporadic model. Two-locus models provided the best fit to the data, the optimal model being a recessive gene (frequency .57) plus a modifier locus. Individuals infected at an early age and with recurrent lesions are genetically more susceptible than those infected with a single episode of disease at a later age. Among people with no lesions, those with a positive skin-test response are genetically less susceptible than those with a negative response. The possibility of the involvement of more than one gene together with environmental effects has implications for the design of future linkage studies. 31 refs., 7 tabs.

  11. Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis.

    PubMed Central

    Mock, B A; Krall, M M; Dosik, J K

    1993-01-01

    Plasmacytomas (PCTs) were induced in 47% of BALB/cAnPt mice by the intraperitoneal injection of pristane, in 2% of (BALB/c x DBA/2N)F1, and in 11% of 773 BALB/cAnPt x (BALB/cAnPt x DBA/2N)F1 N2 backcross mice. This result indicates a multigenic mode of inheritance for PCT susceptibility. To locate genes controlling this complex genetic trait, tumor susceptibility in backcross progeny generated from BALB/c and DBA/2N (resistant) mice was correlated with alleles of 83 marker loci. The genotypes of the PCT-susceptible progeny displayed an excess homozygosity for BALB/c alleles within a 32-centimorgan stretch of mouse chromosome 4 (> 95% probability of linkage) with minimal recombination (12%) near Gt10. Another susceptibility gene on mouse chromosome 1 may be linked to Fcgr2 (90% probability of linkage); there were excess heterozygotes for Fcgr2 among the susceptible progeny and excess homozygotes among the resistant progeny. Regions of mouse chromosomes 4 and 1 that are correlated with PCT susceptibility share extensive linkage homology with regions of human chromosome 1 that have been associated with cytogenetic abnormalities in multiple myeloma and lymphoid, breast, and endocrine tumors. PMID:8105477

  12. Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis

    SciTech Connect

    Mock, B.A.; Krall, M.M.; Dosik, J.K. )

    1993-10-15

    Plasmacytomas (PCTs) were induced in 47% of BALB/cAnPt mice by the intraperitoneal injection of pristane, in 2% of (BALB/c [times] DBA/2N)F[sub 1], and in 11% of 773 BALB/cAnPt [times] (BALB/cAnPt [times] DBA/2N)F[sub 1]N[sub 2] backcross mice. This result indicates a multigenic mode of inheritance for PCT susceptibility. To locate genes controlling this complex genetic trait, tumor susceptibility in backcross progeny generated from BALB/c and DBA/2N (resistant) mice was correlated with alleles of 83 marker loci. The genotypes of the PCT-susceptible progeny displayed an excess homozygosity for BALB/c alleles with a 32-centimorgan stretch of mouse chromosome 4 (>95% probability of linkage) with minimal recombination (12%) near Gt10. Another susceptibility gene on mouse chromosome 1 may be linked to Fcgr2 (90% probability of linkage); there were excess heterozygotes for Fcgr2 among the susceptible progeny and excess homozygotes among the resistant progeny. Regions of mouse chromosomes 4 and 1 that are correlated with PCT susceptibility share extensive linkage homology with regions of human chromosome 1 that have been associated with cytogenetic abnormalities in multiple myeloma and lymphoid, breast, and endocrine tumors. 68 refs., 2 figs., 1 tab.

  13. Antibody-mediated glomerulonephritis in mice: the role of endotoxin, complement and genetic background

    PubMed Central

    ROBSON, M G; COOK, H T; PUSEY, C D; WALPORT, M J; DAVIES, K A

    2003-01-01

    Antibody-mediated glomerulonephritis in man may be exacerbated by infection and this effect may be mediated by bacterial endotoxin. There is evidence supporting a role for endotoxin in heterologous nephrotoxic nephritis in rats, but the role of endotoxin in this model in mice has not previously been explored. Previous data in mice on the role of complement in this model are conflicting and this may be due to the mixed genetic background of mice used in these studies. We used the model of heterologous nephrotoxic nephritis in mice and explored the role of endotoxin, complement and genetic background. In this study we show a synergy between antibody and endotoxin in causing a neutrophil influx. We also show that C1q-deficient mice have an increased susceptibility to glomerular inflammation but this is seen only on a mixed 129/Sv × C57BL/6 genetic background. On a C57BL/6 background we did not find any differences in disease susceptibility when wildtype, C1q, factor B or factor B/C2 deficient mice were compared. We also demonstrate that C57BL/6 mice are more susceptible to glomerular inflammation than 129/Sv mice. These results show that endotoxin is required in this model in mice, and that complement does not play a major role in glomerular inflammation in C57BL/6 mice. C1q may play a protective role in mixed-strain 129/Sv × C57BL/6 mice, but the data may also be explained by systematic bias in background genes, as there is a large difference in disease susceptibility between C57BL/6 and 129/Sv mice. PMID:12930357

  14. Genetic Susceptibility to Interstitial Lung Disease Associated with Systemic Sclerosis

    PubMed Central

    Tochimoto, Akiko; Kawaguchi, Yasushi; Yamanaka, Hisashi

    2015-01-01

    Systemic sclerosis (SSc) is a connective tissue disease that is characterized by tissue fibrosis, microvasculopathy, and autoimmunity. Interstitial lung disease (ILD) is a common complication of SSc and is one of the frequent causes of mortality in SSc. Although the exact etiology of SSc remains unknown, clinical and experimental investigations have suggested that genetic and environmental factors are relevant to the pathogenesis of SSc and SSc-ILD. More than 30 genes have been identified as susceptibility loci for SSc, most of which are involved in immune regulation and inflammation. It is thought that the key pathogenesis of SSc-ILD is caused by the release of profibrotic mediators such as transforming growth factor β1 and connective tissue growth factor from lung cells induced by a persistent damage. This review presents the genetic susceptibility to SSc-ILD, including human leukocyte antigen and non-human leukocyte antigen genes, especially focusing on connective tissue growth factor. PMID:26997879

  15. Host Genetic Background Strongly Influences the Response to Influenza A Virus Infections

    PubMed Central

    Srivastava, Barkha; Błażejewska, Paulina; Heßmann, Manuela; Bruder, Dunja; Geffers, Robert; Mauel, Susanne; Gruber, Achim D.; Schughart, Klaus

    2009-01-01

    The genetic make-up of the host has a major influence on its response to combat pathogens. For influenza A virus, several single gene mutations have been described which contribute to survival, the immune response and clearance of the pathogen by the host organism. Here, we have studied the influence of the genetic background to influenza A H1N1 (PR8) and H7N7 (SC35M) viruses. The seven inbred laboratory strains of mice analyzed exhibited different weight loss kinetics and survival rates after infection with PR8. Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains. The LD50 to the influenza virus PR8 in DBA/2J mice was more than 1000-fold lower than in C57BL/6J mice. High susceptibility in DBA/2J mice was also observed after infection with influenza strain SC35M. In addition, infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, and a more severe and extended lung pathology compared to infected C57BL/6J mice. These findings indicate a major contribution of the genetic background of the host to influenza A virus infections. The overall response in highly susceptible DBA/2J mice resembled the pathology described for infections with the highly virulent influenza H1N1-1918 and newly emerged H5N1 viruses. PMID:19293935

  16. Genetic susceptibility to the respiratory effects of air pollution.

    PubMed

    Yang, I A; Fong, K M; Zimmerman, P V; Holgate, S T; Holloway, J W

    2009-08-01

    There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels). PMID:19633009

  17. Genetic susceptibility to the respiratory effects of air pollution.

    PubMed

    Yang, I A; Fong, K M; Zimmerman, P V; Holgate, S T; Holloway, J W

    2008-06-01

    There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels). PMID:18511640

  18. Genetic variation and shared biological susceptibility underlying comorbidity in neuropsychiatry.

    PubMed

    Palomo, Tomas; Kostrzewa, Richard M; Beninger, Richard J; Archer, Trevor

    2007-07-01

    Genetic factors underlying alcoholism, substance abuse, antisocial and violent behaviour, psychosis, schizophrenia and psychopathy are emerging to implicate dopaminergic and cannabinoid, but also monoaminergic and glutamatergic systems through the maze of promoter genes and polymorphisms. Candidate gene association studies suggest the involvement of a range of genes in different disorders of CNS structure and function. Indices of comorbidity both complicate the array of gene-involvement and provide a substrate of hazardous interactivity. The putative role of the serotonin transporter gene in affective-dissociative spectrum disorders presents both plausible genetic variation and complication of comorbidity The position of genetic variation is further complicated through ethnic, contextual and social factors that provide geometric progressions in the comordity already underlying diagnostic obstacles. The concept of shared biological susceptibility to two or more disorder conditions of comorbidity seems a recurring observation, e.g., bipolar disorder with alcoholism or schizophrenia with alcohol/substance abuse or diabetes with schizopsychotic disorder. Several lines of evidence seem to suggest that the factors influencing variation in one set of symptoms and those affecting one or more disorders are observed to a marked extent which ought to facilitate the search for susceptibility genes in comorbid brain disorders. Identification of regional genetic factors is awaited for a more compelling outline that ought eventually to lead to greater efficacy of symptom-disorder arrangements and an augmentation of current pharmacological treatment therapies. PMID:17513198

  19. Innate immunity and genetic determinants of urinary tract infection susceptibility

    PubMed Central

    Godaly, Gabriela; Ambite, Ines; Svanborg, Catharina

    2015-01-01

    Purpose of review Urinary tract infections (UTIs) are common, dangerous and interesting. Susceptible individuals experience multiple, often clustered episodes, and in a subset of patients, infections progress to acute pyelonephritis (APN), sometimes accompanied by uro-sepsis. Others develop asymptomatic bacteriuria (ABU). Here, we review the molecular basis for these differences, with the intention to distinguish exaggerated host responses that drive disease from attenuated responses that favour protection and to highlight the genetic basis for these extremes, based on knock-out mice and clinical studies. Recent findings The susceptibility to UTI is controlled by specific innate immune signalling and by promoter polymorphisms and transcription factors that modulate the expression of genes controlling these pathways. Gene deletions that disturb innate immune activation either favour asymptomatic bacteriuria or create acute morbidity and disease. Promoter polymorphisms and transcription factor variants affecting those genes are associated with susceptibility in UTI-prone patients. Summary It is time to start using genetics in UTI-prone patients, to improve diagnosis and to assess the risk for chronic sequels such as renal malfunction, hypertension, spontaneous abortions, dialysis and transplantation. Furthermore, the majority of UTI patients do not need follow-up, but for lack of molecular markers, they are unnecessarily investigated. PMID:25539411

  20. Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer’s disease

    PubMed Central

    Cassidy, Michael R.; Roberts, J. Scott; Bird, Thomas D.; Steinbart, Ellen J.; Cupples, L. Adrienne; Chen, Clara A.; Linnenbringer, Erin; Green, Robert C.

    2008-01-01

    Background Genetic risk for Alzheimer’s disease (AD) may be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the ε4 allele increases the risk of developing late-onset Alzheimer’s disease but is not a definitive predictor of the disease, or by autosomal dominant mutations (e.g., the presenilins), which almost inevitably result in early-onset familial Alzheimer’s disease. The purpose of this study was to compare the psychological impact of using these two different types of genetic information to disclose genetic risk for AD to family members of affected patients. Methods Data were compared from two separate protocols. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study is a randomized, multi-site clinical trial that evaluated the impact of susceptibility testing for Alzheimer’s disease with APOE in 101 adult children of Alzheimer’s disease patients. A separate study, conducted at the University of Washington, assessed the impact of deterministic genetic testing by disclosing presenilin-1, presenilin-2, or TAU genotype to 22 individuals at risk for familial Alzheimer’s disease or frontotemporal dementia. In both protocols, participants received genetic counseling and completed the Impact of Event Scale (IES), a measure of test-specific distress. Scores were analyzed at the time point closest to one year post-disclosure at which IES data were available. The role of genetic test result (positive vs. negative) and type of genetic testing (deterministic vs. susceptibility) in predicting log-transformed IES scores was assessed with linear regression, controlling for age, gender, and time from disclosure. Results Subjects from the REVEAL Study who learned that they were positive for the susceptibility gene APOE ε4+ experienced similar, low levels of test-specific distress compared to those who received positive results of deterministic testing in the University of Washington study (p= 0.78). APOE ε4+ individuals in the susceptibility protocol experienced more test-specific distress than those who tested ε4− in the same study (p= 0.04); however, among those receiving deterministic test disclosure, the subjects who received positive results did not experience significantly higher levels of distress when compared to those who received negative results (p= 0.88). Conclusions The findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and that the majority of participants receiving genotype disclosure do not experience clinically significant distress as indicated by IES scores one year after learning of their test results. PMID:19012865

  1. Anthrax Susceptibility: Human Genetic Polymorphisms Modulating ANTXR2 Expression

    PubMed Central

    Zhang, Zhang; Zhang, Yan; Shi, Minglei; Ye, Bingyu; Shen, Wenlong; Li, Ping; Xing, Lingyue; Zhang, Xiaopeng; Hou, Lihua; Xu, Junjie; Zhao, Zhihu; Chen, Wei

    2015-01-01

    Anthrax toxin causes anthrax pathogenesis and expression levels of ANTXR2 (anthrax toxin receptor 2) are strongly correlated with anthrax toxin susceptibility. Previous studies found that ANTXR2 transcript abundance varies considerably in individuals of different ethnic/geographical groups, but no eQTLs (expression quantitative trait loci) have been identified. By using 3C (chromatin conformation capture), CRISPR-mediated genomic deletion and dual-luciferase reporter assay, gene loci containing cis-regulatory elements of ANTXR2 were localized. Two SNPs (single nucleotide polymorphism) at the conserved CREB-binding motif, rs13140055 and rs80314910 in the promoter region of the gene, modulating ANTXR2 promoter activity were identified. Combining these two regulatory SNPs with a previously reported SNP, rs12647691, for the first time, a statistically significant correlation between human genetic variations and anthrax toxin sensitivity was observed. These findings further our understanding of human variability in ANTXR2 expression and anthrax toxin susceptibility. PMID:26703731

  2. Anthrax Susceptibility: Human Genetic Polymorphisms Modulating ANTXR2 Expression.

    PubMed

    Zhang, Zhang; Zhang, Yan; Shi, Minglei; Ye, Bingyu; Shen, Wenlong; Li, Ping; Xing, Lingyue; Zhang, Xiaopeng; Hou, Lihua; Xu, Junjie; Zhao, Zhihu; Chen, Wei

    2016-01-01

    Anthrax toxin causes anthrax pathogenesis and expression levels of ANTXR2 (anthrax toxin receptor 2) are strongly correlated with anthrax toxin susceptibility. Previous studies found that ANTXR2 transcript abundance varies considerably in individuals of different ethnic/geographical groups, but no eQTLs (expression quantitative trait loci) have been identified. By using 3C (chromatin conformation capture), CRISPR-mediated genomic deletion and dual-luciferase reporter assay, gene loci containing cis-regulatory elements of ANTXR2 were localized. Two SNPs (single nucleotide polymorphism) at the conserved CREB-binding motif, rs13140055 and rs80314910 in the promoter region of the gene, modulating ANTXR2 promoter activity were identified. Combining these two regulatory SNPs with a previously reported SNP, rs12647691, for the first time, a statistically significant correlation between human genetic variations and anthrax toxin sensitivity was observed. These findings further our understanding of human variability in ANTXR2 expression and anthrax toxin susceptibility. PMID:26703731

  3. Evidence for a Shared Genetic Susceptibility to Migraine and Epilepsy

    PubMed Central

    Winawer, Melodie R.; Connors, Robert

    2012-01-01

    Purpose Although epilepsy and migraine are known to co-occur within individuals, the contribution of a shared genetic susceptibility to this comorbidity remains unclear. We investigated the hypothesis of shared genetic effects on migraine and epilepsy in the Epilepsy Phenome/Genome Project (EPGP) cohort. Methods We studied prevalence of a history of migraine in 730 EPGP participants aged ≥12 years with non-acquired focal epilepsy (NAFE) or generalized epilepsy (GE) from 501 families containing ≥2 individuals with epilepsy of unknown cause. Information on migraine without aura (MO) and migraine with aura (MA) was collected using an instrument validated for individuals ≥12 years. Since many individuals have both MO and MA, we considered two non-overlapping groups of individuals with migraine: those who met criteria for MA in any of their headaches (MA), and those who did not (“MO-only”). EPGP participants were interviewed about the history of seizure disorders in additional non-enrolled family members. We evaluated associations of migraine prevalence in enrolled subjects with family history of seizure disorders in additional non-enrolled relatives, using generalized estimating equations to control for the non-independence of observations within families. Key Findings Prevalence of a history of MA (but not MO-only) was significantly increased in enrolled participants with ≥2 additional affected first degree relatives. Significance These findings support the hypothesis of a shared genetic susceptibility to epilepsy and MA. PMID:23294289

  4. Vitiligo: pathomechanisms and genetic polymorphism of susceptible genes.

    PubMed

    Shajil, E M; Chatterjee, Sreejata; Agrawal, Deepali; Bagchi, T; Begum, Rasheedunnisa

    2006-07-01

    Vitiligo is a depigmenting disorder resulting from the loss of melanocytes in the skin and affects 1-4% of the world population. Incidence of vitiligo is found to be 0.5-2.5% in India with a high prevalence of 8.8% in Gujarat and Rajasthan states. The cellular and molecular mechanisms that lead to melanocyte destruction in this disorder are not yet been fully elucidated. Genetic factors, neural factors, toxic ROS metabolites, autoantibodies and autoreactive T lymphocytes may be the causative agents for the selective destruction of melanocytes. Three major hypotheses of pathogenesis of vitiligo are neural, autoimmune and oxidative stress hypotheses, however none of them explains the pathogenesis of vitiligo in toto. Genetics of vitiligo is characterized by incomplete penetrance, multiple susceptibility loci and genetic heterogeneity. Recent advances in this field are linkage and association of candidate gene studies. The linkage and association studies provide a strong evidence for the presence of multiple vitiligo susceptibility genes on different chromosomes. Several candidate genes for vitiligo are identified from different populations. In this review, we have provide an overview of different hypotheses of vitiligo pathogenesis, and discuss the recent advances in this field with special reference to linkage, association and candidate gene approach. PMID:16872041

  5. Genetic susceptibility in childhood acute leukaemias: a systematic review.

    PubMed

    Brisson, Gisele D; Alves, Liliane R; Pombo-de-Oliveira, Maria S

    2015-01-01

    Acute leukaemias (AL) correspond to 25-35% of all cancer cases in children. The aetiology is still sheltered, although several factors are implicated in causality of AL subtypes. Childhood acute leukaemias are associated with genetic syndromes (5%) and ionising radiation as risk factors. Somatic genomic alterations occur during fetal life and are initiating events to childhood leukaemia. Genetic susceptibility has been explored as a risk factor, since environmental exposure of the child to xenobiotics, direct or indirectly, can contribute to the accumulation of somatic mutations. Hence, a systematic review was conducted in order to understand the association between gene polymorphisms and childhood leukaemia risk. The search was performed in the electronic databases PubMed, Lilacs, and Scielo, selecting articles published between 1995 and 2013. This review included 90 case-control publications, which were classified into four groups: xenobiotic system (n = 50), DNA repair (n = 16), regulatory genes (n = 15), and genome wide association studies (GWAS) (n = 9). We observed that the most frequently investigated genes were: NQO1, GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, CYP2D6, CYP2E1, MDR1 (ABCB1), XRCC1, ARID5B, and IKZF1. The collected evidence suggests that genetic polymorphisms in CYP2E1, GSTM1, NQO1, NAT2, MDR1, and XRCC1 are capable of modulating leukaemia risk, mainly when associated with environmental exposures, such as domestic pesticides and insecticides, smoking, trihalomethanes, alcohol consumption, and x-rays. More recently, genome wide association studies identified significant associations between genetic polymorphisms in ARID5B e IKZF1 and acute lymphoblastic leukaemia, but only a few studies have replicated these results until now. In conclusion, genetic susceptibility contributes to the risk of childhood leukaemia through the effects of gene-gene and gene-environment interactions. PMID:26045716

  6. Genetic susceptibility in childhood acute leukaemias: a systematic review

    PubMed Central

    Brisson, Gisele D; Alves, Liliane R; Pombo-de-Oliveira, Maria S

    2015-01-01

    Acute leukaemias (AL) correspond to 25–35% of all cancer cases in children. The aetiology is still sheltered, although several factors are implicated in causality of AL subtypes. Childhood acute leukaemias are associated with genetic syndromes (5%) and ionising radiation as risk factors. Somatic genomic alterations occur during fetal life and are initiating events to childhood leukaemia. Genetic susceptibility has been explored as a risk factor, since environmental exposure of the child to xenobiotics, direct or indirectly, can contribute to the accumulation of somatic mutations. Hence, a systematic review was conducted in order to understand the association between gene polymorphisms and childhood leukaemia risk. The search was performed in the electronic databases PubMed, Lilacs, and Scielo, selecting articles published between 1995 and 2013. This review included 90 case-control publications, which were classified into four groups: xenobiotic system (n = 50), DNA repair (n = 16), regulatory genes (n = 15), and genome wide association studies (GWAS) (n = 9). We observed that the most frequently investigated genes were: NQO1, GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, CYP2D6, CYP2E1, MDR1 (ABCB1), XRCC1, ARID5B, and IKZF1. The collected evidence suggests that genetic polymorphisms in CYP2E1, GSTM1, NQO1, NAT2, MDR1, and XRCC1 are capable of modulating leukaemia risk, mainly when associated with environmental exposures, such as domestic pesticides and insecticides, smoking, trihalomethanes, alcohol consumption, and x-rays. More recently, genome wide association studies identified significant associations between genetic polymorphisms in ARID5B e IKZF1 and acute lymphoblastic leukaemia, but only a few studies have replicated these results until now. In conclusion, genetic susceptibility contributes to the risk of childhood leukaemia through the effects of gene–gene and gene–environment interactions. PMID:26045716

  7. Additional mechanisms conferring genetic susceptibility to Alzheimer’s disease

    PubMed Central

    Calero, Miguel; Gómez-Ramos, Alberto; Calero, Olga; Soriano, Eduardo; Avila, Jesús; Medina, Miguel

    2015-01-01

    Familial Alzheimer’s disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1, and PSEN2) involved in the production of the amyloid β peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies there is a mounting list of genetic risk factors associated with common genetic variants that have been associated with sporadic AD. Besides apolipoprotein E, that presents a strong association with the disease (OR∼4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated with AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways, and networks rather than the contribution of specific genes. PMID:25914626

  8. Additional mechanisms conferring genetic susceptibility to Alzheimer's disease.

    PubMed

    Calero, Miguel; Gómez-Ramos, Alberto; Calero, Olga; Soriano, Eduardo; Avila, Jesús; Medina, Miguel

    2015-01-01

    Familial Alzheimer's disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1, and PSEN2) involved in the production of the amyloid β peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies there is a mounting list of genetic risk factors associated with common genetic variants that have been associated with sporadic AD. Besides apolipoprotein E, that presents a strong association with the disease (OR∼4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated with AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways, and networks rather than the contribution of specific genes. PMID:25914626

  9. Patients' understanding of genetic susceptibility testing in mainstream medicine: qualitative study on thrombophilia

    PubMed Central

    Saukko, Paula M; Ellard, Sian; Richards, Suzanne H; Shepherd, Maggie H; Campbell, John L

    2007-01-01

    Background UK and US policy initiatives have suggested that, in the future, patients and clinicians in mainstream medicine could use genetic information to prevent common illnesses. There are no studies on patients' experience and understanding of the process of testing for common genetic susceptibilities in mainstream medicine. Methods Qualitative interviews with 42 individuals who had undergone testing for a genetic susceptibility for deep vein thrombosis in primary and secondary care in the UK. Results Some participants, often from higher social classes, had a good understanding of the test and its implications. They had often sought additional information on thrombophilia from relatives and from the Internet. Others, often from less privileged backgrounds, had a poorer understanding of the test – seven individuals were unaware of having had the genetic test. Features of genetic information led to misunderstandings: (i) at referral, (ii) when communicating results, and (iii) when making sense of the implications of testing. Participants' accounts indicated that non-specialist doctors may feel obliged to refer a patient for a genetic test they know little about, because a patient requests it after a relative had tested positive. Sometimes a referral for a genetic test was lost under information overload when multiple tests and issues were considered. The inconsistent and informal ways of communicating test results – for example by phone – in mainstream medicine also led to confusion. Participants did not generally overestimate their risk, but some were uncertain about whether they were taking the right preventive actions and/or whether their children were at risk. Information about genetic susceptibilities was difficult to make sense of, as it related to ambiguous risks for participants and family members, complicated and unfamiliar terminology and multiple genes and preventive strategies. Conclusion Policy visions of clinicians and patients in mainstream medicine seeking and using genetic information at their own initiative may not be realistic. Patients need more direct support in making sense of genetic information, if this information is to bring the anticipated health benefits, and not fuel health inequalities or create ethical problems. Clinicians in secondary and primary care need guidance to help them introduce genetic tests, communicate their results and explain their implications. PMID:17565670

  10. Genetic susceptibility to teratogens: state of the art.

    PubMed

    Cassina, Matteo; Salviati, Leonardo; Di Gianantonio, Elena; Clementi, Maurizio

    2012-09-01

    There is evidence that the susceptibility to the teratogenic effect of drugs within human populations varies extremely from one individual to another, even after identical exposures. One of the factors that may explain these interindividual differences is the genetic makeup in the pharmacokinetics and pharmacodynamics of the respective drugs. In fact, both maternal and embryonic/fetal genotypes can affect placental transport, absorption, metabolism, distribution and receptor binding of an agent, influencing its teratogenicity. We have reviewed the literature and commented on the reported correlations between genetic factors and drug-induced birth defects. There is still a clear lack of knowledge regarding this issue and the available data are often conflicting. However, the identification of specific polymorphisms associated with predisposition to teratogenesis may allow in the future the development of personalized non-teratogenic therapies for pregnant women. PMID:22659091

  11. Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation.

    PubMed

    Fontenot, Andrew P; Falta, Michael T; Kappler, John W; Dai, Shaodong; McKee, Amy S

    2016-01-01

    Chronic beryllium (Be) disease is a granulomatous lung disorder that results from Be exposure in a genetically susceptible host. The disease is characterized by the accumulation of Be-responsive CD4(+) T cells in the lung, and genetic susceptibility is primarily linked to HLA-DPB1 alleles possessing a glutamic acid at position 69 of the β-chain. Recent structural analysis of a Be-specific TCR interacting with a Be-loaded HLA-DP2-peptide complex revealed that Be is coordinated by amino acid residues derived from the HLA-DP2 β-chain and peptide and showed that the TCR does not directly interact with the Be(2+) cation. Rather, the TCR recognizes a modified HLA-DP2-peptide complex with charge and conformational changes. Collectively, these findings provide a structural basis for the development of this occupational lung disease through the ability of Be to induce posttranslational modifications in preexisting HLA-DP2-peptide complexes, resulting in the creation of neoantigens. PMID:26685315

  12. Mutualism effectiveness and vertical transmission of symbiotic fungal endophytes in response to host genetic background

    PubMed Central

    Gundel, Pedro E; Martínez-Ghersa, María A; Omacini, Marina; Cuyeu, Romina; Pagano, Elba; Ríos, Raúl; Ghersa, Claudio M

    2012-01-01

    Certain species of the Pooideae subfamily develop stress tolerance and herbivory resistance through symbiosis with vertically transmitted, asexual fungi. This symbiosis is specific, and genetic factors modulate the compatibility between partners. Although gene flow is clearly a fitness trait in allogamous grasses, because it injects hybrid vigor and raw material for evolution, it could reduce compatibility and thus mutualism effectiveness. To explore the importance of host genetic background in modulating the performance of symbiosis, Lolium multiflorum plants, infected and noninfected with Neotyphodium occultans, were crossed with genetically distant plants of isolines (susceptible and resistant to diclofop-methyl herbicide) bred from two cultivars and exposed to stress. The endophyte improved seedling survival in genotypes susceptible to herbicide, while it had a negative effect on one of the genetically resistant crosses. Mutualism provided resistance to herbivory independently of the host genotype, but this effect vanished under stress. While no endophyte effect was observed on host reproductive success, it was increased by interpopulation plant crosses. Neither gene flow nor herbicide had an important impact on endophyte transmission. Host fitness improvements attributable to gene flow do not appear to result in direct conflict with mutualism while this seems to be an important mechanism for the ecological and contemporary evolution of the symbiotum. PMID:23346228

  13. Genetic Background Modulates Gene Expression Profile Induced by Skin Irradiation in Ptch1 Mice

    SciTech Connect

    Galvan, Antonella; Noci, Sara; Mancuso, Mariateresa; Pazzaglia, Simonetta; Saran, Anna; Dragani, Tommaso A.

    2008-12-01

    Purpose: Ptch1 germ-line mutations in mice predispose to radiation-induced basal cell carcinoma of the skin, with tumor incidence modulated by the genetic background. Here, we examined the possible mechanisms underlying skin response to radiation in F1 progeny of Ptch1{sup neo67/+} mice crossed with either skin tumor-susceptible (Car-S) or -resistant (Car-R) mice and X-irradiated (3 Gy) at 2 days of age or left untreated. Methods and Materials: We conducted a gene expression profile analysis in mRNA samples extracted from the skin of irradiated or control mice, using Affymetrix whole mouse genome expression array. Confirmation of the results was done using real-time reverse-transcriptase polymerase chain reaction. Results: Analysis of the gene expression profile of normal skin of F1 mice at 4 weeks of age revealed a similar basal profile in the nonirradiated mice, but alterations in levels of 71 transcripts in irradiated Ptch1{sup neo67/+} mice of the Car-R cross and modulation of only eight genes in irradiated Ptch1{sup neo67/+} mice of the Car-S cross. Conclusions: These results indicate that neonatal irradiation causes a persistent change in the gene expression profile of the skin. The tendency of mice genetically resistant to skin tumorigenesis to show a more complex pattern of transcriptional response to radiation than do genetically susceptible mice suggests a role for this response in genetic resistance to basal cell tumorigenesis.

  14. Complex genetic background in a large family with Brugada syndrome

    PubMed Central

    Saber, Siamak; Amarouch, Mohamed?Yassine; Fazelifar, Amir?Farjam; Haghjoo, Majid; Emkanjoo, Zahra; Alizadeh, Abolfath; Houshmand, Massoud; Gavrilenko, Alexander V.; Abriel, Hugues; Zaklyazminskaya, Elena V.

    2015-01-01

    Abstract The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST?segment elevation in V1V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 1530% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole?cell patch?clamp experiments using HEK293 cells expressing wild?type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant?induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A?negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant. PMID:25626866

  15. Complex genetic background in a large family with Brugada syndrome.

    PubMed

    Saber, Siamak; Amarouch, Mohamed-Yassine; Fazelifar, Amir-Farjam; Haghjoo, Majid; Emkanjoo, Zahra; Alizadeh, Abolfath; Houshmand, Massoud; Gavrilenko, Alexander V; Abriel, Hugues; Zaklyazminskaya, Elena V

    2015-01-01

    The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST-segment elevation in V1-V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 15-30% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole-cell patch-clamp experiments using HEK293 cells expressing wild-type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant-induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A-negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant. PMID:25626866

  16. Genetic, clinical and radiographic signs in knee osteoarthritis susceptibility

    PubMed Central

    2014-01-01

    Introduction Osteoarthritis (OA) is considered to be a multifactorial and polygenic disease and diagnosis is mainly clinical and radiological. Correlation between radiographic data and clinical status has been reported. However, very few studies, especially in Caucasian people, describe the association between the Kellgren and Lawrence OA grading scale (KL) and genetic alterations to better understand OA etiopathogenesis and susceptibility. In order to update the knee OA grading, in this study we assessed the associations between KL grade, clinical features such as American Knee Society Score (AKSS), age, and polymorphisms in the principal osteoarthritis susceptibility (OS) genes in Sicilian individuals. Methods In 66 Sicilian individuals affected by primary knee OA, the clinical and radiographic evaluation was performed using 2 sub-scores of AKSS (knee score (KS) and function score (FS)) and KL. The patients were also classified according to age. Online Mendelian Inheritance in Man (OMIM) and Database of Single Nucleotide Polymorphisms (dbSNP) Short Genetic Variations databases were used to select gene regions containing the following polymorphisms to analyze: FRZB rs288326 and rs7775, MATN3 rs77245812, ASPN D14 repeats, PTHR2 rs76758470, GDF5 rs143383 and DVWA rs11718863. Patient genotypes were obtained using Sanger DNA sequencing analysis. Results In our cohort of patients a statistical association between the variables analyzed was reported in all associations tested (KL versus KS, FS and age). We observed that a mild to severe OA radiographic grade is related to severe clinical conditions and loss of articular function and that the severity of symptoms increases with age. Concerning the genotyping analysis, our results revealed a significant statistical association between KL grading and GDF5 rs143383 and DVWA rs11718863 genetic alterations. The latter was also associated with a more severe radiographic grade, displaying its predictive role as OA marker progression. Statistically significant association between clinical, radiographic and genetic signs observed, suggests extending the actual grading of knee OA based mainly on X-ray features. Conclusions This work represents a multidisciplinary and translational medicine approach to study OA where clinical, radiological, and OS5 and OS6 SNPs evaluation could contribute to better define grading and progression of OA and to the development of new therapies. PMID:24716474

  17. Acute lung injury: functional genomics and genetic susceptibility.

    PubMed

    Leikauf, George D; McDowell, Susan A; Wesselkamper, Scott C; Hardie, William D; Leikauf, John E; Korfhagen, Thomas R; Prows, Daniel R

    2002-03-01

    Initiated by numerous factors, acute lung injury is marked by epithelial and endothelial cell perturbation and inflammatory cell influx that leads to surfactant disruption, pulmonary edema, and atelectasis. This syndrome has been associated with a myriad of mediators including cytokines, oxidants, and growth factors. To better understand gene-environmental interactions controlling this complex process, the sensitivity of inbred mouse strains was investigated following acute lung injury that was induced by fine nickel sulfate aerosol. Measuring survival time, protein and neutrophil concentrations in BAL fluid, lung wet-to-dry weight ratio, and histology, we found that these responses varied between inbred mouse strains and that susceptibility is heritable. To assess the progression of acute lung injury, the temporal expression of genes and expressed sequence tags was assessed by complementary DNA microarray analysis. Enhanced expression was noted in genes that were associated with oxidative stress, antiprotease function, and extracellular matrix repair. In contrast, expression levels of surfactant proteins (SPs) and Clara cell secretory protein (ie, transcripts that are constitutively expressed in the lung) decreased markedly. Genome-wide analysis was performed with offspring derived from a sensitive and resistant strain (C57BL/6xA F(1) backcrossed with susceptible A strain). Significant linkage was identified for a locus on chromosome 6 (proposed as Aliq4), a region that we had identified previously following ozone-induced acute lung injury. Two suggestive linkages were identified on chromosomes 1 and 12. Using haplotype analysis to estimate the combined effect of these regions (along with putative modifying loci on chromosomes 9 and 16), we found that five loci interact to account for the differences in survival time of the parental strains. Candidate genes contained in Aliq4 include SP-B, aquaporin 1, and transforming growth factor-alpha. Thus, the functional genomic approaches of large gene set expression (complementary DNA microarray) and genome-wide analyses continue to provide novel insights into the genetic susceptibility of lung injury. PMID:11893692

  18. Contribution of environment and genetics to pancreatic cancer susceptibility.

    PubMed

    Hocevar, Barbara A; Kamendulis, Lisa M; Pu, Xinzhu; Perkins, Susan M; Wang, Zheng-Yu; Johnston, Erica L; DeWitt, John M; Li, Lang; Loehrer, Patrick J; Klaunig, James E; Chiorean, E Gabriela

    2014-01-01

    Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05) versus both healthy unrelated and related controls (0.70 ± 0.06, p<0.001 and 0.82 ± 0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA -308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer. PMID:24651674

  19. New Genetic Susceptibility Factors for Sjögren's Syndrome Revealed

    MedlinePlus

    ... 1999 Spotlight on Research 2014 March 2014 (historical) New Genetic Susceptibility Factors for Sjögren’s Syndrome Revealed By ... the journal Nature Genetics, could help researchers develop new strategies to diagnose and treat the condition. In ...

  20. Association between Genetic Polymorphisms in DEFB1 and Susceptibility to Digestive Diseases

    PubMed Central

    Huang, Yin-Peng; Wang, Tian-Yi; Wang, Wei; Sun, Hong-Zhi

    2015-01-01

    Background Aberrant expression of defensins is implicated in the pathogenesis of digestive diseases. However, the contribution of specific defensins and the influence of their genetic polymorphisms on the progression of digestive diseases remain controversial. In the present meta-analysis, we investigated the association between DEFB1 SNPs and the susceptibility to digestive diseases. Material/Methods Case-control studies that reported the correlation between DEFB1 SNPs and the susceptibility to digestive diseases were identified through electronic databases searches, and high-quality studies that satisfied our inclusion criteria were selected for this meta-analysis. Statistical analyses were performed utilizing STATA software version 12.0. Results The present meta-analysis revealed that patients with digestive diseases exhibited higher frequencies of the DEFB1 genetic variants rs11362G>A, rs1800972C>G, and rs1799946G>A compared to healthy controls under the allele model. Subgroup analysis based on country showed that the rs1800972C>G variant under allele model and rs1799946G>A are associated with the susceptibility to digestive diseases in Hungarian and Italian populations, respectively. Subgroup analysis based on disease type showed that: (1) rs11362G>A variant was strongly associated with severe acute pancreatitis (SAP) and chronic gastritis, (2) frequency of rs1800972C>G variant was higher in SAP subgroup, and (3) frequency of rs1799946G>A variant was positively associated with the susceptibility to Crohns disease (CD) under the allele model and with SAP. Conclusions Our meta-analysis provides evidence that DEFB1 genetic polymorphisms rs11362G>A, rs1800972C>G and rs1799946G>A are important contributing factors to the development of digestive diseases. PMID:26232989

  1. Genetic susceptibility to non-polyposis colorectal cancer

    PubMed Central

    Lynch, H.; de la Chapelle, A.

    1999-01-01

    Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APC gene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for approximately 5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1, MSH2, MSH6, PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still molecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example.
Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (1) tumours that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor β type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such as K-ras, APC, and p53, and behave aggressively, of which FAP is an example.
This review focuses most heavily on the clinical features, pathology, molecular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a detailed differential diagnosis of the several hereditary CRC variants is provided. The extant genetic and phenotypic heterogeneity in CRC leads to the conclusion that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Therefore, it is important to ascertain cancer of all anatomical sites, as well as non-cancer phenotypic stigmata (such as the perioral and mucosal pigmentations in Peutz-Jeghers syndrome), when taking a family cancer history.


Keywords: colorectal cancer; hereditary non-polyposis colorectal cancer; genetic susceptibility PMID:10544223

  2. Multipactor susceptibility on a dielectric with a bias dc electric field and a background gas

    NASA Astrophysics Data System (ADS)

    Zhang, Peng; Lau, Y. Y.; Franzi, Matthew; Gilgenbach, R. M.

    2011-05-01

    We use Monte Carlo simulations and analytical calculations to derive the condition for the onset of multipactor discharge on a dielectric surface at various combinations of the bias dc electric field, rf electric field, and background pressures of noble gases, such as Argon. It is found that the presence of a tangential bias dc electric field on the dielectric surface lowers the magnitude of rf electric field threshold to initiate multipactor, therefore plausibly offering robust protection against high power microwaves. The presence of low pressure gases may lead to a lower multipactor saturation level, however. The combined effects of tangential dc electric field and external gases on multipactor susceptibility are presented.

  3. Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia.

    PubMed

    Aguilar-Salinas, Carlos A; Tusie-Luna, Teresa; Pajukanta, Päivi

    2014-07-01

    Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explain the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia. PMID:24768220

  4. Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia

    PubMed Central

    Aguilar-Salinas, Carlos A.; Tusie-Luna, Teresa; Pajukanta, Pivi

    2014-01-01

    Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explains the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia. PMID:24768220

  5. Genetic polymorphism of xenobiotic metabolising enzymes, diet and cancer susceptibility.

    PubMed

    Reszka, Edyta; Wasowicz, Wojciech; Gromadzinska, Jolanta

    2006-10-01

    There is increasing evidence identifying the crucial role of numerous dietary components in modifying the process of carcinogenesis. The varied effects exerted by nutrient and non-nutrient dietary compounds on human health and cancer risk are one of the new challenges for nutritional sciences. In the present paper, an attempt is made to review the most recent epidemiological data on interactions between dietary factors and metabolic gene variants in terms of cancer risk. The majority of case-control studies indicate the significant relationship between cancer risk and polymorphic xenobiotic metabolising enzymes in relation to dietary components. The risk of colorectal cancer is associated not only with CYP2E1 high-activity alleles, but also GSTA1 low-activity alleles, among consumers of red or processed meat. Genetic polymorphisms of NAT1 and NAT2 may be also a breast-cancer susceptibility factor among postmenopausal women with a high intake of well-done meat. On the other hand, phytochemicals, especially isothiocyanates, have a protective effect against colorectal and lung cancers in individuals lacking GST genes. Moreover, polymorphism of GSTM1 seems to be involved in the dietary regulation of DNA damage. The European Prospective Investigation into Cancer and Nutrition study shows a significant inverse association between the polycyclic aromatic hydrocarbon-DNA adduct level and dietary antioxidants only among GSTM1-null individuals. However, the absence of a modulatory effect of polymorphic xenobiotic metabolising enzymes and diet on the development of cancer has been indicated by some epidemiological investigations. Studies of interactions between nutrients and genes may have great potential for exploring mechanisms, identifying susceptible populations/individuals and making practical use of study results to develop preventive strategies beneficial to human health. PMID:17010218

  6. Reconfiguring phosphorylation signaling by genetic polymorphisms affects cancer susceptibility.

    PubMed

    Wang, Yongbo; Cheng, Han; Pan, Zhicheng; Ren, Jian; Liu, Zexian; Xue, Yu

    2015-06-01

    Large-scale sequencing has characterized an enormous number of genetic variations (GVs), and the functional analysis of GVs is fundamental to understanding differences in disease susceptibility and therapeutic response among and within populations. Using a combination of a sequence-based predictor with known phosphorylation and protein-protein interaction information, we computationally detected 9606 potential phosSNPs (phosphorylation-related single nucleotide polymorphisms), including 720 known, disease-associated SNPs that dramatically modify the human phosSNP-associated kinase-substrate network. Further analyses demonstrated that the proteins in the network are heavily associated in various signaling and cancer pathways, while cancer genes and drug targets are significantly enriched. We re-constructed four population-specific kinase-substrate networks and found that several inherited disease or cancer genes, such as IRS1, RAF1, and EGFR, were differentially regulated by phosSNPs. Thus, phosSNPs may influence disease susceptibility and be involved in cancer development by reconfiguring phosphorylation networks in different populations. Moreover, by systematically characterizing potential phosphorylation-related cancer mutations (phosCMs) in 12 types of cancers, we observed that both types of GVs preferentially occur in the known cancer genes, while a considerable number of phosphorylated proteins, especially those over-representing cancer genes, contain both phosSNPs and phosCMs. Furthermore, it was observed that phosSNPs were significantly enriched in amplification genes identified from breast cancers and tyrosine kinase circuits of lung cancers. Taken together, these results should prove helpful for further elucidation of the functional impacts of disease-associated SNPs. PMID:25722345

  7. Genetic Factors Affecting Late-Onset Alzheimer's Disease Susceptibility.

    PubMed

    Rezazadeh, Maryam; Khorrami, Aziz; Yeghaneh, Tarlan; Talebi, Mahnaz; Kiani, Seyed Jalal; Heshmati, Yaser; Gharesouran, Jalal

    2016-03-01

    Alzheimer's disease is considered a progressive brain disease in the older population. Late-onset Alzheimer's disease (LOAD) as a multifactorial dementia has a polygenic inheritance. Age, environment, and lifestyle along with a growing number of genetic factors have been reported as risk factors for LOAD. Our aim was to present results of LOAD association studies that have been done in northwestern Iran, and we also explored possible interactions with apolipoprotein E (APOE) status. We re-evaluated the association of these markers in dominant, recessive, and additive models. In all, 160 LOAD and 163 healthy control subjects of Azeri Turkish ethnicity were studied. The Chi-square test with Yates' correction and Fisher's exact test were used for statistical analysis. A Bonferroni-corrected p value, based on the number of statistical tests, was considered significant. Our results confirmed that chemokine receptor type 2 (CCR2), estrogen receptor 1 (ESR1), toll-like receptor 2 (TLR2), tumor necrosis factor alpha (TNF α), APOE, bridging integrator 1 (BIN1), and phosphatidylinositol-binding clathrin assembly protein (PICALM) are LOAD susceptibility loci in Azeri Turk ancestry populations. Among them, variants of CCR2, ESR1, TNF α, and APOE revealed associations in three different genetic models. After adjusting for APOE, the association (both allelic and genotypic) with CCR2, BIN1, and ESRα (PvuII) was evident only among subjects without the APOE ε4, whereas the association with CCR5, without Bonferroni correction, was significant only among subjects carrying the APOE ε4 allele. This result is an evidence of a synergistic and antagonistic effect of APOE on variant associations with LOAD. PMID:26553058

  8. Genetic Susceptibility and Predictors of Paradoxical Reactions in Buruli Ulcer

    PubMed Central

    Johnson, Roch Christian; Phillips, Richard O.; van der Veer, Eveline; van Diemen, Cleo; van der Werf, Tjip S.; Stienstra, Ymkje

    2016-01-01

    Introduction Buruli ulcer (BU) is the third most frequent mycobacterial disease in immunocompetent persons after tuberculosis and leprosy. During the last decade, eight weeks of antimicrobial treatment has become the standard of care. This treatment may be accompanied by transient clinical deterioration, known as paradoxical reaction. We investigate the incidence and the risks factors associated with paradoxical reaction in BU. Methods The lesion size of participants was assessed by careful palpation and recorded by serial acetate sheet tracings. For every time point, surface area was compared with the previous assessment. All patients received antimicrobial treatment for 8 weeks. Serum concentration of 25-hydroxyvitamin D, the primary indicator of vitamin D status, was determined in duplex for blood samples at baseline by a radioimmunoassay. We genotyped four polymorphisms in the SLC11A1 gene, previously associated with susceptibility to BU. For testing the association of genetic variants with paradoxical responses, we used a binary logistic regression analysis with the occurrence of a paradoxical response as the dependent variable. Results Paradoxical reaction occurred in 22% of the patients; the reaction was significantly associated with trunk localization (p = .039 by Χ2), larger lesions (p = .021 by Χ2) and genetic factors. The polymorphisms 3’UTR TGTG ins/ins (OR 7.19, p < .001) had a higher risk for developing paradoxical reaction compared to ins/del or del/del polymorphisms. Conclusions Paradoxical reactions are common in BU. They are associated with trunk localization, larger lesions and polymorphisms in the SLC11A1 gene. PMID:27097163

  9. Genetic susceptibility for specific cancers. Medical liability of the clinician.

    PubMed

    Severin, M J

    1999-12-01

    The use of genetic profiling techniques to detect individuals with an increased susceptibility to heritable cancers has provoked recent legal interest in the duties of the attending physician and in the rights of patients and their families. In the current study specific prima facie and recently litigated cases are presented and explored to delineate the issues facing physicians and to illustrate the prerogatives of patients who are caught up in a heritable cancer enigma. Various courts have attempted to answer questions involving lawsuits in which incidents of breast/ovarian carcinoma and colon carcinoma have provoked claims of negligence against health care providers. Health care workers involved in the care of these patients have specific duties to these individuals. It would appear that physicians are being forced to assume the additional duty of delving into a patient's family history of cancer through multiple generations. This duty is followed by a responsibility to provide detailed counseling to those patients in whom such activity impacts the diagnosis and management of familial cancer. PMID:10630182

  10. Consumers’ Use of Web-Based Information and Their Decisions About Multiplex Genetic Susceptibility Testing

    PubMed Central

    McBride, Colleen M; Wade, Christopher; Alford, Sharon Hensley; Brody, Lawrence C; Baxevanis, Andreas D

    2010-01-01

    Background Few data exist to inform concerns raised by online direct-to-consumer marketing of genetic susceptibility tests, such as those offered by commercial entities like 23andme, Navigenics, and DNA Direct. The Multiplex Initiative, a population-based study of healthy adults, provides the first opportunity to evaluate how use of a Web-based decision tool that conveyed information about a genetic susceptibility test influenced individuals’ test decisions. Objective To inform the ongoing debate over whether individuals offered genetic susceptibility testing without the involvement of a health care provider (eg, through direct-to-consumer testing) can make informed decisions about testing when guided by online decision aids. Methods Participants were 526 members of a large health maintenance organization aged 25 to 40 years old who visited a study website. Multivariate logistic regression models were tested to examine the association of website usage with downstream test decisions. Results Participants viewed an average of 2.9 of the 4 pages introducing the multiplex test, 2.2 of the 8 pages describing the health conditions, and 3.2 of the 15 pages describing the genes. For each page viewed, participants were more likely to describe their decision-making as easy (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.01-1.07) and to decide to be tested (OR 1.08, 95% CI 1.05-1.11). Conclusions Healthy adults in this study perceived Web-based genomic information presented using evidence-based communications approaches to be helpful in supporting both decisions to test and not to test. Continued research is needed to ensure that these results generalize to target groups with lower literacy and less Internet savvy. PMID:20884465

  11. Cancer morphology, carcinogenesis and genetic instability: a background.

    PubMed

    Bignold, Leon P; Coghlan, B L D; Jersmann, H P A

    2006-01-01

    Morphological abnormalities of both the nuclei and the cell bodies of tumour cells were described by Müller in the late 1830s. Abnormalities of mitoses and chromosomes in tumour cells were described in the late 1880s. Von Hansemann, in the 1890s, suggested that tumour cells develop from normal cells because of a tendency to mal-distribution and other changes of chromosomes occurring during mitosis. In the first decades of the 20th century, Mendelian genetics and "gene mapping" of chromosomes were established, and the dominant or recessive bases of the familial predispositions to certain tumour types were recognised. In the same period, the carcinogenic effects of ionising radiations, of certain chemicals and of particular viruses were described. A well-developed "somatic gene-mutational theory" of tumours was postulated by Bauer in 1928. In support of this, in the next three decades, many environmental agents were found to cause mitotic and chromosomal abnormalities in normal cells as well as mutations in germ-line cells of experimental animals. Nevertheless, mitotic, chromosomal, and other mutational theories were not popular explanations of tumour pathogenesis in the first half of the 20th century. Only in the 1960s did somatic mutational mechanisms come to dominate theories of tumour formation, especially as a result of the discoveries of the reactivity of carcinogens with DNA, and that the mutation responsible for xeroderma pigmentosum causes loss of function of a gene involved in the repair of DNA after damage by ultraviolet light (Cleaver in 1968). To explain the complexity of tumourous phenomena, "multi-hit" models gained popularity over "single-hit" models of somatic mutation, and "epigenetic" mechanisms of gene regulation began to be studied in tumour cells. More recently, the documentation of much larger-than-expected numbers of genomic events in tumour cells (by Stoler and co-workers, in 1999) has raised the issue of somatic genetic instability in tumour cells, a field which was pioneered in the 1970s mainly by Loeb. Here these discoveries are traced, beginning with "nuclear instability" though mitotic-and-chromosomal theories, single somatic mutation theories, "multi-hit" somatic theories, "somatic, non-chromosomal, genetic instability" and epigenetic mechanisms in tumour cells as a background to the chapters which follow. PMID:16383012

  12. Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease

    PubMed Central

    2013-01-01

    Background Monogenic gain-of-function protein aggregation diseases, including Huntington’s disease, exhibit substantial variability in age of onset, penetrance, and clinical symptoms, even between individuals with similar or identical mutations. This difference in phenotypic expression of proteotoxic mutations is proposed to be due, at least in part, to the variability in genetic background. To address this, we examined the role of natural variation in defining the susceptibility of genetically diverse individuals to protein aggregation and toxicity, using the Caenorhabditis elegans polyglutamine model. Results Introgression of polyQ40 into three wild genetic backgrounds uncovered wide variation in onset of aggregation and corresponding toxicity, as well as alteration in the cell-specific susceptibility to aggregation. To further dissect these relationships, we established a panel of 21 recombinant inbred lines that showed a broad range of aggregation phenotypes, independent of differences in expression levels. We found that aggregation is a transgressive trait, and does not always correlate with measures of toxicity, such as early onset of muscle dysfunction, egg-laying deficits, or reduced lifespan. Moreover, distinct measures of proteotoxicity were independently modified by the genetic background. Conclusions Resistance to protein aggregation and the ability to restrict its associated cellular dysfunction are independently controlled by the natural variation in genetic background, revealing important new considerations in the search for targets for therapeutic intervention in conformational diseases. Thus, our C. elegans model can serve as a powerful tool to dissect the contribution of natural variation to individual susceptibility to proteotoxicity. Please see related commentary by Kaeberlein, http://www.biomedcentral.com/1741-7007/11/102. PMID:24079614

  13. Identifying predictors of activity based anorexia susceptibility in diverse genetic rodent populations.

    PubMed

    Pjetri, Eneda; de Haas, Ria; de Jong, Simone; Gelegen, Cigdem; Oppelaar, Hugo; Verhagen, Linda A W; Eijkemans, Marinus J C; Adan, Roger A; Olivier, Berend; Kas, Martien J

    2012-01-01

    Animal studies are very useful in detection of early disease indicators and in unravelling the pathophysiological processes underlying core psychiatric disorder phenotypes. Early indicators are critical for preventive and efficient treatment of progressive psychiatric disorders like anorexia nervosa. Comparable to physical hyperactivity observed in anorexia nervosa patients, in the activity-based anorexia rodent model, mice and rats express paradoxical high voluntary wheel running activity levels when food restricted. Eleven inbred mouse strains and outbred Wistar WU rats were exposed to the activity-based anorexia model in search of identifying susceptibility predictors. Body weight, food intake and wheel running activity levels of each individual mouse and rat were measured. Mouse strains and rats with high wheel running activity levels during food restriction exhibited accelerated body weight loss. Linear mixed models for repeated measures analysis showed that baseline wheel running activity levels preceding the scheduled food restriction phase strongly predicted activity-based anorexia susceptibility (mice: Beta  =  -0.0158 (±0.003 SE), P<0.0001; rats: Beta  =  -0.0242 (±0.004 SE), P<0.0001) compared to other baseline parameters. These results suggest that physical activity levels play an important role in activity-based anorexia susceptibility in different rodent species with genetically diverse background. These findings support previous retrospective studies on physical activity levels in anorexia nervosa patients and indicate that pre-morbid physical activity levels could reflect an early indicator for disease severity. PMID:23226287

  14. Systems genetics of susceptibility to obesity-induced diabetes in mice

    PubMed Central

    van Nas, Atila; Castellani, Lawrence W.; Zhao, Yi; Zhou, Zhiqiang; Wen, Pingzi; Yu, Suzanne; Qi, Hongxiu; Rosales, Melenie; Schadt, Eric E.; Broman, Karl W.; Péterfy, Miklós; Lusis, Aldons J.

    2012-01-01

    Inbred strains of mice are strikingly different in susceptibility to obesity-driven diabetes. For instance, deficiency in leptin receptor (db/db) leads to hyperphagia and obesity in both C57BL/6 and DBA/2 mice, but only on the DBA/2 background do the mice develop beta-cell loss leading to severe diabetes, while C57BL/6 mice are relatively resistant. To further investigate the genetic factors predisposing to diabetes, we have studied leptin receptor-deficient offspring of an F2 cross between C57BL/6J (db/+) males and DBA/2J females. The results show that the genetics of diabetes susceptibility are enormously complex and a number of quantitative trait loci (QTL) contributing to diabetes-related traits were identified, notably on chromosomes 4, 6, 7, 9, 10, 11, 12, and 19. The Chr. 4 locus is likely due to a disruption of the Zfp69 gene in C57BL/6J mice. To identify candidate genes and to model coexpression networks, we performed global expression array analysis in livers of the F2 mice. Expression QTL (eQTL) were identified and used to prioritize candidate genes at clinical trait QTL. In several cases, clusters of eQTLs colocalized with clinical trait QTLs, suggesting a common genetic basis. We constructed coexpression networks for both 5 and 12 wk old mice and identified several modules significantly associated with clinical traits. One module in 12 wk old mice was associated with several measures of hepatic fat content as well as with other lipid- and diabetes-related traits. These results add to the understanding of the complex genetic interactions contributing to obesity-induced diabetes. PMID:22010005

  15. Systems genetics of susceptibility to obesity-induced diabetes in mice.

    PubMed

    Davis, Richard C; van Nas, Atila; Castellani, Lawrence W; Zhao, Yi; Zhou, Zhiqiang; Wen, Pingzi; Yu, Suzanne; Qi, Hongxiu; Rosales, Melenie; Schadt, Eric E; Broman, Karl W; Pterfy, Mikls; Lusis, Aldons J

    2012-01-18

    Inbred strains of mice are strikingly different in susceptibility to obesity-driven diabetes. For instance, deficiency in leptin receptor (db/db) leads to hyperphagia and obesity in both C57BL/6 and DBA/2 mice, but only on the DBA/2 background do the mice develop beta-cell loss leading to severe diabetes, while C57BL/6 mice are relatively resistant. To further investigate the genetic factors predisposing to diabetes, we have studied leptin receptor-deficient offspring of an F2 cross between C57BL/6J (db/+) males and DBA/2J females. The results show that the genetics of diabetes susceptibility are enormously complex and a number of quantitative trait loci (QTL) contributing to diabetes-related traits were identified, notably on chromosomes 4, 6, 7, 9, 10, 11, 12, and 19. The Chr. 4 locus is likely due to a disruption of the Zfp69 gene in C57BL/6J mice. To identify candidate genes and to model coexpression networks, we performed global expression array analysis in livers of the F2 mice. Expression QTL (eQTL) were identified and used to prioritize candidate genes at clinical trait QTL. In several cases, clusters of eQTLs colocalized with clinical trait QTLs, suggesting a common genetic basis. We constructed coexpression networks for both 5 and 12 wk old mice and identified several modules significantly associated with clinical traits. One module in 12 wk old mice was associated with several measures of hepatic fat content as well as with other lipid- and diabetes-related traits. These results add to the understanding of the complex genetic interactions contributing to obesity-induced diabetes. PMID:22010005

  16. Evidence for genetic heterogeneity of malignant hyperthermia susceptibility

    PubMed Central

    Deufel, T.; Golla, A.; Iles, D.; Meindl, A.; Meitinger, T.; Schindelhauer, D.; DeVries, A.; Pongratz, D.; MacLennan, D. H.; Johnson, K. J.; Lehmann-Horn, F.

    1992-01-01

    A locus for malignant hyperthermia susceptibility (MHS) has been localized on chromosome 19q12-13.2, while at the same time the gene encoding the skeletal muscle ryanodine receptor (RYR1) also has been mapped to this region and has been found to be tightly linked to MHS. RYR1 was consequently postulated as the candidate for the molecular defect causing MHS, and a point mutation in the gene has now been identified and is thought to be the cause of MH in at least some MHS patients. Here we report the results of a linkage study done with 19q12-13.2 markers, including the RYR1 cDNA, in two Bavarian families with MHS. In one of the families, three unambiguous recombination events between MHS and the RYR1 locus were found. In the second family only one informative meiosis was seen with RYR1. However, segregation analysis with markers for D19S75, D19S28, D19S47, CYP2A, BCL3, and APOC2 shows that the crossovers in the first family involve the entire haplotype defined by these markers flanking RYR1 and, furthermore, reveals multiple crossovers between these haplotypes and MHS in the second family. In these families, pairwise and multipoint lod scores below –2 exclude MHS from an interval spanning more than 26 cM and comprising the RYR1 and the previously described MHS locus. Our findings thus strongly suggest genetic heterogeneity of the MHS trait and prompt the search for another MHS locus. PMID:1598899

  17. Genetic susceptibility to wild and vaccine polio virus: genotypes and their frequency.

    PubMed

    Wyatt, H V

    1978-11-17

    The frequency of proposed genotypes which predispose to poliomyelitis, is tabled. Susceptibility is due to a gene or linkage group of genes with a frequency of 2% for the homozygote and 24% for the heterozygote. Two subgroups are identified where a second gene might make the persons susceptible to vaccine strains of virus. Cutter vaccinees might form a third group with increased susceptibility under special circumstances. The age at which genetic susceptibility changes to phenotypic susceptibility may be modified by physical factors such as those due to congenital syphilis and Salvarsan, and thalidomide. PMID:214687

  18. PKCε overexpression, irrespective of genetic background, sensitizes skin to ultraviolet radiation-induced development of squamous cell carcinomas

    PubMed Central

    Sand, Jordan Marshall; Aziz, Moammir Hasan; Dreckschmidt, Nancy Ellen; Havighurst, Thomas; Kim, KyungMann; Verma, Ajit Kumar

    2009-01-01

    Chronic exposure to ultraviolet radiation (UVR) is the major etiologic factor in the development of human skin cancers including squamous cell carcinoma (SCC). We have shown that PKCε transgenic mice on FVB/N background, which overexpress PKCε protein approximately 8-fold over endogenous levels in epidermis, exhibit about 3-fold more sensitivity than wild-type littermates to UVR-induced development of SCC (Cancer Research, 64, 7756, 2004). To determine whether it is PKCε and not the mouse genetic background, that determines susceptibility to UVR carcinogenesis, we cross-bred PKCε FVB/N transgenic mice with SKH-1 hairless mice to generate PKCε overexpressing SKH-1 hairless mice. To evaluate the susceptibility of PKCε SKH-1 hairless transgenic mice to UVR carcinogenesis, the mice were exposed to UVR (1–2 KJ/m2) three times weekly from a bank of six kodacel-filtered FS40 sunlamps. As compared to the wild-type hairless mice, PKCε overexpression in SKH-1 hairless mice decreased the latency (12 weeks) while increased the incidence (2-fold) and multiplicity (4-fold) of SCC. The SKH hairless transgenic mice were observed to be as sensitive as FVB/N transgenic mice to UVR-induced development of SCC and expression of proliferative markers (PCNA, Stat3 and ERK1/2). The results indicate that PKCε level dictates susceptibility, irrespective of genetic background, to UVR carcinogenesis. PMID:19626035

  19. PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas.

    PubMed

    Sand, Jordan M; Aziz, Moammir H; Dreckschmidt, Nancy E; Havighurst, Thomas C; Kim, KyungMann; Oberley, Terry D; Verma, Ajit K

    2010-01-01

    Chronic exposure to UVR is the major etiologic factor in the development of human skin cancers including squamous-cell carcinoma (SCC). We have previously shown that protein Kinase C epsilon (PKCepsilon) transgenic mice on FVB/N background, which overexpress PKCepsilon protein approximately eightfold over endogenous levels in epidermis, exhibit about threefold more sensitivity than wild-type littermates to UVR-induced development of SCC. To determine whether it is PKCepsilon and not the mouse genetic background that determines susceptibility to UVR carcinogenesis, we cross-bred PKCepsilon FVB/N transgenic mice with SKH-1 hairless mice to generate PKCepsilon-overexpressing SKH-1 hairless mice. To evaluate the susceptibility of PKCepsilon SKH-1 hairless transgenic mice to UVR carcinogenesis, the mice were exposed to UVR (1-2 KJ m(-2)) three times weekly from a bank of six kodacel-filtered FS40 sunlamps. As compared with the wild-type hairless mice, PKCepsilon overexpression in SKH-1 hairless mice decreased the latency (12 weeks), whereas it increased the incidence (twofold) and multiplicity (fourfold) of SCC. The SKH hairless transgenic mice were observed to be as sensitive as FVB/N transgenic mice to UVR-induced development of SCC and expression of proliferative markers (proliferating cell nuclear antigen, signal transducers and activators of transcription 3, and extracellular signal-regulated kinase 1/2). The results indicate that PKCepsilon level dictates susceptibility, irrespective of genetic background, to UVR carcinogenesis. PMID:19626035

  20. Genetic Architecture of Susceptibility to PCB126-Induced Developmental Cardiotoxicity in Zebrafish

    PubMed Central

    Waits, Eric R.; Nebert, Daniel W.

    2011-01-01

    Variability in risk of developmental defects caused by dioxin-like compounds (DLCs) has been demonstrated within and among several vertebrate species. Beyond our knowledge of the aryl hydrocarbon receptor (AHR) and its role in mediating toxicity for this class of compounds, little else is known concerning precise downstream targets influencing this vulnerability. In the present study, zebrafish with divergent genetic backgrounds were screened for susceptibility to developmental cardiotoxicity caused by the prototypical DLC, 3,3?,4,4?,5-pentachlorobiphenyl (PCB126); a range up to ?40-fold differences was observed. Differentially sensitive zebrafish were chosen for a genetic cross, and the recombinant generation was used for genome-wide quantitative trait loci (QTL) mapping. Multiple QTLs were identifiedseveral acting alone, one additively, and two others via epistatic interaction. Together, these QTLs account for 24% of the phenotypic variance observed in cardioteratogenicity resulting from PCB126 exposure (logarithm of the odds = 13.55, p = 1.89 10?10). Candidate genes in these QTL regions include the following: ahr2, bcor, and capn1 (Chr 22); e2f1 and pdyn (Chr 23); ctnnt2, plcg1, eno3, tgm1, and tgm2 (interacting on Chr 23); and vezf1 (Chr 15). These data demonstrate that DLC-induced cardiac teratogenicity is a multifactorial complex trait influenced by gene gene and gene environment interactions. The identified QTLs harbor many DLC-responsive genes critical to cardiovascular development and provide insight into the genetic basis of susceptibility to AHR-mediated developmental toxicity. PMID:21613231

  1. Does your gene need a background check? How genetic background impacts the analysis of mutations, genes, and evolution

    PubMed Central

    Chandler, Christopher H.; Chari, Sudarshan; Dworkin, Ian

    2013-01-01

    The premise of genetic analysis is that a causal link exists between phenotypic and allelic variation. Yet it has long been documented that mutant phenotypes are not a simple result of a single DNA lesion, but rather are due to interactions of the focal allele with other genes and the environment. Although an experimentally rigorous approach focused on individual mutations and isogenic control strains has facilitated amazing progress within genetics and related fields, a glimpse back suggests that a vast complexity has been omitted from our current understanding of allelic effects. Armed with traditional genetic analyses and the foundational knowledge they have provided, we argue that the time and tools are ripe to return to the under-explored aspects of gene function and embrace the context-dependent nature of genetic effects. We assert that a broad understanding of genetic effects and the evolutionary dynamics of alleles requires identifying how mutational outcomes depend upon the “wild-type” genetic background. Furthermore, we discuss how best to exploit genetic background effects to broaden genetic research programs. PMID:23453263

  2. On the relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus genetic diversity.

    PubMed

    Renzette, Nicholas; Kowalik, Timothy F; Jensen, Jeffrey D

    2016-01-01

    A central focus of population genetics has been examining the contribution of selective and neutral processes in shaping patterns of intraspecies diversity. In terms of selection specifically, surveys of higher organisms have shown considerable variation in the relative contributions of background selection and genetic hitchhiking in shaping the distribution of polymorphisms, although these analyses have rarely been extended to bacteria and viruses. Here, we study the evolution of a ubiquitous, viral pathogen, human cytomegalovirus (HCMV), by analysing the relationship among intraspecies diversity, interspecies divergence and rates of recombination. We show that there is a strong correlation between diversity and divergence, consistent with expectations of neutral evolution. However, after correcting for divergence, there remains a significant correlation between intraspecies diversity and recombination rates, with additional analyses suggesting that this correlation is largely due to the effects of background selection. In addition, a small number of loci, centred on long noncoding RNAs, also show evidence of selective sweeps. These data suggest that HCMV evolution is dominated by neutral mechanisms as well as background selection, expanding our understanding of linked selection to a novel class of organisms. PMID:26211679

  3. Differential effect of caffeine intake in subjects with genetic susceptibility to Parkinson's Disease.

    PubMed

    Kumar, Prakash M; Paing, Swe Swe Thet; Li, HuiHua; Pavanni, R; Yuen, Y; Zhao, Y; Tan, Eng King

    2015-01-01

    We examined if caffeine intake has a differential effect in subjects with high and low genetic susceptibility to Parkinson's disease (PD), a common neurodegenerative disorder. A case control study involving 812 subjects consisting of PD and healthy controls were conducted. Caffeine intake assessed by a validated questionnaire and genotyping of PD gene risk variant (LRRK2 R1628P) was carried out. Compared to caffeine takers with the wild-type genotype (low genetic susceptibility), non-caffeine takers with R1628P variant (high genetic susceptibility) had a 15 times increased risk of developing PD (OR = 15.4, 95% CI = (1.94, 122), P = 0.01), whereas caffeine takers with R1628P (intermediate susceptibility) had a 3 times risk (OR = 3.07, 95% CI = (2.02, 4.66), P < 0.001). Caffeine intake would significantly reduce the risk of PD much more in those with high genetic susceptibility compared to those with low genetic susceptibility. PMID:26522888

  4. Research Review: Genetic Vulnerability or Differential Susceptibility in Child Development--The Case of Attachment

    ERIC Educational Resources Information Center

    Bakermans-Kranenburg, Marian J.; van IJzendoorn, Marinus H.

    2007-01-01

    Gene-environment interactions interpreted in terms of differential susceptibility may play a large part in the explanation of individual differences in human development. Reviewing studies on the behavioral and molecular genetics of attachment, we present evidence for interactions between genetic and environmental factors explaining individual

  5. Research Review: Genetic Vulnerability or Differential Susceptibility in Child Development--The Case of Attachment

    ERIC Educational Resources Information Center

    Bakermans-Kranenburg, Marian J.; van IJzendoorn, Marinus H.

    2007-01-01

    Gene-environment interactions interpreted in terms of differential susceptibility may play a large part in the explanation of individual differences in human development. Reviewing studies on the behavioral and molecular genetics of attachment, we present evidence for interactions between genetic and environmental factors explaining individual…

  6. Genetic differential susceptibility on trial: meta-analytic support from randomized controlled experiments.

    PubMed

    van Ijzendoorn, Marinus H; Bakermans-Kranenburg, Marian J

    2015-02-01

    The most stringent test of differential susceptibility theory is provided by randomized control trials examining the moderating role of genetic markers of differential susceptibility in experimental manipulations of the environment (Gene × Experimental Environment interactions), being at least 10 times more powerful than correlational Gene × Environment interaction studies. We identified 22 experiments involving 3,257 participants with various developmental outcomes (e.g., externalizing problems, internalizing behaviors, and cognitive development). Effect sizes contrasting experimental versus control group were computed both for subjects with the polymorphism considered indicative of heightened susceptibility (e.g., the dopamine receptor D4 gene seven-repeat allele and the serotonin transporter polymorphic region short allele) and others expected to be low in susceptibility (e.g., the dopamine receptor D4 gene four-repeat allele and the serotonin transporter polymorphic region short allele). Clear-cut experimental support for genetic differential susceptibility emerged: the combined effect size of the interventions for the susceptible genotypes amounted to r = .33 (95% confidence interval = 0.23, 0.42; p < .01) versus a nonsignificant r = .08 (95% confidence interval = -0.02, 0.17; p = .12) for the hypothesized nonsusceptible genotypes. Macrotrials showed more evidence of genetic differential susceptibility than microtrials, and differential susceptibility was more clearly observed in trials with externalizing and cognitive outcomes than with internalizing problems. This meta-analysis shows proof of principle for genetic differential susceptibility and indicates that it is time to explore its mechanisms and limits. The concept of differential susceptibility alters the idea of constitutional "risk" factors (reactive temperament and risk genotypes), and points to intervention efficacy hidden in Gene × Environment interactions. PMID:25640837

  7. Genetics of patent ductus arteriosus susceptibility and treatment.

    PubMed

    Hajj, Hanine; Dagle, John M

    2012-04-01

    The ductus arteriosus is a vital fetal structure designed to close shortly after birth. Although many physiologic and pharmacologic investigations have characterized the closure of this structure, genetic studies of persistent patency of the ductus arteriosus (patent ductus arteriosus, PDA) are relatively recent. Progress in the identification of specific genes associated with PDA is well behind that of many adult-onset diseases because of several reasons ranging from the lack of large biorepositories for this unique population to the belief that any genetic contribution to PDA is minimal. Viewing the PDA as a complex, developmentally influenced disease with both genetic and environmental risk factors has resulted in initial successes in some genetic studies. We will introduce several genetic approaches, which have been or are currently being applied to the study of PDA, that have been successful in identifying polymorphisms associated with adult diseases. Genetic investigations of PDA will be discussed with respect to heritability, in general, and to specific risk genes. Several animal models that have been used to study PDA-related genes will also be presented. Further advances in discovering genetic variation causing PDA will drive the more rational use of current therapies, and may help identify currently unknown targets for future therapeutic manipulation. PMID:22414880

  8. Familial gastric cancer: genetic susceptibility, pathology, and implications for management.

    PubMed

    Oliveira, Carla; Pinheiro, Hugo; Figueiredo, Joana; Seruca, Raquel; Carneiro, Ftima

    2015-02-01

    Familial gastric cancer comprises at least three major syndromes: hereditary diffuse gastric cancer, gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. The risk of development of gastric cancer is high in families affected b-y these syndromes, but only hereditary diffuse gastric cancer is genetically explained (caused by germline alterations of CDH1, which encodes E-cadherin). Gastric cancer is also associated with a range of several cancer-associated syndromes with known genetic causes, such as Lynch, Li-Fraumeni, Peutz-Jeghers, hereditary breast-ovarian cancer syndromes, familial adenomatous polyposis, and juvenile polyposis. We present contemporary knowledge on the genetics, pathogenesis, and clinical features of familial gastric cancer, and discuss research and technological developments, which together are expected to open avenues for new genetic testing approaches and novel therapeutic strategies. PMID:25638682

  9. Relationships of OPG Genetic Polymorphisms with Susceptibility to Cardiovascular Disease: A Meta-Analysis

    PubMed Central

    Song, De-Hua; Zhou, Peng-Zhen; Xiu, Xiao-Lin; Zou, Guang-Hui; Sun, Yu-Xia; Song, Chun

    2016-01-01

    Background The aim of this meta-analysis was to determine whether genetic polymorphisms in the osteoprotegerin (OPG) gene contribute to increased risk of cardiovascular disease (CVD). Material/Methods Electronic databases were searched carefully without any language restriction. Analyses of data were conducted using STATA software. Odds ratios (OR) and 95% confidence intervals (95%CI) were also calculated. Results Seven clinical case-control studies that enrolled 1170 CVD patients and 1194 healthy subjects were included. The results indicated that OPG gene polymorphism might be closely associated with susceptibility to CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms. Ethnicity-stratified analysis indicated that genetic polymorphism in the OPG were closely related with the pathogenesis of CVD among Asians (all P<0.001), but no obvious relationship was found among Caucasians (all P>0.05). Conclusions Our meta-analysis provided quantitative evidence that OPG gene polymorphism may be closely related to an increased risk of CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms. PMID:27068490

  10. Evolutionary Determinants of Genetic Variation in Susceptibility to Infectious Diseases in Humans

    PubMed Central

    Baker, Christi; Antonovics, Janis

    2012-01-01

    Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology. PMID:22242158

  11. A Systems Genetic Approach to Identify Low Dose Radiation-Induced Lymphoma Susceptibility/DOE2013FinalReport

    SciTech Connect

    Balmain, Allan; Song, Ihn Young

    2013-05-15

    The ultimate goal of this project is to identify the combinations of genetic variants that confer an individual's susceptibility to the effects of low dose (0.1 Gy) gamma-radiation, in particular with regard to tumor development. In contrast to the known effects of high dose radiation in cancer induction, the responses to low dose radiation (defined as 0.1 Gy or less) are much less well understood, and have been proposed to involve a protective anti-tumor effect in some in vivo scientific models. These conflicting results confound attempts to develop predictive models of the risk of exposure to low dose radiation, particularly when combined with the strong effects of inherited genetic variants on both radiation effects and cancer susceptibility. We have used a €œSystems Genetics approach in mice that combines genetic background analysis with responses to low and high dose radiation, in order to develop insights that will allow us to reconcile these disparate observations. Using this comprehensive approach we have analyzed normal tissue gene expression (in this case the skin and thymus), together with the changes that take place in this gene expression architecture a) in response to low or high- dose radiation and b) during tumor development. Additionally, we have demonstrated that using our expression analysis approach in our genetically heterogeneous/defined radiation-induced tumor mouse models can uniquely identify genes and pathways relevant to human T-ALL, and uncover interactions between common genetic variants of genes which may lead to tumor susceptibility.

  12. Genetic polymorphisms in C-reactive protein increase cancer susceptibility

    PubMed Central

    Geng, Peiliang; Sa, Rina; Li, Jianjun; Li, Hongtao; Liu, Chen; Liao, Yunmei; Xiang, Lisha; Wang, Ning; Ou, Juanjuan; Xie, Ganfeng; Liang, Houjie

    2016-01-01

    Elevated levels of C-reactive protein (CRP) partially induced by polymorphisms in the CRP gene have been associated with human cancer. The purpose of this study was to test the hypothesis that CRP gene polymorphisms (+942G>C, 1846C>T) modify inherited susceptibility to cancer. We systematically identified the publications addressing the association of CRP gene polymorphisms with cancer susceptibility. Studies that fulfilled all inclusion criteria were considered eligible in this meta-analysis. We analyzed a total of 8 case-control studies. Individuals with the CC genotype were found to have an almost 4?fold higher risk of cancer than those with the GG or GC and GG genotypes. A significant association was also indicated in subgroup of colorectal cancer. Meta-analysis of 1846C>T polymorphism showed increased cancer risk in relation to the 1846?TT genotype (TT vs. CC: OR?=?1.15, 95% CI?=?1.011.31; TT vs. CT?+?CC; OR?=?1.17, 95% CI?=?1.031.32). Similar results were suggested in Caucasian populations and colorectal cancer. These data suggest that both +942G>C and 1846C>T polymorphisms in the CRP gene may influence cancer susceptibility. PMID:26912098

  13. Genetically susceptible mice remain proportionally more susceptible to tuberculosis after vaccination

    PubMed Central

    Medina, E; North, R J

    1999-01-01

    DBA/2 mice are much more susceptible to infection with Mycobacterium tuberculosis than major histocompatibility complex-compatible BALB/c mice. It is shown here that, although vaccination provided mice of both strains with a capacity to reduce the level of infection in their lungs, vaccinated DBA/2 mice remained much more susceptible in this organ than vaccinated BALB/c mice. Consequently, the former mice developed more lung pathology and died much earlier than the latter. On the other hand, colony-forming unit counts and histology suggest that vaccination provided mice of both strains with an increased and equal ability to express immunity in the liver and spleen, thereby indicating that they possessed equal systemic levels of vaccine-induced immunity at the time of M. tuberculosis challenge. The results indicate that inefficient expression of immunity in the lungs is likely to prove an obstacle to successful vaccination against tuberculosis in resistant and susceptible mouse strains, but more so in the latter strains. PMID:10233673

  14. Genetic Characterization of Optochin-Susceptible Viridans Group Streptococci

    PubMed Central

    Martín-Galiano, Antonio J.; Balsalobre, Luz; Fenoll, Asunción; de la Campa, Adela G.

    2003-01-01

    Two clinical isolates of viridans group streptococci (VS) with different degrees of susceptibility to optochin (OPT), i.e., fully OPT-susceptible (Opts) VS strain 1162/99 (for which the MIC was equal to that for Streptococcus pneumoniae, 0.75 μg/ml) and intermediate Opts VS strain 1174/97 (MIC, 6 μg/ml) were studied. Besides being OPT susceptible, they showed characteristics typical of VS, such as bile insolubility; lack of reaction with pneumococcal capsular antibodies; and lack of hybridization with rRNA (AccuProbe)-, lytA-, and pnl-specific pneumococcal probes. However, these VS Opts strains and VS type strains hybridized with ant, a gene not present in S. pneumoniae. A detailed characterization of the genes encoding the 16S rRNA and SodA classified isolates 1162/99 and 1174/97 as Streptococcus mitis. Analysis of the atpCAB region, which encodes the c, a, and b subunits of the F0F1 H+-ATPase, the target of optochin, revealed high degrees of similarity between S. mitis 1162/99 and S. pneumoniae in atpC, atpA, and the N terminus of atpB. Moreover, amino acid identity between S. mitis 1174/97 and S. pneumoniae was found in α helix 5 of the a subunit. The organization of the chromosomal region containing the atp operon of the two Opts VS and VS type strains was spr1284-atpC, with spr1284 being located 296 to 556 bp from atpC, whereas in S. pneumoniae this distance was longer than 68 kb. In addition, the gene order in S. pneumoniae was IS1239-74 bp-atpC. The results suggest that the full OPT susceptibility of S. mitis 1162/99 is due to the acquisition of atpC, atpA, and part of atpB from S. pneumoniae and that the intermediate OPT susceptibility of S. mitis 1174/97 correlates with the amino acid composition of its a subunit. PMID:14506029

  15. Genetic characterization of optochin-susceptible viridans group streptococci.

    PubMed

    Martín-Galiano, Antonio J; Balsalobre, Luz; Fenoll, Asunción; de la Campa, Adela G

    2003-10-01

    Two clinical isolates of viridans group streptococci (VS) with different degrees of susceptibility to optochin (OPT), i.e., fully OPT-susceptible (Opt(s)) VS strain 1162/99 (for which the MIC was equal to that for Streptococcus pneumoniae, 0.75 micro g/ml) and intermediate Opt(s) VS strain 1174/97 (MIC, 6 micro g/ml) were studied. Besides being OPT susceptible, they showed characteristics typical of VS, such as bile insolubility; lack of reaction with pneumococcal capsular antibodies; and lack of hybridization with rRNA (AccuProbe)-, lytA-, and pnl-specific pneumococcal probes. However, these VS Opt(s) strains and VS type strains hybridized with ant, a gene not present in S. pneumoniae. A detailed characterization of the genes encoding the 16S rRNA and SodA classified isolates 1162/99 and 1174/97 as Streptococcus mitis. Analysis of the atpCAB region, which encodes the c, a, and b subunits of the F(0)F(1) H(+)-ATPase, the target of optochin, revealed high degrees of similarity between S. mitis 1162/99 and S. pneumoniae in atpC, atpA, and the N terminus of atpB. Moreover, amino acid identity between S. mitis 1174/97 and S. pneumoniae was found in alpha helix 5 of the a subunit. The organization of the chromosomal region containing the atp operon of the two Opt(s) VS and VS type strains was spr1284-atpC, with spr1284 being located 296 to 556 bp from atpC, whereas in S. pneumoniae this distance was longer than 68 kb. In addition, the gene order in S. pneumoniae was IS1239-74 bp-atpC. The results suggest that the full OPT susceptibility of S. mitis 1162/99 is due to the acquisition of atpC, atpA, and part of atpB from S. pneumoniae and that the intermediate OPT susceptibility of S. mitis 1174/97 correlates with the amino acid composition of its a subunit. PMID:14506029

  16. Final Technical Report for the grant entitled "Genetic Factors Affecting Susceptibility to Low-Dose Radiation"

    SciTech Connect

    Morgan, William, F., Ph.D., D.Sc.

    2006-11-22

    The goal of this proposal was to test the hypothesis that mice heterozygous for the Nijmegen Breakage Syndrome (NBS1) gene are genetically susceptible to low doses of ionizing radiation. The rationale for this is that patients with NBS are radiation sensitive, because of defects in cellular responses to radiation induced genetic damage and haploinsufficiency at this genetic locus provides the potential for genetic susceptibility to low doses of ionizing radiation. Wild type and heterozygous NBS1 mice were irradiated and followed over their lifetime for radiation induced genomic instability, carcinogenesis and non-specific life shortening. No differences in cytogenetic damage, cancer induction or life span were observed between the hypomorphic mice indicating that genetic imbalance at the NBS1 loci does not modulate low dose radiation sensitivity.

  17. Pheochromocytoma and Paraganglioma: Understanding the Complexities of the Genetic Background

    PubMed Central

    Fishbein, Lauren; Nathanson, Katherine L.

    2012-01-01

    Pheochromocytomas and paragangliomas (PCC/PGL) are tumors derived from the adrenal medulla or extra adrenal ganglia, respectively. They are rare and often benign tumors which are associated with high morbidity and mortality due to mass effect and high circulating catecholamines. Although most pheochromocytomas and paragangliomas are thought to be sporadic, over one third are associated with ten known susceptibility genes. Mutations in three genes causing well characterized tumor syndromes are associated with an increased risk of developing pheochromocytomas and paragangliomas including VHL (von Hippel-Lindau disease), NF1 (Neurofibromatosis Type 1), and RET (Multiple Endocrine Neoplasia Type 2). Mutations in any of the succinate dehydrogenase (SDH) complex subunit genes (SDHA, SDHB, SDHC, SDHD) can lead to pheochromocytomas and paragangliomas with variable penetrance, as can mutations in the subunit cofactor, SDHAF2. Recently, two additional genes have been identified, TMEM127 and MAX. Although these tumors are rare in the general population, occurring in 2–8 per million people, they are more commonly associated with an inherited mutation than any other cancer type. This review summarizes the known germline and somatic mutations leading to pheochromocytoma and paraganglioma development, as well as biochemical profiling for PCC/PGL and screening of mutation carriers. PMID:22429592

  18. Patients' Attitudes Towards Disclosure of Genetic Test Results to Family Members: The Impact of Patients' Sociodemographic Background and Counseling Experience.

    PubMed

    Gilbar, Roy; Shalev, Stavit; Spiegel, Ronen; Pras, Elon; Berkenstadt, Michal; Sagi, Michal; Ben-Yehuda, Adi; Mor, Pnina; Perry, Shlomit; Zaccai, Tzipora Falik; Borochowitz, Zvi; Barnoy, Sivia

    2016-04-01

    Many factors predict the intention to disclose genetic information to relatives. The article examines the impact of patients' socio-demographic factors on their intention to disclose genetic testing results to their relatives. Data were collected in eight genetic clinics in Israel. Patients were requested to fill in a questionnaire after counseling. A convenience sample of 564 participants who visited these clinics was collected for a response rate of 85 %. Of them, 282 participants came for susceptibility testing for hereditary cancers (cancer group), and 282 for genetic screening tests (prenatal group). In the cancer group, being secular and having more years of education correlated positively with the intention to disclose test results to relatives. In the prenatal group, being married and female correlated positively with the intention to disclose. In the cancer group, being religious and with less years of education correlated positively with the view that the clinician should deliver the results to the family. In the prenatal group, being male and unmarried correlated positively with this belief. In both groups, being of young age correlated with the perception that genetic information is private. Varied sociodemographic factors affect the intention to inform family members. Thus, knowing the social background of patients will shed light on people's attitudes to genetic information and will help clinicians provide effective counseling in discussions with patients about the implications of test results for relatives. PMID:26371363

  19. Assessment of genetic susceptibility to ethanol intoxication in mice

    PubMed Central

    Rustay, Nathan R.; Wahlsten, Douglas; Crabbe, John C.

    2003-01-01

    Increased use of gene manipulation in mice (e.g., targeted or random mutagenesis) has been accompanied by increased reliance on a very few rapid and simple behavioral assays, each of which aspires to model a human behavioral domain. Yet, each assay comprises multiple traits, influenced by multiple genetic factors. Motor incoordination (ataxia), a common characteristic of many neurological disorders, may reflect disordered balance, muscle strength, proprioception, and/or patterned gait. Impaired motor performance can confound interpretation of behavioral assays of learning and memory, exploration, motivation, and sensory competence. The rotarod is one of the most commonly used tests to measure coordination in mice. We show here that exactly how the rotarod test is performed can markedly alter the apparent patterns of genetic influence both in undrugged performance and sensitivity to ethanol intoxication. However, when tested with well chosen parameters, the accelerating rotarod test showed very high inter- and intralaboratory reliability. Depending on test conditions, ethanol can either disrupt or enhance performance in some strains. Genetic contribution to performance on the accelerating versus the fixed-speed rotarod assay can be completely dissociated under some test conditions, and multiple test parameters are needed to assess the range of genetic influence adequately. PMID:12584362

  20. Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression.

    PubMed

    Ferguson, B; Ram, R; Handoko, H Y; Mukhopadhyay, P; Muller, H K; Soyer, H P; Morahan, G; Walker, G J

    2015-05-28

    Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations. PMID:25088201

  1. Interactions between Genetic Background, Insulin Resistance and ?-cell Function

    PubMed Central

    Kahn, Steven E.; Suvag, Seda; Wright, Lorena A.; Utzschneider, Kristina M.

    2013-01-01

    An interaction between genes and the environment is a critical component underlying the pathogenesis of the hyperglycemia of type 2 diabetes. The development of more sophisticated techniques for studying gene variants and for analyzing genetic data has led to the discovery of some 40 genes associated with type 2 diabetes. Most of these genes are related to changes in ?-cell function, with a few associated with decreased insulin sensitivity and obesity. Interestingly, using quantitative traits based on continuous measures rather than dichotomous ones, it has become evident that not all genes associated with changes in fasting or post-prandial glucose are also associated with a diagnosis of type 2 diabetes. Identification of these gene variants has provided novel insights into the physiology and pathophysiology of the ?-cell, including the identification of molecules involved in ?-cell function that were not previously recognized as playing a role in this critical cell. PMID:22928564

  2. Genetic factors for nerve susceptibility to injuries – lessons from PMP22 deficiency

    PubMed Central

    Li, Jun

    2014-01-01

    Genetic factors may be learnt from families with gene mutations that render nerve-injury susceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure palsies (HNPP). HNPP is caused by a heterozygous deletion of PMP22 gene. PMP22 deficiency disrupts myelin junctions (such as tight junction and adherens junctions), leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury. This finding should motivate investigators to identify additional genetic factors contributing to nerve vulnerability of injury. PMID:25374586

  3. Genetic factors for nerve susceptibility to injuries - lessons from PMP22 deficiency.

    PubMed

    Li, Jun

    2014-09-15

    Genetic factors may be learnt from families with gene mutations that render nerve-injury susceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure palsies (HNPP). HNPP is caused by a heterozygous deletion of PMP22 gene. PMP22 deficiency disrupts myelin junctions (such as tight junction and adherens junctions), leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury. This finding should motivate investigators to identify additional genetic factors contributing to nerve vulnerability of injury. PMID:25374586

  4. Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma

    PubMed Central

    Anderson, Michael G; Libby, Richard T; Mao, Mao; Cosma, Ioan M; Wilson, Larry A; Smith, Richard S; John, Simon WM

    2006-01-01

    Background DBA/2J (D2) mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP) and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s) are necessary for the distinct later stages of disease. We initiated a study of congenic strains to further define the genetic requirements and disease mechanisms of the D2 glaucoma. Results To further understand D2 glaucoma, we created congenic strains of mice on the C57BL/6J (B6) genetic background. B6 double-congenic mice carrying D2-derived Gpnmb and Tyrp1 mutations develop a D2-like iris disease. B6 single-congenics with only the Gpnmb and Tyrp1 mutations develop milder forms of iris disease. Genetic epistasis experiments introducing a B6 tyrosinase mutation into the congenic strains demonstrated that both the single and double-congenic iris diseases are rescued by interruption of melanin synthesis. Importantly, our experiments analyzing mice at ages up to 27 months indicate that the B6 double-congenic mice are much less prone to IOP elevation and glaucoma than are D2 mice. Conclusion As demonstrated here, the Gpnmb and Tyrp1 iris phenotypes are both individually dependent on tyrosinase function. These results support involvement of abnormal melanosomal events in the diseases caused by each gene. In the context of the inbred D2 mouse strain, the glaucoma phenotype is clearly influenced by more genes than just Gpnmb and Tyrp1. Despite the outward similarity of pigment-dispersing iris disease between D2 and the B6 double-congenic mice, the congenic mice are much less susceptible to developing high IOP and glaucoma. These new congenic strains provide a valuable new resource for further studying the genetic and mechanistic complexity of this form of glaucoma. PMID:16827931

  5. Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity

    PubMed Central

    Ahmed, Mahbubl; Dorling, Leila; Kerns, Sarah; Fachal, Laura; Elliott, Rebecca; Partliament, Matt; Rosenstein, Barry S; Vega, Ana; Gómez-Caamaño, Antonio; Barnett, Gill; Dearnaley, David P; Hall, Emma; Sydes, Matt; Burnet, Neil; Pharoah, Paul D P; Eeles, Ros; West, Catharine M L

    2016-01-01

    Background: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. Methods: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. Results: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. Conclusion: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens. PMID:27070714

  6. Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization

    PubMed Central

    Randles, Michael J.; Woolf, Adrian S.; Huang, Jennifer L.; Byron, Adam; Humphries, Jonathan D.; Price, Karen L.; Kolatsi-Joannou, Maria; Collinson, Sophie; Denny, Thomas; Knight, David; Mironov, Aleksandr; Starborg, Toby; Korstanje, Ron; Humphries, Martin J.; Long, David A.

    2015-01-01

    Glomerular disease often features altered histologic patterns of extracellular matrix (ECM). Despite this, the potential complexities of the glomerular ECM in both health and disease are poorly understood. To explore whether genetic background and sex determine glomerular ECM composition, we investigated two mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined with proteomic glomerular ECM analyses. These studies, undertaken in healthy young adult animals, revealed unique strain- and sex-dependent glomerular ECM signatures, which correlated with variations in levels of albuminuria and known predisposition to progressive nephropathy. Among the variation, we observed changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin 1-α, and meprin 1-β. Differences in protein abundance were validated by quantitative immunohistochemistry and Western blot analysis, and the collective differences were not explained by mutations in known ECM or glomerular disease genes. Within the distinct signatures, we discovered a core set of structural ECM proteins that form multiple protein–protein interactions and are conserved from mouse to man. Furthermore, we found striking ultrastructural changes in glomerular basement membranes in FVB mice. Pathway analysis of merged transcriptomic and proteomic datasets identified potential ECM regulatory pathways involving inhibition of matrix metalloproteases, liver X receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch, and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer susceptibility to disease. PMID:25896609

  7. Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization.

    PubMed

    Randles, Michael J; Woolf, Adrian S; Huang, Jennifer L; Byron, Adam; Humphries, Jonathan D; Price, Karen L; Kolatsi-Joannou, Maria; Collinson, Sophie; Denny, Thomas; Knight, David; Mironov, Aleksandr; Starborg, Toby; Korstanje, Ron; Humphries, Martin J; Long, David A; Lennon, Rachel

    2015-12-01

    Glomerular disease often features altered histologic patterns of extracellular matrix (ECM). Despite this, the potential complexities of the glomerular ECM in both health and disease are poorly understood. To explore whether genetic background and sex determine glomerular ECM composition, we investigated two mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined with proteomic glomerular ECM analyses. These studies, undertaken in healthy young adult animals, revealed unique strain- and sex-dependent glomerular ECM signatures, which correlated with variations in levels of albuminuria and known predisposition to progressive nephropathy. Among the variation, we observed changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin 1-?, and meprin 1-?. Differences in protein abundance were validated by quantitative immunohistochemistry and Western blot analysis, and the collective differences were not explained by mutations in known ECM or glomerular disease genes. Within the distinct signatures, we discovered a core set of structural ECM proteins that form multiple protein-protein interactions and are conserved from mouse to man. Furthermore, we found striking ultrastructural changes in glomerular basement membranes in FVB mice. Pathway analysis of merged transcriptomic and proteomic datasets identified potential ECM regulatory pathways involving inhibition of matrix metalloproteases, liver X receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch, and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer susceptibility to disease. PMID:25896609

  8. The genetics of bone mass and susceptibility to bone diseases.

    PubMed

    Karasik, David; Rivadeneira, Fernando; Johnson, Mark L

    2016-06-01

    Osteoporosis is characterized by low bone mass and an increased risk of fracture. Genetic factors, environmental factors and gene-environment interactions all contribute to a person's lifetime risk of developing an osteoporotic fracture. This Review summarizes key advances in understanding of the genetics of bone traits and their role in osteoporosis. Candidate-gene approaches dominated this field 20 years ago, but clinical and preclinical genetic studies published in the past 5 years generally utilize more-sophisticated and better-powered genome-wide association studies (GWAS). High-throughput DNA sequencing, large genomic databases and improved methods of data analysis have greatly accelerated the gene-discovery process. Linkage analyses of single-gene traits that segregate in families with extreme phenotypes have led to the elucidation of critical pathways controlling bone mass. For example, components of the Wnt-β-catenin signalling pathway have been validated (in both GWAS and functional studies) as contributing to various bone phenotypes. These notable advances in gene discovery suggest that the next decade will witness cataloguing of the hundreds of genes that influence bone mass and osteoporosis, which in turn will provide a roadmap for the development of new drugs that target diseases of low bone mass, including osteoporosis. PMID:27052486

  9. Major Histocompatibility Complex and Background Genes in Chickens Influence Susceptibility to High Pathogenicity Avian Influenza Virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chicken’s major histocompatibility complex (MHC) haplotype has profound influence on the resistance or susceptibility to certain pathogens such as B21 MHC haplotype confers resistance to Marek’s disease (MD). However, non-MHC genes are also important in disease resistance. For example, both line...

  10. Salmonella penetration through eggshells of chickens of different genetic backgrounds.

    PubMed

    Rathgeber, Bruce M; McCarron, Paige; Budgell, Krista L

    2013-09-01

    Eggs have been identified as a source of salmonellosis, making the transmission of Salmonella to eggs of great concern to the poultry industry. The goal of this experiment was to determine the ability of Salmonella to penetrate the eggshell of 5 different breeds of noncommercial chicken, Barred Plymouth Rock, White Leghorn, Brown Leghorn, Fayoumi, and Light Sussex, and 1 commercial Lohmann LSL-Lite. Egg weight, breaking force, shell weight, and shell thickness measurements were taken for 30 eggs per breed. A 1 cm in diameter hole was cut out from the narrow end of 30 additional eggs per breed. The shells were filled with plate count agar containing tetracycline and 0.1% 2,3,5-triphenyl terazolium chloride and sealed with paraffin wax. Agar-filled eggs were submerged for 1 min in an overnight culture of tetracycline-resistant Salmonella Heidelberg and incubated at 37°C for 40 h. Eggs were candled and visual colonies were counted and reported as cfu per egg and cfu per gram of shell. The SAS mixed model was used to evaluate differences between breeds for egg quality characteristics and the number of cfu per egg and per gram of shell. Commercial layers (62.6 g) and Barred Plymouth Rock (61.5 g) produced the largest eggs, whereas Fayoumi (47.1 g) produced the smallest (P < 0.05). Force to break the shell was lowest (P < 0.05) for Barred Plymouth Rock (3.6 kg) and greatest for the commercial (4.4 kg), White Leghorn (4.4 kg), and Fayoumi (4.2 kg). Bacteria penetrating the shell was lowest (P < 0.05) for Barred Plymouth Rock (10.7 cfu/g) and highest for Light Sussex (27.7 cfu/g) and Brown Leghorn (27.2 cfu/g), with other breeds intermediate. These results indicate that there are breed-specific influences on the ability of an egg to resist Salmonella, which cannot be explained by shell quality measurements. Further investigations are warranted to determine the contributing factors to shell penetration by bacteria. This study highlights the value in maintaining heritage chicken breeds as a genetic resource for the future. PMID:23960130

  11. Post-Traumatic Brain Injury: Genetic Susceptibility to Outcome.

    PubMed

    Davidson, Jennilee; Cusimano, Michael D; Bendena, William G

    2015-08-01

    It is estimated that 2% of the population from industrialized countries live with lifelong disabilities resulting from traumatic brain injury (TBI) and roughly one in four adults are unable to return to work 1 year after injury because of physical or mental disabilities. TBI is a significant public health issue that causes substantial physical and economical repercussions for the individual and society. Electronic databases (PubMed, Web of Science, Google Scholar) were searched with the keywords traumatic brain injury, TBI, genes and TBI, TBI outcome, head injury. Human studies on non-penetrating traumatic brain injuries reported in English were included. To provide health care workers with the basic information for clinical management we summarize and compare the data on post-TBI outcome with regard to the impact of genetic variation: apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), calcium channel, voltage dependent P/Q type, catechol-O-methyltransferase (COMT), dopamine receptor D2 and ankyrin repeat and kinase domain containing 1 (DRD2 and ANKK1), interleukin-1 (IL-1), interleukin-6 (IL-6), kidney and brain expressed protein (KIBRA), neurofilament, heavy polypeptide (NEFH), endothelial nitric oxide synthase 3 (NOS3), poly (ADP-ribose) polymerase-1 (PARP-1), protein phosphatase 3, catalytic subunit, gamma isozyme (PPP3CC), the serotonin transporter (5-HTT) gene solute carrier family 6 member (SLC6A4) and tumor protein 53 (TP53). It is evident that contradicting results are attributable to the heterogeneity of studies, thus further researches are warranted to effectively assess a relation between genetic traits and clinical outcome following traumatic injuries. PMID:25059577

  12. Genetic Based Plant Resistance and Susceptibility Traits to Herbivory Influence Needle and Root Litter Nutrient Dynamics

    SciTech Connect

    Classen, Aimee T; Chapman, Samantha K.; Whitham, Thomas G; Hart, Stephen C; Koch, George W

    2007-01-01

    It is generally assumed that leaf and root litter decomposition have similar drivers and that nutrient release from these substrates is synchronized. Few studies have examined these assumptions, and none has examined how plant genetics (i.e., plant susceptibility to herbivory) could affect these relationships. Here we examine the effects of herbivore susceptibility and resistance on needle and fine root litter decomposition of pi on pine, Pinus edulis. The study population consists of individual trees that are either susceptible or resistant to herbivory by the pi on needle scale, Matsucoccus acalyptus, or the stem-boring moth, Dioryctria albovittella. Genetic analyses and experimental removals and additions of these insects have identified trees that are naturally resistant and susceptible to these insects. These herbivores increase the chemical quality of litter inputs and alter soil microclimate, both of which are important decomposition drivers. Our research leads to four major conclusions: Herbivore susceptibility and resistance effects on 1) needle litter mass loss and phosphorus (P) retention in moth susceptible and resistant litter are governed by microclimate, 2) root litter nitrogen (N) and P retention, and needle litter N retention are governed by litter chemical quality, 3) net nutrient release from litter can reverse over time, 4) root and needle litter mass loss and nutrient release are determined by location (above- vs. belowground), suggesting that the regulators of needle and root decomposition differ at the local scale. Understanding of decomposition and nutrient retention in ecosystems requires consideration of herbivore effects on above- and belowground processes and how these effects may be governed by plant genotype. Because an underlying genetic component to herbivory is common to most ecosystems of the world and herbivory may increase in climatic change scenarios, it is important to evaluate the role of plant genetics in affecting carbon and nutrient fluxes.

  13. Alcohol Induces Sensitization to Gluten in Genetically Susceptible Individuals: A Case Control Study

    PubMed Central

    Currie, Stuart; Hoggard, Nigel; Clark, Matthew J. R.; Sanders, David S.; Wilkinson, Iain D.; Griffiths, Paul D.; Hadjivassiliou, Marios

    2013-01-01

    Background The mechanisms of cerebellar degeneration attributed to prolonged and excessive alcohol intake remain unclear. Additional or even alternative causes of cerebellar degeneration are often overlooked in suspected cases of alcohol-related ataxia. The objectives of this study were two fold: (1) to investigate the prevalence of gluten-related serological markers in patients with alcohol-related ataxia and; (2) to compare the pattern of brain involvement on magnetic resonance imaging between patients with alcohol and gluten ataxias. Materials & Methods Patients diagnosed with alcohol and gluten ataxias were identified from a retrospective review of patients attending a tertiary clinic. HLA genotype and serological markers of gluten-related disorders were recorded. Cerebellar volumetry, MR spectroscopy and voxel-based morphometric analyses were performed on patients and compared with matched control data. Results Of 904 registered patients, 104 had alcohol ataxia and 159 had gluten ataxia. 61% of the alcohol ataxia group and 70% of the gluten ataxia group had HLA DQ2/DQ8 genotype compared to 30% in healthy local blood donors. 44% of patients with alcohol ataxia had antigliadin antibodies compared to 12% in the healthy local population and 10% in patients with genetically confirmed ataxias. None of the patients with alcohol ataxia and antigliadin antibodies had celiac disease compared to 40% in patients with gluten ataxia. The pattern of structural brain abnormality in patients with alcohol ataxia who had antigliadin antibodies differed from gluten ataxia and was identical to that of alcohol ataxia. Conclusions Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten. Such sensitization may result from a primary cerebellar insult, but a more systemic effect is also possible. The duration and amount of exposure to alcohol may not be the only factors responsible for the cerebellar insult. PMID:24204900

  14. Investigating the genetic background of bovine digital dermatitis using improved definitions of clinical status.

    PubMed

    Schöpke, K; Gomez, A; Dunbar, K A; Swalve, H H; Döpfer, D

    2015-11-01

    Bovine digital dermatitis (DD) is an increasing claw health problem in all cattle production systems worldwide. The objective of this study was to evaluate the use of an improved scoring of the clinical status for DD via M-scores accounting for the dynamics of the disease; that is, the transitions from one stage to another. The newly defined traits were then subjected to a genetic analysis to determine the genetic background for susceptibility to DD. Data consisted of 6,444 clinical observations from 729 Holstein heifers in a commercial dairy herd, collected applying the M-score system. The M-score system is a classification scheme for stages of DD that allows a macroscopic scoring based on clinical inspections of the bovine foot, thus it describes the stages of lesion development. The M-scores were used to define new DD trait definitions with different complexities. Linear mixed models and logistic models were used to identify fixed environmental effects and to estimate variance components. In total, 68% of all observations showed no DD status, whereas 11% were scored as infectious for and affected by DD, and 21% of all observations exhibited an affected but noninfectious status. For all traits, the probability of occurrence and clinical status were associated with age at observation and period of observation. Risk of becoming infected increased with age, and month of observation significantly affected all traits. Identification of the optimal month concerning DD herd status was consistent for all trait definitions; the last month of the trial was identified. In contrast, months exhibiting the highest least squares means of transformed scores differed depending on trait definition. In this respect, traits that can distinguish between healthy, infectious, and noninfectious stages of DD can account for the infectious potential of the herd and can serve as an alert tool. Estimates of heritabilities of traits studied ranged between 0.19 (±0.11) and 0.52 (±0.17), revealing a tendency for higher values for more complex trait definitions. In terms of genetic selection, all trait definitions identified the best (i.e., most resistant) animals, but only the new trait definitions were able to distinguish between animals with average and high predispositions for DD. Considering repeated measurements resulted in heritability estimates ranging between 0.13 (±0.05) and 0.29 (±0.10). PMID:26364113

  15. Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma

    PubMed Central

    2009-01-01

    Background Translocations are hallmarks of non-Hodgkin lymphoma (NHL) genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN) complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. Methods We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. Results 114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. Conclusion These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role. PMID:19917125

  16. Functional implications of genetic variation in non-coding DNA for disease susceptibility and gene regulation.

    PubMed

    Knight, Julian C

    2003-05-01

    The role of host genetic variation in determining susceptibility to complex disease traits is the subject of much research effort, but it often remains unclear whether disease-associated genetic polymorphisms are themselves functionally relevant or acting only as markers within an extended haplotype. Experimental approaches to investigate the functional impact of polymorphisms in non-coding regulatory DNA sequences for gene expression are discussed, including the role of gel-shift assays, DNA footprinting and reporter gene analysis. The limitations of different experimental approaches are presented together with future prospects for in vivo analysis. The strategic application of these functional approaches is discussed and illustrated by analysis of the role of genetic variation in the tumour necrosis factor promoter region in determining susceptibility to severe malaria. PMID:12513691

  17. Role of Toll-like receptor-4 in genetic susceptibility to lung injury induced by residual oil fly ash.

    PubMed

    Cho, Hye-Youn; Jedlicka, Anne E; Clarke, Robert; Kleeberger, Steven R

    2005-06-16

    The mechanisms of susceptibility to particle-induced lung injury are not clearly understood. To evaluate the contribution of genetic background to pulmonary pathogenesis, we compared the lung injury responses to residual oil fly ash (ROFA) in inbred mouse strains and calculated heritability estimates. Significant interstrain (genetic) variation was observed in ROFA-induced lung inflammation and hyperpermeability phenotypes; broad-sense heritability ranged from approximately 0.43 to 0.62, and the coefficient of genetic determination ranged from 0.28 to 0.45. C3H/HeJ (HeJ) mice were most resistant to the ROFA-induced injury responses. This was particularly important, as HeJ mice contain a dominant negative mutation in Toll-like receptor-4 (Tlr4). We then characterized ROFA-induced injury and TLR4 signaling in HeJ mice and its coisogenic strain C3H/HeOuJ (OuJ; Tlr4 normal) to understand the potential role of Tlr4 in this model. ROFA-induced lung injury was significantly greater in OuJ mice compared with HeJ mice. ROFA also significantly enhanced transcript and protein levels of lung TLR4 in OuJ but not in HeJ mice. Greater activation of downstream signal molecules (i.e., MYD88, TRAF6, IRAK-1, NF-kappaB, MAPK, AP-1) was observed in OuJ mice than in HeJ mice before the development of ROFA-induced pulmonary injury. Putative TLR4-dependent inflammatory genes that were differentially induced by ROFA in the two strains include interleukin-1beta and tumor necrosis factor-alpha. Results support an important contribution of genetic background to particle-mediated lung injury, and Tlr4 is a candidate susceptibility gene. PMID:15784698

  18. Coffee consumption, genetic susceptibility and bladder cancer risk

    PubMed Central

    Villanueva, Cristina M.; Silverman, Debra T; Murta-Nascimento, Cristiane; Malats, Núria; Garcia-Closas, Montserrat; Castro, Francesc; Tardon, Adonina; Garcia-Closas, Reina; Serra, Consol; Carrato, Alfredo; Rothman, Nathaniel; Real, Francisco X; Dosemeci, Mustafa; Kogevinas, Manolis

    2010-01-01

    Objective We evaluated the bladder cancer risk associated with coffee consumption in a case-control study in Spain and examined the gene-environment interactions for genetic variants of caffeine metabolizing enzymes. Methods The analyses included 1136 incident cases with urothelial carcinoma of the urinary bladder and 1138 controls. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for area, age, gender, amount of cigarette smoking and years since quitting among former smokers. Results The OR (95%CI) for ever consumed coffee was 1.25 (0.95–1.64). For consumers of 1, 2, 3 and 4 or more cups/day relative to never drinkers, OR were, respectively: 1.24 (0.92–1.66), 1.11 (95%CI 0.82–1.51), 1.57 (1.13–2.19) and 1.27 (0.88–1.81). Coffee consumption was higher in smokers compared to never smokers. The OR for drinking at least 4 cups/day was: 1.13 (0.61–2.09) in current smokers, 1.57 (0.86–2.90) in former smokers, and 1.23 (0.55–2.76) in never smokers. Gene-coffee interactions evaluated in NAT2, CYP1A2, and CYP2E1-02 and CYP1A1 were not identified after adjusting for multiple testing. Conclusion The modest increased bladder cancer risk among coffee drinkers supports the hypothesis that coffee is a weak carcinogen, although results may, in part, be explained by residual confounding by smoking. The findings from the gene-coffee interactions need replication in further studies. PMID:18798002

  19. SEPTIN12 Genetic Variants Confer Susceptibility to Teratozoospermia

    PubMed Central

    Lin, Ying-Hung; Wang, Ya-Yun; Chen, Hau-Inh; Kuo, Yung-Che; Chiou, Yu-Wei; Lin, Hsi-Hui; Wu, Ching-Ming; Hsu, Chao-Chin; Chiang, Han-Sun; Kuo, Pao-Lin

    2012-01-01

    It is estimated that 1015% of couples are infertile and male factors account for about half of these cases. With the advent of intracytoplasmic sperm injection (ICSI), many infertile men have been able to father offspring. However, teratozoospermia still remains a big challenge to tackle. Septins belong to a family of cytoskeletal proteins with GTPase activity and are involved in various biological processes e.g. morphogenesis, compartmentalization, apoptosis and cytokinesis. SEPTIN12, identified by c-DNA microarray analysis of infertile men, is exclusively expressed in the post meiotic male germ cells. Septin12+/+/Septin12+/? chimeric mice have multiple reproductive defects including the presence of immature sperm in the semen, and sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make SEPTIN12 a potential sterile gene in humans. In this study, we sequenced the entire coding region of SEPTIN12 in infertile men (n?=?160) and fertile controls (n?=?200) and identified ten variants. Among them is the c.474 G>A variant within exon 5 that encodes part of the GTP binding domain. The variant creates a novel splice donor site that causes skipping of a portion of exon 5, resulting in a truncated protein lacking the C-terminal half of SEPTIN12. Most individuals homozygous for the c.474 A allele had teratozoospermia (abnormal sperm <14%) and their sperm showed bent tail and de-condensed nucleus with significant DNA damage. Ex vivo experiment showed truncated SEPT12 inhibits filament formation in a dose-dependent manner. This study provides the first causal link between SEPTIN12 genetic variant and male infertility with distinctive sperm pathology. Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development. PMID:22479503

  20. Identification of susceptibility genes and genetic modifiers of human diseases

    NASA Astrophysics Data System (ADS)

    Abel, Kenneth; Kammerer, Stefan; Hoyal, Carolyn; Reneland, Rikard; Marnellos, George; Nelson, Matthew R.; Braun, Andreas

    2005-03-01

    The completion of the human genome sequence enables the discovery of genes involved in common human disorders. The successful identification of these genes is dependent on the availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform technology based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology, we generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes. We also established a large DNA sample bank comprised of more than 50,000 consented healthy and diseased individuals. This combination of reagents and technology allows the execution of large-scale genome-wide association studies. Taking advantage of MassARRAY"s capability for quantitative analysis of nucleic acids, allele frequencies are estimated in sample pools containing large numbers of individual DNAs. To compare pools as a first-pass "filtering" step is a tremendous advantage in throughput and cost over individual genotyping. We employed this approach in numerous genome-wide, hypothesis-free searches to identify genes associated with common complex diseases, such as breast cancer, osteoporosis, and osteoarthritis, and genes involved in quantitative traits like high density lipoproteins cholesterol (HDL-c) levels and central fat. Access to additional well-characterized patient samples through collaborations allows us to conduct replication studies that validate true disease genes. These discoveries will expand our understanding of genetic disease predisposition, and our ability for early diagnosis and determination of specific disease subtype or progression stage.

  1. Genetic background impacts soluble and cell wall-bound aromatics in brown midrib mutants of sorghum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To evaluate the effects that genetic background has on two sorghum brown midrib (bmr) mutants, plant phenolics, lignin biosynthetic enzymes and stem anatomy were evaluated in wild-type (WT), bmr-6, bmr-12 and double-mutants (bmr-6 and bmr-12) in near isogenic , RTx430 and Wheatland backgrounds. The...

  2. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment.

    PubMed

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H; Blakely, Eleanor A; Bissell, Mina J; Barcellos-Hoff, Mary Helen; Snijders, Antoine M; Mao, Jian-Hua

    2015-01-01

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures. PMID:25747469

  3. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

    DOE PAGESBeta

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; et al

    2015-03-09

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genesmore » involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.« less

  4. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

    SciTech Connect

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; Snijders, Antoine M.; Mao, Jian-Hua

    2015-03-09

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

  5. Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways

    PubMed Central

    2013-01-01

    Background Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage. Methods Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. Results The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. Conclusions Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets. PMID:24330528

  6. Metabolomics of Apc Min/+ mice genetically susceptible to intestinal cancer

    PubMed Central

    2014-01-01

    Background To determine how diets high in saturated fat could increase polyp formation in the mouse model of intestinal neoplasia, Apc Min/+ , we conducted large-scale metabolome analysis and association study of colon and small intestine polyp formation from plasma and liver samples of Apc Min/+ vs. wild-type littermates, kept on low vs. high-fat diet. Label-free mass spectrometry was used to quantify untargeted plasma and acyl-CoA liver compounds, respectively. Differences in contrasts of interest were analyzed statistically by unsupervised and supervised modeling approaches, namely Principal Component Analysis and Linear Model of analysis of variance. Correlation between plasma metabolite concentrations and polyp numbers was analyzed with a zero-inflated Generalized Linear Model. Results Plasma metabolome in parallel to promotion of tumor development comprises a clearly distinct profile in Apc Min/+ mice vs. wild type littermates, which is further altered by high-fat diet. Further, functional metabolomics pathway and network analyses in Apc Min/+ mice on high-fat diet revealed associations between polyp formation and plasma metabolic compounds including those involved in amino-acids metabolism as well as nicotinamide and hippuric acid metabolic pathways. Finally, we also show changes in liver acyl-CoA profiles, which may result from a combination of Apc Min/+ -mediated tumor progression and high fat diet. The biological significance of these findings is discussed in the context of intestinal cancer progression. Conclusions These studies show that high-throughput metabolomics combined with appropriate statistical modeling and large scale functional approaches can be used to monitor and infer changes and interactions in the metabolome and genome of the host under controlled experimental conditions. Further these studies demonstrate the impact of diet on metabolic pathways and its relation to intestinal cancer progression. Based on our results, metabolic signatures and metabolic pathways of polyposis and intestinal carcinoma have been identified, which may serve as useful targets for the development of therapeutic interventions. PMID:24954394

  7. Application of a hybrid model of neural networks and genetic algorithms to evaluate landslide susceptibility

    NASA Astrophysics Data System (ADS)

    Wang, H. B.; Li, J. W.; Zhou, B.; Yuan, Z. Q.; Chen, Y. P.

    2013-03-01

    In the last few decades, the development of Geographical Information Systems (GIS) technology has provided a method for the evaluation of landslide susceptibility and hazard. Slope units were found to be appropriate for the fundamental morphological elements in landslide susceptibility evaluation. Following the DEM construction in a loess area susceptible to landslides, the direct-reverse DEM technology was employed to generate 216 slope units in the studied area. After a detailed investigation, the landslide inventory was mapped in which 39 landslides, including paleo-landslides, old landslides and recent landslides, were present. Of the 216 slope units, 123 involved landslides. To analyze the mechanism of these landslides, six environmental factors were selected to evaluate landslide occurrence: slope angle, aspect, the height and shape of the slope, distance to river and human activities. These factors were extracted in terms of the slope unit within the ArcGIS software. The spatial analysis demonstrates that most of the landslides are located on convex slopes at an elevation of 100-150 m with slope angles from 135°-225° and 40°-60°. Landslide occurrence was then checked according to these environmental factors using an artificial neural network with back propagation, optimized by genetic algorithms. A dataset of 120 slope units was chosen for training the neural network model, i.e., 80 units with landslide presence and 40 units without landslide presence. The parameters of genetic algorithms and neural networks were then set: population size of 100, crossover probability of 0.65, mutation probability of 0.01, momentum factor of 0.60, learning rate of 0.7, max learning number of 10 000, and target error of 0.000001. After training on the datasets, the susceptibility of landslides was mapped for the land-use plan and hazard mitigation. Comparing the susceptibility map with landslide inventory, it was noted that the prediction accuracy of landslide occurrence is 93.02%, whereas units without landslide occurrence are predicted with an accuracy of 81.13%. To sum up, the verification shows satisfactory agreement with an accuracy of 86.46% between the susceptibility map and the landslide locations. In the landslide susceptibility assessment, ten new slopes were predicted to show potential for failure, which can be confirmed by the engineering geological conditions of these slopes. It was also observed that some disadvantages could be overcome in the application of the neural networks with back propagation, for example, the low convergence rate and local minimum, after the network was optimized using genetic algorithms. To conclude, neural networks with back propagation that are optimized by genetic algorithms are an effective method to predict landslide susceptibility with high accuracy.

  8. Association of elevated mutagenesis in the spleen with genetic susceptibility to induced plasmacytoma development in mice.

    PubMed

    Felix, K; Kelliher, K; Bornkamm, G W; Janz, S

    1998-04-15

    Using the phage lambdaLIZ-based transgenic in vivo mutagenesis assay, mean mutant rates were determined in the spleen of mice exposed to sustained oxidative stress and were found to be increased approximately 3-fold in plasmacytoma-susceptible BALB/c and C.D2-Idh1-Pep3 mice, but not in plasmacytoma-resistant DBA/2N mice. This finding suggests a correlation between the genetic susceptibility to inflammation-induced peritoneal plasmacytomagenesis and the phenotype of increased mutagenesis in lymphoid tissues, raising the possibility that plasmacytoma resistance genes may inhibit tumor development by minimizing oxidative mutagenesis in B cells. PMID:9563470

  9. Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice

    PubMed Central

    2013-01-01

    Background Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes. Methods To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity. Results One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior. Conclusions Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans. PMID:24083388

  10. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.

    PubMed

    Robson, Mark E; Bradbury, Angela R; Arun, Banu; Domchek, Susan M; Ford, James M; Hampel, Heather L; Lipkin, Stephen M; Syngal, Sapna; Wollins, Dana S; Lindor, Noralane M

    2015-11-01

    The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services. PMID:26324357

  11. Genetic Analysis in Young-Age-of-Onset Graves' Disease Reveals New Susceptibility Loci

    PubMed Central

    Brown, Rosalind S.; Lombardi, Angela; Hasham, Alia; Greenberg, David A.; Gordon, Joshua; Concepcion, Erlinda; Hammerstad, Sara S.; Lotay, Vaneet; Zhang, Weijia

    2014-01-01

    Context: Genetic and environmental factors play an essential role in the pathogenesis of Graves' Disease (GD). Children with GD have less exposure time to environmental factors and therefore are believed to harbor stronger genetic susceptibility than adults. Objective: The aim of the study was to identify susceptibility loci that predispose to GD in patients with young-age-of-onset (YAO) GD. Setting and Design: One hundred six patients with YAO GD (onset <30 y) and 855 healthy subjects were studied. Cases and controls were genotyped using the Illumina Infinium Immunochip, designed to genotype 196,524 polymorphisms. Case control association analyses were performed using the PLINK computer package. Ingenuity Pathway Analysis program (QIAGEN) was used to carry out pathway analyses. Results: Immunochip genetic association analysis identified 30 single-nucleotide polymorphisms in several genes that were significantly associated with YAO GD, including major histocompatibility complex class I and class II genes, BTNL2, NOTCH4, TNFAIP3, and CXCR4. Candidate gene analysis revealed that most of the genes previously shown to be associated with adult-onset GD were also associated with YAO GD. Pathway analysis demonstrated that antigen presentation, T-helper cell differentiation, and B cell development were the major pathways contributing to the pathogenesis of YAO GD. Conclusions: Genetic analysis identified novel susceptibility loci in YAO GD adding a new dimension to the understanding of GD etiology. PMID:24684463

  12. The role of test accuracy in predicting acceptance of genetic susceptibility testing for Alzheimer's disease.

    PubMed

    Bassett, Susan Spear; Havstad, Suzanne L; Chase, Gary A

    2004-01-01

    A survey questionnaire regarding perceptions of risk and genetic susceptibility to Alzheimer's disease (AD) was completed by 518 offspring of AD cases from families with multiple affected, ascertained as part of a genetic linkage study of late onset AD. The questionnaire focused on respondents' perceptions of their own risk for AD as well as on the properties of real and hypothetical susceptibility tests, including error rates for false-positive and false-negative test results. Our findings showed that about 20% of the sample would refuse a susceptibility test with zero error rates, about 40% would accept tests with very high error rates in both directions, and the remainder would exercise some discrimination. Acceptance of high test error rates was significantly associated with male gender, low education, and high perceived lifetime risk of AD. In a previous paper related to this work, we showed that physicians caring for these families exercised much more discrimination in judging the acceptability of genetic tests they would offer to these same respondents. The findings show that there is a pressing need to educate the public, particularly those with relatives affected by a complex disease, to expect standards of accuracy for genetic tests comparable to those that prevail in other diagnostic and prognostic testing efforts in the broad field of clinical medicine. PMID:15345108

  13. Genetic diversity and antimicrobial susceptibility of Nocardia species among patients with nocardiosis

    PubMed Central

    Hashemi-Shahraki, Abodolrazagh; Heidarieh, Parvin; Bostanabad, Saeed Zaker; Hashemzadeh, Mohamad; Feizabadi, Mohamad Mehdi; Schraufnagel, Dean; Mirsaeidi, Mehdi

    2015-01-01

    The aim of this multicenter study was to determine the genetic diversity and antibiotic susceptibility of clinically isolated Nocardia species. One hundred twenty-seven patients with nocardiosis were randomly selected from 5 provinces of Iran. Molecular diagnosis of Nocardia species was performed using multilocus sequence analysis of gyrase B of the β subunit of DNA topoisomerase (gyrB), and 16S rRNA and subunit A of SecA preproteintranslocase (secA1). Antimicrobial susceptibility testing was performed following the Clinical and Laboratory Standards Institute recommendations. Thirty-five N. cyriacigeorgica, 30 N. asteroides, 26 N. farcinica, 12 N. otitidiscaviarum, and 10 N. abscessus cultures were studied. All isolates were susceptible to linezolid. All isolates of N. cyriacigeorgica, N. asteroides, N. abscessus, and N. otitidiscaviarum were susceptible to trimethoprim-sulfamethoxazole, while 8% of N. farcinica isolates were resistant to this drug. All N. otitidiscaviarum isolates were highly resistant to imipenem, but N. cyriacigeorgica, N. asteroides, N. farcinica, and N. abscessus were only moderate resistant. The susceptibility patterns vary with different species of Nocardia. Resistance to trimethoprim-sulfamethoxazole in Iran is low and this drug should be first line therapy, unless drug susceptibility testing shows resistance. Linezolid also covers Nocardia well and could be a second line agent. PMID:26638771

  14. Lung cell responses to M. tuberculosis in genetically susceptible and resistant mice following intratracheal challenge

    PubMed Central

    ERUSLANOV, E B; MAJOROV, K B; ORLOVA, M O; MISCHENKO, V V; KONDRATIEVA, T K; APT, A S; LYADOVA, I V

    2004-01-01

    One approach to study the role of distinct cellular mechanisms in susceptibility/resistance to tuberculosis (TB) is to compare parameters of response to infection in the lungs of mouse strains exhibiting genetically determined differences in TB susceptibility/severity. Interstrain differences in antimycobacterial macrophage reactions, T cell responses & inflammation in the lungs of TB-susceptible I/St, TB-resistant A/Sn and (I/St × A/Sn)F1 mice were analysed following intratracheal inoculation of 103 CFUs of M. tuberculosis H37Rv. The antimycobacterial responses in the lungs of susceptible I/St mice were characterized by: (i) increased inflammatory infiltration by all major immune cell subsets; (ii) decreased type 1 cytokine production; (iii) impaired antimycobacterial activity of lung macrophages; (iv) unusually high proliferation of lung T lymphocytes. Differences in several parameters of anti-TB immunity between susceptible and resistant mice corresponded well to the polygenic pattern of TB control previously established in this mouse model. Importantly, lung macrophages isolated from noninfected mice were unable to respond to IFN-γ by increasing their mycobactericidal function, but between weeks 3 and 5 of the infection this capacity developed in all mice. However, by this time point susceptible but not resistant mice demonstrated a pronounced decrease in IFN-γ production by lung cells. This chain of events may explain the inability of I/St mice to control both early and chronic TB infection. PMID:14678260

  15. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms.

    PubMed

    Huber, Amanda; Menconi, Francesca; Corathers, Sarah; Jacobson, Eric M; Tomer, Yaron

    2008-10-01

    Type 1 diabetes (T1D) and autoimmune thyroid diseases (AITD) frequently occur together within families and in the same individual. The co-occurrence of T1D and AITD in the same patient is one of the variants of the autoimmune polyglandular syndrome type 3 [APS3 variant (APS3v)]. Epidemiological data point to a strong genetic influence on the shared susceptibility to T1D and AITD. Recently, significant progress has been made in our understanding of the genetic association between T1D and AITD. At least three genes have been confirmed as major joint susceptibility genes for T1D and AITD: human leukocyte antigen class II, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22. Moreover, the first whole genome linkage study has been recently completed, and additional genes will soon be identified. Not unexpectedly, all the joint genes for T1D and AITD identified so far are involved in immune regulation, specifically in the presentation of antigenic peptides to T cells. One of the lessons learned from the analysis of the joint susceptibility genes for T1D and AITD is that subset analysis is a key to dissecting the etiology of complex diseases. One of the best demonstrations of the power of subset analysis is the CTLA-4 gene in T1D. Although CTLA-4 showed very weak association with T1D, when analyzed in the subset of patients with both T1D and AITD, the genetic effect of CTLA-4 was significantly stronger. Gene-gene and genetic-epigenetic interactions most likely play a role in the shared genetic susceptibility to T1D and AITD. Dissecting these mechanisms will lead to a better understanding of the etiology of T1D and AITD, as well as autoimmunity in general. PMID:18776148

  16. Complex genetic susceptibility to vascular dementia and an evidence for its underlying genetic factors associated with memory and associative learning.

    PubMed

    Lee, Chaeyoung; Kim, Younyoung

    2013-03-01

    Genetic basis for vascular dementia (VD) as a typical complex disease has been limitedly reported from association studies conducted with candidate genes. Even recent genomewide association studies (GWAS) could hardly identify additional genetic factors for VD. Although a considerable complexity for its genetic architecture was suspected, there were some challenges to identify false negative associations that resulted from the GWAS. Challenges to identifying genetic factors and their functions after the trials of GWAS revealed that splicing of primary transcript was inhibited (SYK) or delayed (PHLDB2) by a nucleotide substitution of the corresponding gene. The studies gave us the lesson that integrated investigations with statistical genomics as well as functional genomics are needed to identify false negatives from the GWAS. Such endeavors would provide key insights into aspects of underlying nucleotide architectures of VD and incorporate the genetic factors into clinical practice. The recent genetic association studies for susceptibility to VD were briefly overviewed in this article. We also showed a challenge to understanding genetic dissection of VD by a genomic region enrichment analysis with distal cis-regulatory sequences. The analysis with a variant set of potential false negatives from the GWAS revealed that the variants were significantly enriched near genes involved in critical biological processes to VD. PMID:23262336

  17. Genetically Determined Susceptibility to Tuberculosis in Mice Causally Involves Accelerated and Enhanced Recruitment of Granulocytes

    PubMed Central

    Keller, Christine; Hoffmann, Reinhard; Lang, Roland; Brandau, Sven; Hermann, Corinna; Ehlers, Stefan

    2006-01-01

    Classical twin studies and recent linkage analyses of African populations have revealed a potential involvement of host genetic factors in susceptibility or resistance to Mycobacterium tuberculosis infection. In order to identify the candidate genes involved and test their causal implication, we capitalized on the mouse model of tuberculosis, since inbred mouse strains also differ substantially in their susceptibility to infection. Two susceptible and two resistant mouse strains were aerogenically infected with 1,000 CFU of M. tuberculosis, and the regulation of gene expression was examined by Affymetrix GeneChip U74A array with total lung RNA 2 and 4 weeks postinfection. Four weeks after infection, 96 genes, many of which are involved in inflammatory cell recruitment and activation, were regulated in common. One hundred seven genes were differentially regulated in susceptible mouse strains, whereas 43 genes were differentially expressed only in resistant mice. Data mining revealed a bias towards the expression of genes involved in granulocyte pathophysiology in susceptible mice, such as an upregulation of those for the neutrophil chemoattractant LIX (CXCL5), interleukin 17 receptor, phosphoinositide kinase 3 delta, or gamma interferon-inducible protein 10. Following M. tuberculosis challenge in both airways or peritoneum, granulocytes were recruited significantly faster and at higher numbers in susceptible than in resistant mice. When granulocytes were efficiently depleted by either of two regimens at the onset of infection, only susceptible mice survived aerosol challenge with M. tuberculosis significantly longer than control mice. We conclude that initially enhanced recruitment of granulocytes contributes to susceptibility to tuberculosis. PMID:16790804

  18. A candidate gene approach for the genetic analysis of susceptibility to tuberculosis

    SciTech Connect

    Morgan, K.; Liu, J.; Boothroyd, L.

    1994-09-01

    Tuberculosis is the most frequent and severe human disease caused by mycobacteria. In the mouse a candidate gene for innate resistance to mycobacteria (Bcg) was recently isolated and termed Nramp. We used SSCA and DNA sequencing to identify mutations in the human homologue, NRAMP, in chromosome region 2q35 in order to test if NRAMP contributes to susceptibility to tuberculosis. We have identified 16 sequence variants in or near NRAMP and defined haplotypes segregating in multiplex tuberculosis families from Canada, Columbia and Hong Kong. We defined a recessive susceptibility model for linkage analysis with four liability classes which take into account clinical status, age, exposure, and BCG vaccination. Our preliminary results support a role of NRAMP in tuberculosis susceptibility in an epidemic situation. This research was supported by grants from the Medical Research Council of Canada and the Canadian Genetic Diseases Network.

  19. Borna disease virus-induced neuronal degeneration dependent on host genetic background and prevented by soluble factors.

    PubMed

    Wu, Yuan-Ju; Schulz, Herbert; Lin, Chia-Ching; Saar, Kathrin; Patone, Giannino; Fischer, Heike; Hübner, Norbert; Heimrich, Bernd; Schwemmle, Martin

    2013-01-29

    Infection of newborn rats with Borne disease virus (BDV) results in selective degeneration of granule cell neurons of the dentate gyrus (DG). To study cellular countermechanisms that might prevent this pathology, we screened for rat strains resistant to this BDV-induced neuronal degeneration. To this end, we infected hippocampal slice cultures of different rat strains with BDV and analyzed for the preservation of the DG. Whereas infected cultures of five rat strains, including Lewis (LEW) rats, exhibited a disrupted DG cytoarchitecture, slices of three other rat strains, including Sprague-Dawley (SD), were unaffected. However, efficiency of viral replication was comparable in susceptible and resistant cultures. Moreover, these rat strain-dependent differences in vulnerability were replicated in vivo in neonatally infected LEW and SD rats. Intriguingly, conditioned media from uninfected cultures of both LEW and SD rats could prevent BDV-induced DG damage in infected LEW hippocampal cultures, whereas infection with BDV suppressed the availability of these factors from LEW but not in SD hippocampal cultures. To gain further insights into the genetic basis for this rat strain-dependent susceptibility, we analyzed DG granule cell survival in BDV-infected cultures of hippocampal neurons derived from the F1 and F2 offspring of the crossing of SD and LEW rats. Genome-wide association analysis revealed one resistance locus on chromosome (chr) 6q16 in SD rats and, surprisingly, a locus on chr3q21-23 that was associated with susceptibility. Thus, BDV-induced neuronal degeneration is dependent on the host genetic background and is prevented by soluble protective factors in the disease-resistant SD rat strain. PMID:23319640

  20. Results of the BRD CAP project: progress toward identifying genetic markers associated with BRD susceptibility.

    PubMed

    Van Eenennaam, Alison; Neibergs, Holly; Seabury, Christopher; Taylor, Jeremy; Wang, Zeping; Scraggs, Erik; Schnabel, Robert D; Decker, Jared; Wojtowicz, Andrzej; Aly, Sharif; Davis, Jessica; Blanchard, Patricia; Crossley, Beate; Rossitto, Paul; Lehenbauer, Terry; Hagevoort, Robert; Chavez, Erik; Neibergs, J Shannon; Womack, James E

    2014-12-01

    The Bovine Respiratory Disease Coordinated Agricultural Project (BRD CAP) is a 5-year project funded by the United States Department of Agriculture (USDA), with an overriding objective to use the tools of modern genomics to identify cattle that are less susceptible to BRD. To do this, two large genome wide association studies (GWAS) were conducted using a case:control design on preweaned Holstein dairy heifers and beef feedlot cattle. A health scoring system was used to identify BRD cases and controls. Heritability estimates for BRD susceptibility ranged from 19 to 21% in dairy calves to 29.2% in beef cattle when using numerical scores as a semi-quantitative definition of BRD. A GWAS analysis conducted on the dairy calf data showed that single nucleotide polymorphism (SNP) effects explained 20% of the variation in BRD incidence and 17-20% of the variation in clinical signs. These results represent a preliminary analysis of ongoing work to identify loci associated with BRD. Future work includes validation of the chromosomal regions and SNPs that have been identified as important for BRD susceptibility, fine mapping of chromosomes to identify causal SNPs, and integration of predictive markers for BRD susceptibility into genetic tests and national cattle genetic evaluations. PMID:25384903

  1. EXPERIMENTAL INDUCTION OF CHRONIC PULMONARY DISEASE IN GENETICALLY SUSCEPTIBLE RAT MODEL

    EPA Science Inventory



    Experimental induction of chronic pulmonary disease in genetically susceptible rat model. M.C.Schladweiler, BS 1, A.D.Ledbetter 1, K.E.Pinkerton, PhD 2, K.R.Smith, PhD 2, P.S.Gilmour, PhD 1, P.A.Evansky 1, D.L.Costa, ScD 1, W.P.Watkinson, PhD 1, J.P.Nolan 1 and U.P.Kodava...

  2. Genetic and Molecular Functional Characterization of Variants within TNFSF13B, a Positional Candidate Preeclampsia Susceptibility Gene on 13q

    PubMed Central

    Roten, Linda T.; Aas, Per A.; Forsmo, Siri; Klepper, Kjetil; East, Christine E.; Abraham, Lawrence J.; Blangero, John; Brennecke, Shaun P.; Austgulen, Rigmor; Moses, Eric K.

    2010-01-01

    Background Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility. Methodology/Principal Findings The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion) were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals). Borderline association to preeclampsia (p = 0.0153) was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946) in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/control cohort (The Nord-Trøndelag Health Study (HUNT2), 851 preeclamptic and 1,440 non-preeclamptic women). Conclusion/Significance TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in preeclampsia pathogenesis, and propose the rs16972194 variant as a candidate for further functional evaluation. PMID:20927378

  3. CTLA4 Variants and Haplotype Contribute Genetic Susceptibility to Myasthenia Gravis in Northern Chinese Population

    PubMed Central

    Xie, Yanchen; Zhang, Hua; Zhang, Zheng; Wang, Xiaoxia; Jiang, Bin; Li, Wei; Li, Yao; Yang, Ze

    2014-01-01

    Background Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a critical negative regulator of the T-cell response, has been considered a candidate for many autoimmune diseases. Evidence from Caucasians supported a genetic predisposition of CTLA4 to myasthenia gravis (MG), but the contribution in East Asians has not been established. Objectives To investigate the role of CTLA4 variants in the susceptibility to MG and the contribution to subtypes of MG. Methods Six autoimmune disease-related risk alleles of CTLA4 (rs1863800, rs733618, rs4553808, rs5742909, rs231775, and rs3087243) were investigated for MG in northern Chinese. 168 patients with MG (mean age 37.120.5 years, 64 men and 104 women) and 233 healthy controls (mean age 53.38.7 years, 96 men and 137 women) were screened, and the contribution of CTLA4 to the general risk of MG and each subgroup was explored. Results rs1863800*C, rs733618*C, and rs231775*G were significantly associated with the whole cohort of patients with MG after permutation correction for multiple-testing adjustment (P?=?0.027, 0.001, and 0.032, respectively). A risk haplotype (CCACG) [odds ratio (OR)?=?1.535, range?=?1.1502.059, P?=?0.004)] was also identified. The stratified subtype analysis indicated that the positive contribution was possibly derived from early onset MG (EOMG), seropositive MG (SPMG), female patients, and MG without thymoma. No association was observed in juvenile MG/LOMG, and MG coupled with thymoma. Conclusion A predisposing effect of rs1863800*C, rs733618*C, and rs231775*G of CTLA4 gene to general risk of MG in Chinese was demonstrated for the first time, which was likely derived from EOMG, SPMG, MG without thymoma and the female patients. PMID:25003519

  4. Genetic relatedness, antimicrobial and biocide susceptibility comparative analysis of methicillin-resistant and -susceptible Staphylococcus pseudintermedius from Portugal.

    PubMed

    Couto, Natacha; Belas, Adriana; Couto, Isabel; Perreten, Vincent; Pomba, Constança

    2014-08-01

    Forty methicillin-resistant and -susceptible Staphylococcus pseudintermedius (MRSP and MSSP, respectively) from colonization and infection in dogs and cats were characterized for clonality, antimicrobial, and biocide susceptibility. MSSP were genetically more diverse than MRSP by multi-locus sequence typing and pulsed-field gel electrophoresis. Three different spa types (t06, t02, t05) and two SCCmec types (II-III and V) were detected in the MRSP isolates. All MRSP and two MSSP strains were multidrug-resistant. Several antibiotic resistance genes (mecA, blaZ, tet(M), tet(K), aac(6')-Ie-aph(2')-Ia, aph(3')-III, ant(6)-Ia, sat4, erm(B), lnu(A), dfr(G), and catp(C221)) were identified by microarray and double mutations in the gyrA and grlA genes and a single mutation in the rpoB gene were detected by sequence analysis. No differences were detected between MSSP and MRSP in the chlorhexidine acetate (CHA) minimum inhibitory concentrations (MICs). However, two MSSP had elevated MIC to triclosan (TCL) and one to benzalkonium chloride and ethidium bromide. One MSSP isolate harboured a qacA gene, while in another a qacB gene was detected. None of the isolates harboured the sh-fabI gene. Three of the biocide products studied had high bactericidal activity (Otodine(®), Clorexyderm Spot Gel(®), Dermocanis Piocure-M(®)), while Skingel(®) failed to achieve a five log reduction in the bacterial counting. S. pseudintermedius have become a serious therapeutic challenge in particular if methicillin- resistance and/or multidrug-resistance are involved. Biocides, like CHA and TCL, seem to be clinically effective and safe topical therapeutic options. PMID:23819785

  5. Cellular basis of the genetic susceptibility of murine experimental allergic encephalomyelitis

    SciTech Connect

    Binder, T.A.; Greiner, D.L.; Goldschneider, I.

    1986-03-01

    Murine experimental allergic encephalomyelitis (EAE) is an induced autoimmune disease that resembles human multiple sclerosis. The authors have investigated the cellular basis of the genetic predisposition and resistance of inbred strains of mice to EAE using an adoptive transfer system between two H-2 compatible, Thy 1 antigen disparate strains of mice. Genetically EAE susceptible SJL/J strain mice (H-2/sup s/, Thy 1.2) and resistant B10.S Thy 1.1 (H-2/sub s/, Thy 1.1) strain mice were lethally irradiated (700R) and reconstituted with 5-10 x 10/sup 6/ bone marrow cells from either SJL/J or congenic B10.S (Thy 1.1 or Thy 1.2) donors. After 30-45 days, more than 95% of the thymocytes and 75% of the peripheral T cells in the chimeras were of donor origin. These lymphohemopoietic chimeras were then sensitized in their hind footpads with porcine myelin basic protein in complete Freund's adjuvant containing M. tuberculosis H/sub 37/RA, followed at 24 and 72 hours by i.v. injection of B. pertussis. Clinical signs of EAE developed in unirradiated SJL/J, but not B10.S, controls, and in irradiated B10.S and SJL/J recipients of SJL/J, but not B10.S, bone marrow. These results indicate that bone marrow cells can transfer the predisposition to EAE from genetically susceptible to genetically resistant mouse strains. The cellular component in the bone marrow that is responsible for the transfer of the genetic susceptibility to EAE is under investigation.

  6. Validation of Six Genetic Determinants of Susceptibility to Estrogen-Induced Mammary Cancer in the Rat and Assessment of Their Relevance to Breast Cancer Risk in Humans

    PubMed Central

    Colletti, John A.; Leland-Wavrin, Kristin M.; Kurz, Scott G.; Hickman, Maureen Peters; Seiler, Nicole L.; Samanas, Nyssa Becker; Eckert, Quincy A.; Dennison, Kirsten L.; Ding, Lina; Schaffer, Beverly S.; Shull, James D.

    2014-01-01

    When treated with 17?-estradiol, female ACI rats (Rattus norvegicus) rapidly develop mammary cancers that share multiple phenotypes with luminal breast cancers. Seven distinct quantitative trait loci that harbor genetic determinants of susceptibility to 17?-estradiol?induced mammary cancer have been mapped in reciprocal intercrosses between susceptible ACI rats and resistant Brown Norway (BN) rats. A panel of unique congenic rat strains has now been generated and characterized to confirm the existence of these quantitative trait loci, designated Emca3 through Emca9, and to quantify their individual effects on susceptibility to 17?-estradiol?induced mammary cancer. Each congenic strain carries BN alleles spanning an individual Emca locus, introgressed onto the ACI genetic background. Data presented herein indicate that BN alleles at Emca3, Emca4, Emca5, Emca6, and Emca9 reduce susceptibility to 17?-estradiol?induced mammary cancer, whereas BN alleles at Emca7 increase susceptibility, thereby confirming the previous interval mapping data. All of these Emca loci are orthologous to regions of the human genome that have been demonstrated in genome-wide association studies to harbor genetic variants that influence breast cancer risk. Moreover, four of the Emca loci are orthologous to loci in humans that have been associated with mammographic breast density, a biomarker of breast cancer risk. This study further establishes the relevance of the ACI and derived congenic rat models of 17?-estradiol?induced mammary cancer for defining the genetic bases of breast cancer susceptibility and elucidating the mechanisms through which 17?-estradiol contributes to breast cancer development. PMID:24875630

  7. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    PubMed Central

    2011-01-01

    Background Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. Methods CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. Results None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1.00-1.25, P-value = 0.04, log-additive 0, 1, 2 alleles) and borderline significant for rs698 and rs2102302. The rs3803185 variant was not significantly associated with CRC risk in an external cohort (MCC-Spain), but it still showed some borderline significance in the pooled analysis of both cohorts (OR = 1.08, 95% CI = 0.98-1.18, P-value = 0.09, log-additive 0, 1, 2 alleles). Conclusions ARL11, ADH1C, GALNTL2 and IL6 genetic variants may have an effect on CRC risk. Further validation and meta-analyses should be undertaken in larger CRC studies. PMID:21819567

  8. CHEMICALLY AND GENETICALLY IMMUNOCOMPROMISED MICE ARE NOT MORE SUSCEPTIBLE THAN IMMUNOCOMPETENT MICE TO INFECTION WITH CRYPTOSPORIDIUM MURIS

    EPA Science Inventory

    The prevailing paradigm is that immunosuppressed individuals are more susceptible to infection and are at higher risk of infection from Cryptosporidium oocysts if present in drinking water. To test this hypothesis, three immune conditions were examined: genetically immunocomprom...

  9. Obstructive Sleep Apnea Susceptibility Genes in Chinese Population: A Field Synopsis and Meta-Analysis of Genetic Association Studies

    PubMed Central

    Tu, Chunlin; Zhong, Anyuan; Xu, Huajun

    2015-01-01

    Background Epidemiological studies to date have evaluated the association between genetic variants and the susceptibility to obstructive sleep apnea (OSA). However, the results of these studies have been inconclusive. In this current study we performed meta-analysis of genetic association studies (GAS) to pool OSA-susceptible genes in Chinese population, to perform a more precise evaluation of the association. Methods Various databases (i.e., PubMed, EMBASE, HuGE Navigator, Wanfang and CNKI) were searched to identify all eligible GAS-related variants associated with susceptibility to OSA. The generalized odds ratio metric (ORG) and the odds ratio (OR) of the allele contrast were used to quantify the impact of genetic variants on the risk of OSA. Cumulative and recursive cumulative meta-analyses (CMA) were also performed to investigate the trend and stability of effect sizes as evidence was accumulated. Results Thirty-two GAS evaluating 13 polymorphisms in 10 genes were included in our meta-analysis. Significant associations were derived for four polymorphisms either for the allele contrast or for the ORG. The variants TNF-α-308G/A, 5-HTTLPR, 5-HTTVNTR, and APOE showed marginal significance for ORG (95% confidence interval [CI]): 2.01(1.31–3.07); 1.31(1.09–1.58); 1.85(1.16–2.95); 1.79(1.10–2.92); and 1.79(1.10–2.92) respectively. In addition, the TNF-α-308G/A, 5-HTTLPR, and 5-HTTVNTR variants showed significance for the allele contrast: 2.15(1.39–3.31); 2.26(1.58–3.24); 1.32(1.12–1.55); and 1.86(1.12–3.08) respectively. CMA showed a trend towards an association, and recursive CMA indicated that more evidence was needed to determine whether this was significant. Conclusions TNF-α, 5-HTT, and APOE genes can all be proposed as OSA-susceptibility genes in Chinese population. Genome-wide association studies (GWAS) are therefore urgently needed to confirm our findings within a larger sample of OSA patients in China. PMID:26284518

  10. Tuberculin Skin Test Reactivity Is Dependent on Host Genetic Background in Colombian Tuberculosis Household Contacts

    PubMed Central

    Cobat, Aurélie; Barrera, Luis F.; Henao, Hanna; Arbeláez, Patricia; Abel, Laurent; García, Luis F.; Schurr, Erwin

    2012-01-01

    The tuberculin skin test (TST) measures the intensity of antimycobacterial acquired immunity and is used to diagnose latent infection with Mycobacterium tuberculosis. We report evidence for a codominant gene explaining ∼65% of the TST variability. Disregarding the host genetic background may lead to misclassifications of TST-based diagnosis of latent M. tuberculosis infection. PMID:22291100

  11. GENETIC BACKGROUND BUT NOT METALLOTHIONEIN PHENOTYPE DICTATES SENSITIVITY TO CADMIUM-INDUCED TESTICULAR INJURY IN MICE

    EPA Science Inventory

    Genetic Background but not Metallothionein Phenotype Dictates Sensitivity to
    Cadmium-Induced Testicular Injury in Mice

    Jie Liu1,2, Chris Corton3, David J. Dix4, Yaping Liu1, Michael P. Waalkes2
    and Curtis D. Klaassen1

    ABSTRACT

    Parenteral administrati...

  12. Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

    PubMed

    Xu, Ke; Ma, Lu; Li, Yang; Wang, Fang; Zheng, Gu-Yan; Sun, Zhijun; Jiang, Feng; Chen, Yundai; Liu, Huirong; Dang, Aimin; Chen, Xi; Chun, Jerold; Tian, Xiao-Li

    2015-09-01

    Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.0910(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.7310(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. PMID:26123684

  13. The genetic basis of aminoglycoside ototoxicity: The search for susceptibility genes

    SciTech Connect

    Prezant, T.R.; Fischel-Ghodsian, F.

    1994-09-01

    The susceptibility to aminoglycoside ototoxicity appears to be genetically determined. Recently we identified a mutation in the small ribosomal RNA gene of the mitochondrial DNA that can cause deafness after aminoglycoside treatment in families with maternally-inherited susceptibility to the ototoxic effect of these antibiotics. The mutation produces a structural change in the 12S rRNA, which allows increased binding of aminoglycosides, mistranslation of mitochondrial proteins, decreased energy production, and cell death. Because only a minority of sporadic patients have mutations in the 12S rRNA gene, we anticipate the involvement of other genes in ototoxic deafness. We have developed a model system in the yeast Saccharomyces cerevisiae to functionally identify genes whose products interact with aminoglycosides. Besides its small genome size and well-developed genetic tools, a unique advantage of using this haploid organism is that recessive drug-responsive mutations will not be missed. An additional advantage is that yeast can be grown in either fermentative or respiratory media, allowing the functional categorization of mutants. Over 100 antibiotic-resistant mutants have now been isolated. The majority of these mutations (69%) are dominant and are being sorted by segregation tests. The 31% of mutations that are recessive have been sorted into two major complementation groups, indicating that two genes appear to be responsible for most of the recessive cases. Our strategy is to isolate the yeast genes that most commonly acquire mutations, clone the human homologs, and screen patients for susceptibility mutations.

  14. Genetic variant in CXCL13 gene is associated with susceptibility to intrauterine infection of hepatitis B virus.

    PubMed

    Wan, Zhihua; Lin, Xiaofang; Li, Tongyang; Zhou, Aifen; Yang, Mei; Hu, Dan; Feng, Li; Peng, Songxu; Fan, Linlin; Tu, Si; Bin Zhang; Du, Yukai

    2016-01-01

    Intrauterine infection of hepatitis B virus (HBV), which accounts for the majority of mother-to-child transmission, is one of the main reasons for the failure of combined immunoprophylaxis against the transmission. Recent studies have identified that genetic background might influence the susceptibility to intrauterine infection of HBV. We conducted this study to investigate the associations between 10 genetic variants in 9 genes (SLC10A1, HLA-DP, HLA-C, CXCR5, CXCL13, TLR3, TLR4, TLR9 and UBE2L3) of mothers and their neonates and HBV intrauterine infection. A significantly decreased risk of HBV intrauterine transmission were found among mothers who carried the rs355687 CT genotypes in CXCL13 gene compared to those with CC genotypes (OR = 0.25, 95% CI, 0.08-0.82, P = 0.022); and a marginally significantly decreased risk was also observed under the dominant model (OR = 0.34, 95% CI, 0.11-1.01, P = 0.052). Besides, neonatal rs3130542 in HLA-C gene was found to be marginally significantly associated with decreased risk of HBV intrauterine infection under the additive model (OR = 0.55, 95% CI, 0.29-1.04, P = 0.064). However, we found no evidence of associations between the remaining 8 SNPs and risk of HBV intrauterine infection among mothers and their neonates. In conclusion, this study suggested that genetic variant in CXCL13 gene was associated with susceptibility to intrauterine infection of HBV. PMID:27212637

  15. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds

    NASA Astrophysics Data System (ADS)

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-11-01

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO.

  16. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds

    PubMed Central

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-01-01

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO. PMID:26611622

  17. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds.

    PubMed

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-01-01

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO. PMID:26611622

  18. Genetic Background, Maternal Age, and Interaction Effects Mediate Rates of Crossing Over in Drosophila melanogaster Females

    PubMed Central

    Hunter, Chad M.; Robinson, Matthew C.; Aylor, David L.; Singh, Nadia D.

    2016-01-01

    Meiotic recombination is a genetic process that is critical for proper chromosome segregation in many organisms. Despite being fundamental for organismal fitness, rates of crossing over vary greatly between taxa. Both genetic and environmental factors contribute to phenotypic variation in crossover frequency, as do genotype–environment interactions. Here, we test the hypothesis that maternal age influences rates of crossing over in a genotypic-specific manner. Using classical genetic techniques, we estimated rates of crossing over for individual Drosophila melanogaster females from five strains over their lifetime from a single mating event. We find that both age and genetic background significantly contribute to observed variation in recombination frequency, as do genotype–age interactions. We further find differences in the effect of age on recombination frequency in the two genomic regions surveyed. Our results highlight the complexity of recombination rate variation and reveal a new role of genotype by maternal age interactions in mediating recombination rate. PMID:26994290

  19. Genetic Background, Maternal Age, and Interaction Effects Mediate Rates of Crossing Over in Drosophila melanogaster Females.

    PubMed

    Hunter, Chad M; Robinson, Matthew C; Aylor, David L; Singh, Nadia D

    2016-01-01

    Meiotic recombination is a genetic process that is critical for proper chromosome segregation in many organisms. Despite being fundamental for organismal fitness, rates of crossing over vary greatly between taxa. Both genetic and environmental factors contribute to phenotypic variation in crossover frequency, as do genotype-environment interactions. Here, we test the hypothesis that maternal age influences rates of crossing over in a genotypic-specific manner. Using classical genetic techniques, we estimated rates of crossing over for individual Drosophila melanogaster females from five strains over their lifetime from a single mating event. We find that both age and genetic background significantly contribute to observed variation in recombination frequency, as do genotype-age interactions. We further find differences in the effect of age on recombination frequency in the two genomic regions surveyed. Our results highlight the complexity of recombination rate variation and reveal a new role of genotype by maternal age interactions in mediating recombination rate. PMID:26994290

  20. Relative susceptibilities of male germ cells to genetic defects induced by cancer chemotherapies

    SciTech Connect

    Wyrobek, A J; Schmid, T E; Marchetti, F

    2004-06-15

    Some chemotherapy regimens include agents that are mutagenic or clastogenic in model systems. This raises concerns that cancer survivors, who were treated before or during their reproductive years, may be at increased risks for abnormal reproductive outcomes. However, the available data from offspring of cancer survivors are limited, representing diverse cancers, therapies, time-to-pregnancies, and reproductive outcomes. Rodent breeding data after paternal exposures to individual chemotherapeutic agents illustrate the complexity of factors that influence the risk for transmitted genetic damage including agent, dose, endpoint, and the germ-cell susceptibility profiles that vary across agents. Direct measurements of chromosomal abnormalities in sperm of mice and humans by sperm FISH have corroborated the differences in germ-cell susceptibilities. The available evidence suggests that the risk of producing chromosomally defective sperm is highest during the first few weeks after the end of chemotherapy, and decays with time. Thus, sperm samples provided immediately after the initiation of cancer therapies may contain treatment-induced genetic defects that will jeopardize the genetic health of offspring.

  1. No association between genetic ancestry and susceptibility to asthma or atopy in Canary Islanders.

    PubMed

    Pino-Yanes, María; Corrales, Almudena; Cumplido, José; González, Ruperto; Torres-Galván, María José; Fernández, Orlando Acosta; Sánchez-Machín, Inmaculada; Figueroa, Javier; Sánchez-Palacios, Anselmo; Villar, Jesús; Hernández, Mariano; Carrillo, Teresa; Flores, Carlos

    2012-09-01

    Asthma is a complex respiratory disease characterized by chronic inflammation of airways and frequently associated with atopic symptoms. The population from the Canary Islands, which has resulted from a recent admixture of North African and Iberian populations, shows the highest prevalence of asthma and atopic symptoms among the Spanish populations. Although environmental particularities would account for the majority of such disparity, genetic ancestry might play a role in increasing the susceptibility of asthma or atopy, as have been demonstrated in other recently African-admixed populations. Here, we aimed to explore whether genetic ancestry was associated with asthma or related traits in the Canary Islanders. For that, a total of 734 DNA samples from unrelated individuals of the GOA study, self-reporting at least two generations of ancestors from the Canary Islands (391 asthmatics and 343 controls), were successfully genotyped for 83 ancestry informative markers (AIMs), which allowed to precisely distinguishing between North African and Iberian ancestries. No association was found between genetic ancestry and asthma or related traits after adjusting by demographic variables differing among compared groups. Similarly, none of the individual AIMs was associated with asthma when results were considered in the context of the multiple comparisons performed (0.005 ≤ p value ≤ 0.042; 0.221 ≤ q value ≤ 0.443). Our results suggest that if genetic ancestry were involved in the susceptibility to asthma or related traits among Canary Islanders, its effects would be modest. Larger studies, examining more genetic variants, would be needed to explore such possibility. PMID:22710824

  2. Antibacterial resistance, genes encoding toxins and genetic background among Staphylococcus aureus isolated from community-acquired skin and soft tissue infections in France: a national prospective survey.

    PubMed

    Lamy, B; Laurent, F; Gallon, O; Doucet-Populaire, F; Etienne, J; Decousser, J-W

    2012-06-01

    The epidemiology of staphylococcal community-acquired skin and soft tissues infections (CA-SSTIs) has changed dramatically. We described prospectively the characteristics of the Staphylococcus aureus isolated from 71 non-teaching French hospitals and implicated in CA-SSTIs: antimicrobial susceptibility (mecA polymerase chain reaction [PCR], disk diffusion method), virulence factor gene (sea, tst, pvl) prevalence and genetic background (agr allele). During November 2006, 235 strains were collected (wound infection: 51%, abscess: 21%, whitlow: 8%, diabetic foot: 7%, furunculosis: 3%). sea, tst and pvl were identified in 22.1, 13.2 and 8.9% strains, respectively. agr allele 1 was the most frequently encountered genetic background, whatever the methicillin susceptibility. Among the 34 methicillin-resistant S. aureus (MRSA, 14.5% of all S. aureus), only one strain (2.9%) harboured pvl (belonging to the European ST80 clone), four (11.8%) tst (belonging to two endemic French clones) and 18 (52.9%) sea gene (mainly the Lyon clone). According to their in vitro activity, pristinamycin or trimethoprim/sulfamethoxazole could be considered as first-choice antibiotics. To date, the international pvl-positive MRSA clones have not spread in France. MRSA strains isolated from putative CA-SSTIs exhibited a genetic and phenotypic background of hospital-acquired (HA) clones. National survey should be continued, in order to monitor the emergence of virulent clones. PMID:21997773

  3. Enhanced biofilm formation and multi-host transmission evolve from divergent genetic backgrounds in Campylobacter jejuni.

    PubMed

    Pascoe, Ben; Méric, Guillaume; Murray, Susan; Yahara, Koji; Mageiros, Leonardos; Bowen, Ryan; Jones, Nathan H; Jeeves, Rose E; Lappin-Scott, Hilary M; Asakura, Hiroshi; Sheppard, Samuel K

    2015-11-01

    Multicellular biofilms are an ancient bacterial adaptation that offers a protective environment for survival in hostile habitats. In microaerophilic organisms such as Campylobacter, biofilms play a key role in transmission to humans as the bacteria are exposed to atmospheric oxygen concentrations when leaving the reservoir host gut. Genetic determinants of biofilm formation differ between species, but little is known about how strains of the same species achieve the biofilm phenotype with different genetic backgrounds. Our approach combines genome-wide association studies with traditional microbiology techniques to investigate the genetic basis of biofilm formation in 102 Campylobacter jejuni isolates. We quantified biofilm formation among the isolates and identified hotspots of genetic variation in homologous sequences that correspond to variation in biofilm phenotypes. Thirteen genes demonstrated a statistically robust association including those involved in adhesion, motility, glycosylation, capsule production and oxidative stress. The genes associated with biofilm formation were different in the host generalist ST-21 and ST-45 clonal complexes, which are frequently isolated from multiple host species and clinical samples. This suggests the evolution of enhanced biofilm from different genetic backgrounds and a possible role in colonization of multiple hosts and transmission to humans. PMID:26373338

  4. Effect of genetic background on the dystrophic phenotype in mdx mice.

    PubMed

    Coley, William D; Bogdanik, Laurent; Vila, Maria Candida; Yu, Qing; Van Der Meulen, Jack H; Rayavarapu, Sree; Novak, James S; Nearing, Marie; Quinn, James L; Saunders, Allison; Dolan, Connor; Andrews, Whitney; Lammert, Catherine; Austin, Andrew; Partridge, Terence A; Cox, Gregory A; Lutz, Cathleen; Nagaraju, Kanneboyina

    2016-01-01

    Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits. PMID:26566673

  5. Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome.

    PubMed

    Rubinstein, Moran; Westenbroek, Ruth E; Yu, Frank H; Jones, Christina J; Scheuer, Todd; Catterall, William A

    2015-01-01

    Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1(+/-) Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic background have many fewer seizures and much less premature death than in pure C57BL/6 background. These mice also have a higher threshold for thermally induced seizures, fewer myoclonic seizures, and no cognitive impairment, similar to patients with Genetic Epilepsy with Febrile Seizures Plus. Consistent with this mild phenotype, mutation of NaV1.1 channels has much less physiological effect on neuronal excitability in 129/SvJ mice. In hippocampal slices, the excitability of CA1 Stratum Oriens interneurons is selectively impaired, while the excitability of CA1 pyramidal cells is unaffected. NaV1.1 haploinsufficiency results in increased rheobase and threshold for action potential firing and impaired ability to sustain high-frequency firing. Moreover, deletion of NaV1.1 markedly reduces the amplification and integration of synaptic events, further contributing to reduced excitability of interneurons. Excitability is less impaired in inhibitory neurons of Dravet Syndrome mice in 129/SvJ genetic background. Because specific deletion of NaV1.1 in forebrain GABAergic interneuons is sufficient to cause the symptoms of Dravet Syndrome in mice, our results support the conclusion that the milder phenotype in 129/SvJ mice is caused by lesser impairment of sodium channel function and electrical excitability in their forebrain interneurons. This mild impairment of excitability of interneurons leads to a milder disease phenotype in 129/SvJ mice, similar to Genetic Epilepsy with Febrile Seizures Plus in humans. PMID:25281316

  6. Genetic Background Modulates Impaired Excitability of Inhibitory Neurons in a Mouse Model of Dravet Syndrome

    PubMed Central

    Rubinstein, Moran; Westenbroek, Ruth E.; Yu, Frank H.; Jones, Christina J.; Scheuer, Todd; Catterall, William A.

    2014-01-01

    Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1+/− Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic background have many fewer seizures and much less premature death than in pure C57BL/6 background. These mice also have a higher threshold for thermally induced seizures, fewer myoclonic seizures, and no cognitive impairment, similar to patients with Genetic Epilepsy with Febrile Seizures Plus. Consistent with this mild phenotype, mutation of NaV1.1 channels has much less physiological effect on neuronal excitability in 129/SvJ mice. In hippocampal slices, the excitability of CA1 Stratum Oriens interneurons is selectively impaired, while the excitability of CA1 pyramidal cells is unaffected. NaV1.1 haploinsufficiency results in increased rheobase and threshold for action potential firing and impaired ability to sustain high-frequency firing. Moreover, deletion of NaV1.1 markedly reduces the amplification and integration of synaptic events, further contributing to reduced excitability of interneurons. Excitability is less impaired in inhibitory neurons of Dravet Syndrome mice in 129/SvJ genetic background. Because specific deletion of NaV1.1 in forebrain GABAergic interneuons is sufficient to cause the symptoms of Dravet Syndrome in mice, our results support the conclusion that the milder phenotype in 129/SvJ mice is caused by lesser impairment of sodium channel function and electrical excitability in their forebrain interneurons. This mild impairment of excitability of interneurons leads to a milder disease phenotype in 129/SvJ mice, similar to Genetic Epilepsy with Febrile Seizures Plus in humans. PMID:25281316

  7. p27 variant and corticotropinoma susceptibility: a genetic and in vitro study.

    PubMed

    Sekiya, Tomoko; Bronstein, Marcello D; Benfini, Katiuscia; Longuini, Viviane C; Jallad, Raquel S; Machado, Marcio C; Goncalves, Tatiana D; Osaki, Luciana H; Higashi, Leonardo; Viana-Jr, Jose; Kater, Claudio; Lee, Misu; Molatore, Sara; Francisco, Guilherme; Chammas, Roger; Naslavsky, Michel S; Schlesinger, David; Gama, Patricia; Duarte, Yeda A O; Lebro, Maria Lucia; Zatz, Mayana; Meirelles, Osorio; Liberman, Bernardo; Fragoso, Maria Candida B V; Toledo, Sergio P A; Pellegata, Natalia S; Toledo, Rodrigo A

    2014-06-01

    Germline mutations in p27(kip1) are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far. PMID:24532476

  8. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy.

    PubMed

    Jodele, Sonata; Zhang, Kejian; Zou, Fanggeng; Laskin, Benjamin; Dandoy, Christopher E; Myers, Kasiani C; Lane, Adam; Meller, Jaroslav; Medvedovic, Mario; Chen, Jenny; Davies, Stella M

    2016-02-25

    Transplant-associated thrombotic microangiopathy (TA-TMA) occurs frequently after hematopoietic stem cell transplantation (HSCT) and can lead to significant morbidity and mortality. There are no data addressing individual susceptibility to TA-TMA. We performed a hypothesis-driven analysis of 17 candidate genes known to play a role in complement activation as part of a prospective study of TMA in HSCT recipients. We examined the functional significance of gene variants by using gene expression profiling. Among 77 patients undergoing genetic testing, 34 had TMA. Sixty-five percent of patients with TMA had genetic variants in at least one gene compared with 9% of patients without TMA (P < .0001). Gene variants were increased in patients of all races with TMA, but nonwhites had more variants than whites (2.5 [range, 0-7] vs 0 [range, 0-2]; P < .0001). Variants in ≥3 genes were identified only in nonwhites with TMA and were associated with high mortality (71%). RNA sequencing analysis of pretransplantation samples showed upregulation of multiple complement pathways in patients with TMA who had gene variants, including variants predicted as possibly benign by computer algorithm, compared with those without TMA and without gene variants. Our data reveal important differences in genetic susceptibility to HSCT-associated TMA based on recipient genotype. These data will allow prospective risk assessment and intervention to prevent TMA in highly susceptible transplant recipients. Our findings may explain, at least in part, racial disparities previously reported in transplant recipients and may guide treatment strategies to improve outcomes. PMID:26603840

  9. Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

    PubMed

    Dalton, Elizabeth D; Hammen, Constance L; Najman, Jake M; Brennan, Patricia A

    2014-12-01

    Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men. PMID:25347540

  10. Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease: a genetic association study

    PubMed Central

    2010-01-01

    Introduction Streptococcus pneumoniae remains a major global health problem and a leading cause of death in children worldwide. The factors that influence development of pneumococcal sepsis remain poorly understood, although increasing evidence points towards a role for genetic variation in the host's immune response. Recent insights from the study of animal models, rare human primary immunodeficiency states, and population-based genetic epidemiology have focused attention on the role of the proinflammatory transcription factor NF-κB in pneumococcal disease pathogenesis. The possible role of genetic variation in the atypical NF-κB inhibitor IκB-R, encoded by NFKBIL2, in susceptibility to invasive pneumococcal disease has not, to our knowledge, previously been reported upon. Methods An association study was performed examining the frequencies of nine common NFKBIL2 polymorphisms in two invasive pneumococcal disease case-control groups: European individuals from hospitals in Oxfordshire, UK (275 patients and 733 controls), and African individuals from Kilifi District Hospital, Kenya (687 patients with bacteraemia, of which 173 patients had pneumococcal disease, together with 550 controls). Results Five polymorphisms significantly associated with invasive pneumococcal disease susceptibility in the European study, of which two polymorphisms also associated with disease in African individuals. Heterozygosity at these loci was associated with protection from invasive pneumococcal disease (rs760477, Mantel-Haenszel 2 × 2 χ2 = 11.797, P = 0.0006, odds ratio = 0.67, 95% confidence interval = 0.53 to 0.84; rs4925858, Mantel-Haenszel 2 × 2 χ2 = 9.104, P = 0.003, odds ratio = 0.70, 95% confidence interval = 0.55 to 0.88). Linkage disequilibrium was more extensive in European individuals than in Kenyans. Conclusions Common NFKBIL2 polymorphisms are associated with susceptibility to invasive pneumococcal disease in European and African populations. These findings further highlight the importance of control of NF-κB in host defence against pneumococcal disease. PMID:21171993

  11. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement.

    PubMed

    2005-09-01

    This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility, along with the supporting scientific evidence. The complete information on which this statement is based, including evidence tables and references, is included in the evidence synthesis available through the USPSTF Web site (http://www.preventiveservices.ahrq.gov). The recommendation is also posted on the Web site of the National Guideline Clearinghouse (http://www.guideline.gov). PMID:16144894

  12. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

    PubMed Central

    Kasperavičiūtė, Dalia; Catarino, Claudia B.; Heinzen, Erin L.; Depondt, Chantal; Cavalleri, Gianpiero L.; Caboclo, Luis O.; Tate, Sarah K.; Jamnadas-Khoda, Jenny; Chinthapalli, Krishna; Clayton, Lisa M.S.; Shianna, Kevin V.; Radtke, Rodney A.; Mikati, Mohamad A.; Gallentine, William B.; Husain, Aatif M.; Alhusaini, Saud; Leppert, David; Middleton, Lefkos T.; Gibson, Rachel A.; Johnson, Michael R.; Matthews, Paul M.; Hosford, David; Heuser, Kjell; Amos, Leslie; Ortega, Marcos; Zumsteg, Dominik; Wieser, Heinz-Gregor; Steinhoff, Bernhard J.; Krämer, Günter; Hansen, Jörg; Dorn, Thomas; Kantanen, Anne-Mari; Gjerstad, Leif; Peuralinna, Terhi; Hernandez, Dena G.; Eriksson, Kai J.; Kälviäinen, Reetta K.; Doherty, Colin P.; Wood, Nicholas W.; Pandolfo, Massimo; Duncan, John S.; Sander, Josemir W.; Delanty, Norman

    2010-01-01

    Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies. PMID:20522523

  13. [Novel methods and their applicability in the evaluation of the genetic background of endocrine system tumours].

    PubMed

    Patcs, Attila; Lik, Istvn; Butz, Henriett; Baghy, Kornlia; Rcz, Kroly

    2015-12-20

    The technical developments leading to revolution in clinical genetic testing offer new approaches for patients with cancer. From one mutation or one gene approach the scale of genetic testing moved to whole exome or whole genome scale. It is well known that many tumours are genetically determined and they are part of familial tumour syndromes. In addition, some mutations indicate specific molecular targeted therapies. Although sampling and sample preparation are different for testing germline and somatic mutations, the technical background of the analysis is the same. The aim of clinical genetic testing is to identify patients who are carriers of disease-causing mutations or to test tumour tissue for the presence of genetic alterations which may be targets for therapeutic approaches. In this review the authors summarize novel possibilities offered by next-generation sequencing in clinical genetic testing of patients with endocrine tumours. In addition, the authors review recent guidelines on technical and ethical issues related to these novel methods. PMID:26654542

  14. Genetic Variants in the SAMM50 Gene Create Susceptibility to Nonalcoholic Fatty Liver Disease in a Chinese Han Population

    PubMed Central

    Chen, Lizhen; Lin, Zhonghua; Jiang, Man; Lu, Linlin; Zhang, Haiying; Xin, Yongning; Jiang, Xiangjun; Xuan, Shiying

    2015-01-01

    Background: Genome-wide association studies have shown that rs738491, rs2143571, and rs3761472 in the sorting and assembly machinery component 50 homolog (SAMM50) gene are significantly associated with susceptibility to nonalcoholic fatty liver disease (NAFLD). Objectives: The present study evaluated the association between the three genetic variants in the SAMM50 gene and susceptibility to NAFLD in a Chinese Han population. Patients and Methods: Genotypes for 3 single nucleotide polymorphisms (SNPs), viz rs738491, rs2143571, and rs3761472, in the SAMM50 gene were determined using an improved multiplex ligation detection reaction technique in 340 B-type ultrasonography-diagnosed NAFLD patients and 452 healthy controls. Meanwhile, serum lipid profiles and liver enzymes were estimated using standard clinical laboratory methods. The SNP-SNP interactions were analyzed by performing multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality reduction (GMDR). Results: The genotype and allele frequencies of the SAMM50 polymorphisms between the NAFLD group and the control group were significantly different (all Ps < 0.05). In the multivariate analysis adjusted for gender, age, and body mass index, the carriers of the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele had significantly increased susceptibility to NAFLD (OR, 1.507; 95% CI, 1.035 to 2.195; P = 0.032; OR, 1.761; 95% CI, 1.232 to 2.517; P = 0.002; OR, 1.483; 95% CI, 1.039 to 2.115; P = 0.030, respectively). Moreover, the rs738491 T allele carriers had significantly higher levels of alanine aminotransferase (ALT) (P = 0.017) than did the noncarriers. However, differences in the levels of serum triglyceride (TG) and aspartate aminotransferase (AST) were not statistically significant (P = 0.123; P = 0.107). The Rs2143571 A allele and the rs3761472 G allele were both deeply associated with increased levels of serum TG, ALT, and AST (all Ps < 0.05). Furthermore, the MDR and GMDR showed that a synergistic relationship might exist between rs738491, rs2143571, and rs3761472 in the SAMM50 gene and the pathophysiology and genetics of NAFLD. Conclusions: We first demonstrated that the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele in the SAMM50 gene created susceptibility to NAFLD in a Chinese Han population. The combination of the three SNPs in the SAMM50 gene may have synergism to predict the predisposition to NAFLD. PMID:26587038

  15. Classical against molecular-genetic methods for susceptibility testing of antituberculotics.

    PubMed

    Porvaznik, I; Mokry, J; Solovic, I

    2015-01-01

    Tuberculosis currently belongs to rare respiratory diseases in Slovakia. However, the emergence and spread of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are major challenges for global tuberculosis control, since the treatment of resistant forms creates both medical and financial problems. Cultivation methods of diagnosis are time-consuming, many times exceeding the time of the initial phase of tuberculosis treatment. Therefore, in the presented study we compared the standard procedures, based on the cultivation of mycobacteria and subsequent drug susceptibility testing to antituberculotics, with molecular-genetic methods using PCR diagnostic kits. The molecular-genetic testing enables to obtain direct and fast evidence of Mycobacterium tuberculosis, with genomic verification of resistance to the most important anti-tuberculosis drugs - isoniazid and rifampicin in MDR-TB, and ethambutol, aminoglycosides, and fluoroquinolones in XDR-TB. In 2012-2013, we confirmed 19 cases of drug-resistant tuberculosis in Slovakia. The resistance to rifampicin was confirmed in all strains with both methods. In two cases, the molecular-genetic testing did not show resistance to isoniazid, as confirmed by conventional cultivation. Furthermore, two strains demonstrating susceptibility in conventional microbiological testing to ethambutol and five strains to fluoroquinolones were verified as actually being resistant using a PCR method. Rapid diagnosis and identification of MDR-TB or XDR-TB strains using molecular-genetic testing is an essential tool for the timely and appropriate drug treatment and prevention of spread of drug resistant strains. PMID:25252893

  16. Human Leptospirosis: Seroreactivity and Genetic Susceptibility in the Population of São Miguel Island (Azores, Portugal)

    PubMed Central

    Esteves, Lisa M.; Bulhões, Sara M.; Branco, Claudia C.; Mota, Francisco M.; Paiva, Clara; Cabral, Rita; Vieira, Maria Luisa; Mota-Vieira, Luisa

    2014-01-01

    Background Leptospirosis is a worldwide zoonotic and recognized neglected infectious disease. It has been observed that only a proportion of individuals exposed to pathogenic species of Leptospira become infected and develop clinically evident disease. Moreover, little information is available in subsequent reinfections. In the present study, we determine if a first infection with leptospirosis protects against subsequent reinfection, and investigate which of the host genetic factors are involved in the susceptibility and resistance to leptospirosis. Methodology and Findings We conducted, in 2011, a retrospective hospital-based case-control study in the São Miguel Island population (Azores archipelago). In order to determine the seropositivity against pathogenic Leptospira after the first episode of leptospirosis, we performed a serological evaluation in 97 unrelated participants diagnosed with leptospirosis between 1992 and 2011. The results revealed that 46.4% of the 97 participants have circulating anti-Leptospira antibodies, and from these participants 35.6% maintained the seroprevalence for the same serogroup. Moreover, three of them were reinfected with unrelated Leptospira serovars. The genetic study was carried out by adding a control group composed of 470 unrelated healthy blood donors, also from São Miguel Island. Twenty five SNPs among twelve innate immune genes – IL1α, IL1β, IL6, IL10, IL12RB1, TLR2, TLR4, TLR9, CD14, CISH, LTA and TNF – were genotyped, as well as HLA class I (–A and –B) genes. Association analysis indicates that genotypes -511GG (OR = 1.6, 95%CI 1.01-2.56, p = 0.04) in IL1β, +1196CG (OR = 2.0, 95%CI 1.26-3.27, p = 0.003) in IL12RB1, -292TA (OR = 1.8, 95% CI 1.06–2.1, p = 0.03) and +3415CG (OR = 1.8, 95% CI 1.08–3.08, p = 0.02), both in CISH confer susceptibility to pathogenic Leptospira. Conclusion The present study suggests some degree of long-term protection against leptospires with an attenuation of symptoms in case of reinfection. Moreover, our data supports the genetic influence of IL1β, IL12RB1 and CISH genes and the susceptibility to leptospirosis infection. PMID:25255143

  17. Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity

    PubMed Central

    Gidalevitz, Tali; Krupinski, Thomas; Garcia, Susana; Morimoto, Richard I.

    2009-01-01

    Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS) cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles. PMID:19266020

  18. Cumulative role of rare and common putative functional genetic variants at NPAS3 in schizophrenia susceptibility.

    PubMed

    González-Peñas, Javier; Arrojo, Manuel; Paz, Eduardo; Brenlla, Julio; Páramo, Mario; Costas, Javier

    2015-10-01

    Schizophrenia may be considered a human-specific disorder arisen as a maladaptive by-product of human-specific brain evolution. Therefore, genetic variants involved in susceptibility to schizophrenia may be identified among those genes related to acquisition of human-specific traits. NPAS3, a transcription factor involved in central nervous system development and neurogenesis, seems to be implicated in the evolution of human brain, as it is the human gene with most human-specific accelerated elements (HAEs), i.e., .mammalian conserved regulatory sequences with accelerated evolution in the lineage leading to humans after human-chimpanzee split. We hypothesize that any nucleotide variant at the NPAS3 HAEs may lead to altered susceptibility to schizophrenia. Twenty-one variants at these HAEs detected by the 1000 genomes Project, as well as five additional variants taken from psychiatric genome-wide association studies, were genotyped in 538 schizophrenic patients and 539 controls from Galicia. Analyses at the haplotype level or based on the cumulative role of the variants assuming different susceptibility models did not find any significant association in spite of enough power under several plausible scenarios regarding direction of effect and the specific role of rare and common variants. These results suggest that, contrary to our hypothesis, the special evolution of the NPAS3 HAEs in Homo relaxed the strong constraint on sequence that characterized these regions during mammalian evolution, allowing some sequence changes without any effect on schizophrenia risk. PMID:25982957

  19. Common genetic variation in ETV6 is associated with colorectal cancer susceptibility.

    PubMed

    Wang, Meilin; Gu, Dongying; Du, Mulong; Xu, Zhi; Zhang, Suzhan; Zhu, Lingjun; Lu, Jiachun; Zhang, Rui; Xing, Jinliang; Miao, Xiaoping; Chu, Haiyan; Hu, Zhibin; Yang, Lei; Tang, Cuiju; Pan, Lei; Du, Haina; Zhao, Jian; Du, Jiangbo; Tong, Na; Sun, Jielin; Shen, Hongbing; Xu, Jianfeng; Zhang, Zhengdong; Chen, Jinfei

    2016-01-01

    Genome-wide association studies (GWASs) have identified multiple susceptibility loci for colorectal cancer, but much of heritability remains unexplained. To identify additional susceptibility loci for colorectal cancer, here we perform a GWAS in 1,023 cases and 1,306 controls and replicate the findings in seven independent samples from China, comprising 5,317 cases and 6,887 controls. We find a variant at 12p13.2 associated with colorectal cancer risk (rs2238126 in ETV6, P=2.67 × 10(-10)). We replicate this association in an additional 1,046 cases and 1,076 controls of European ancestry (P=0.034). The G allele of rs2238126 confers earlier age at onset of colorectal cancer (P=1.98 × 10(-6)) and reduces the binding affinity of transcriptional enhancer MAX. The mRNA level of ETV6 is significantly lower in colorectal tumours than in paired normal tissues. Our findings highlight the potential importance of genetic variation in ETV6 conferring susceptibility to colorectal cancer. PMID:27145994

  20. Common genetic variation in ETV6 is associated with colorectal cancer susceptibility

    PubMed Central

    Wang, Meilin; Gu, Dongying; Du, Mulong; Xu, Zhi; Zhang, Suzhan; Zhu, Lingjun; Lu, Jiachun; Zhang, Rui; Xing, Jinliang; Miao, Xiaoping; Chu, Haiyan; Hu, Zhibin; Yang, Lei; Tang, Cuiju; Pan, Lei; Du, Haina; Zhao, Jian; Du, Jiangbo; Tong, Na; Sun, Jielin; Shen, Hongbing; Xu, Jianfeng; Zhang, Zhengdong; Chen, Jinfei

    2016-01-01

    Genome-wide association studies (GWASs) have identified multiple susceptibility loci for colorectal cancer, but much of heritability remains unexplained. To identify additional susceptibility loci for colorectal cancer, here we perform a GWAS in 1,023 cases and 1,306 controls and replicate the findings in seven independent samples from China, comprising 5,317 cases and 6,887 controls. We find a variant at 12p13.2 associated with colorectal cancer risk (rs2238126 in ETV6, P=2.67 × 10−10). We replicate this association in an additional 1,046 cases and 1,076 controls of European ancestry (P=0.034). The G allele of rs2238126 confers earlier age at onset of colorectal cancer (P=1.98 × 10−6) and reduces the binding affinity of transcriptional enhancer MAX. The mRNA level of ETV6 is significantly lower in colorectal tumours than in paired normal tissues. Our findings highlight the potential importance of genetic variation in ETV6 conferring susceptibility to colorectal cancer. PMID:27145994

  1. Genetic Susceptibility to ANCA-Associated Vasculitis: State of the Art

    PubMed Central

    Bonatti, Francesco; Reina, Michele; Neri, Tauro Maria; Martorana, Davide

    2014-01-01

    ANCA-associated vasculitis (AAV) is a group of disorders that is caused by inflammation affecting small blood vessels. Both arteries and veins are affected. AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) renamed from Wegeners granulomatosis, and eosinophilic granulomatosis with polyangiitis (EGPA), renamed from ChurgStrauss syndrome. AAV is primarily due to leukocyte migration and resultant damage. Despite decades of research, the mechanisms behind AAV disease etiology are still not fully understood, although it is clear that genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by candidate association studies and two genome-wide association studies. The majority of the identified genetic AAV risk factors are common variants. These have uncovered information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in AAV. We also present the novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms. Finally, we discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice. PMID:25452756

  2. Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans.

    PubMed

    Levran, Orna; Randesi, Matthew; da Rosa, Joel Correa; Ott, Jurg; Rotrosen, John; Adelson, Miriam; Kreek, Mary Jeanne

    2015-05-01

    Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single-marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7-SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent. PMID:25875614

  3. Differential Genetic Susceptibility to Child Risk at Birth in Predicting Observed Maternal Behavior

    PubMed Central

    Fortuna, Keren; van IJzendoorn, Marinus H.; Mankuta, David; Kaitz, Marsha; Avinun, Reut; Ebstein, Richard P.; Knafo, Ariel

    2011-01-01

    This study examined parenting as a function of child medical risks at birth and parental genotype (dopamine D4 receptor; DRD4). Our hypothesis was that the relation between child risks and later maternal sensitivity would depend on the presence/absence of a genetic variant in the mothers, thus revealing a gene by environment interaction (GXE). Risk at birth was defined by combining risk indices of children's gestational age at birth, birth weight, and admission to the neonatal intensive care unit. The DRD4-III 7-repeat allele was chosen as a relevant genotype as it was recently shown to moderate the effect of environmental stress on parental sensitivity. Mothers of 104 twin pairs provided DNA samples and were observed with their children in a laboratory play session when the children were 3.5 years old. Results indicate that higher levels of risk at birth were associated with less sensitive parenting only among mothers carrying the 7-repeat allele, but not among mothers carrying shorter alleles. Moreover, mothers who are carriers of the 7-repeat allele and whose children scored low on the risk index were observed to have the highest levels of sensitivity. These findings provide evidence for the interactive effects of genes and environment (in this study, children born at higher risk) on parenting, and are consistent with a genetic differential susceptibility model of parenting by demonstrating that some parents are inherently more susceptible to environmental influences, both good and bad, than are others. PMID:21603618

  4. Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia

    PubMed Central

    Sherborne, Amy L.; Hemminki, Kari; Kumar, Rajiv; Bartram, Claus R.; Stanulla, Martin; Schrappe, Martin; Petridou, Eleni; Semsei, Ágnes F.; Szalai, Csaba; Sinnett, Daniel; Krajinovic, Maja; Healy, Jasmine; Lanciotti, Marina; Dufour, Carlo; Indaco, Stefania; El-Ghouroury, Eman A; Sawangpanich, Ruchchadol; Hongeng, Suradej; Pakakasama, Samart; Gonzalez-Neira, Anna; Ugarte, Evelia L.; Leal, Valeria P.; Espinoza, Juan P.M.; Kamel, Azza M.; Ebid, Gamal T.A.; Radwan, Eman R.; Yalin, Serap; Yalin, Erdinc; Berkoz, Mehmet; Simpson, Jill; Roman, Eve; Lightfoot, Tracy; Hosking, Fay J.; Vijayakrishnan, Jayaram; Greaves, Mel; Houlston, Richard S.

    2011-01-01

    Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium. PMID:21459794

  5. Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis?

    PubMed Central

    Joshi, Reeti; Reveille, John D.; Brown, Matthew A.; Weisman, Michael H.; Ward, Michael M.; Gensler, Lianne S.; Wordsworth, B. Paul; Evans, David M.; Assassi, Shervin

    2012-01-01

    Objective Several genetic risk variants for ankylosing spondylitis (AS) have been identified in genome wide association studies. Our objective was to examine whether familial AS cases have a higher genetic load of these susceptibility variants. Methods Overall, 502 AS patients were examined, consisting of 312 who had first-degree relatives (FDR) with AS (familial) and 190 who had no FDR with AS or spondyloarthritis (sporadic). All patients and affected FDRs fulfilled the modified New York Criteria for AS. The patients were recruited from two U.S. cohorts (NASC and PSOAS) and from the United Kingdom- Oxford cohort. The frequencies of AS susceptibility loci in IL23R, IL1R2, ANTRX2, ERAP1, two intergenic regions on chromosomes 2p15 and 21q22, and HLA-B27 status as determined by the tag SNP rs4349859 were compared between familial and sporadic cases. Association between SNPs and multiplex status was assessed by logistic regression controlling for sibship size. Results HLA-B27 was significantly more prevalent in familial than sporadic cases of AS (p=0.0001, OR: 4.44, CI: (2.06–9.55)). Furthermore, the AS risk allele at chromosome 21q22 intergenic region showed a trend towards higher frequency in the multiplex cases (p=0.08). The frequency of the other AS risk variants did not differ significantly between familial and sporadic cases, either individually or combined. Conclusions HLA-B27 is more prevalent in familial than sporadic cases of AS, demonstrating higher familial aggregation of AS in patients with HLA-B27 positivity. The frequency of the recently described non-MHC susceptibility loci is not markedly different between the sporadic and familial cases of AS. PMID:22231927

  6. Genetic variation and covariation of susceptibility to parasitoids in the aphid Myzus persicae: no evidence for trade-offs

    PubMed Central

    von Burg, Simone; Ferrari, Julia; Müller, Christine B; Vorburger, Christoph

    2008-01-01

    Parasitoids are an important mortality factor for insects. Susceptibility to parasitoids should thus be under strong negative selection. Nevertheless, ample genetic variation for susceptibility to parasitoids is commonly observed in natural populations, suggesting that trade-offs may constrain the evolution of reduced susceptibility. This can be studied by assessing genetic variation for susceptibility and its covariation with other components of fitness. In a set of 17 clones of the peach potato aphid, Myzus persicae, for which good estimates of heritable variation for life-history traits were available, we found significant clonal variation for susceptibility to two of their common parasitoids: Aphidius colemani and Diaeretiella rapae. One clone, the only one harbouring a facultative endosymbiotic bacterium, Regiella insecticola, was entirely resistant to both parasitoids. Susceptibilities to the two parasitoids exhibited a positive genetic correlation close to unity, implying a general mechanism of defence. However, the susceptibility to parasitoids was uncorrelated to the clones' fecundity or rate of increase, providing no evidence for costs of the ability to resist parasitoids. PMID:18270153

  7. Genetic background affects the expansion of macrophage subsets in the lungs of Mycobacterium tuberculosis-infected hosts.

    PubMed

    Bertolini, Thais Barboza; de Souza, Alexandre Ignacio; Gembre, Ana Flávia; Piñeros, Annie Rocio; Prado, Rafael de Queiroz; Silva, João Santana; Ramalho, Leandra Naira Zambelli; Bonato, Vânia Luiza Deperon

    2016-05-01

    M1 macrophages are more effective in the induction of the inflammatory response and clearance of Mycobacterium tuberculosis than M2 macrophages. Infected C57BL/6 mice generate a stronger cellular immune response compared with BALB/c mice. We hypothesized that infected C57BL/6 mice would exhibit a higher frequency and function of M1 macrophages than infected BALB/c mice. Our findings show a higher ratio of macrophages to M2 macrophages in the lungs of chronically infected C57BL/6 mice compared with BALB/c mice. However, there was no difference in the functional ability of M1 and M2 macrophages for the two strains in vitro. In vivo, a deleterious role for M2 macrophages was confirmed by M2 cell transfer, which rendered the infected C57BL/6, but not the BALB/c mice, more susceptible and resulted in mild lung inflammation compared with C57BL/6 mice that did not undergo cell transfer. M1 cell transfer induced a higher inflammatory response, although not protective, in infected BALB/c mice compared with their counterparts that did not undergo cell transfer. These findings demonstrate that an inflammation mediated by M1 macrophages may not induce bacterial tolerance because protection depends on the host genetic background, which drives the magnitude of the inflammatory response against M. tuberculosis in the pulmonary microenvironment. The contribution of our findings is that although M1 macrophage is an effector leucocyte with microbicidal machinery, its dominant role depends on the balance of M1 and M2 subsets, which is driven by the host genetic background. PMID:26840507

  8. Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns

    PubMed Central

    YAO, GEN-DONG; LI, SHOU-XIA; CHEN, DING-LI; FENG, HAI-QIN; ZHAO, SU-BIN; LIU, YONG-JIE; GUO, LI-LI; YANG, ZHI-MING; ZHANG, XIAO-FANG; SUN, CAI-XIA; WANG, ZE-HUI; ZHANG, WEI-YONG

    2014-01-01

    The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss. PMID:24348793

  9. Dissecting the Genetic Susceptibility to Graves’ Disease in a Cohort of Patients of Italian Origin

    PubMed Central

    Lombardi, Angela; Menconi, Francesca; Greenberg, David; Concepcion, Erlinda; Leo, Marenza; Rocchi, Roberto; Marinó, Michele; Keddache, Mehdi; Tomer, Yaron

    2016-01-01

    Graves’ disease (GD) is an autoimmune oligogenic disorder with a strong hereditary component. Several GD susceptibility genes have been identified and confirmed during the last two decades. However, there are very few studies that evaluated susceptibility genes for GD in specific geographic subsets. Previously, we mapped a new locus on chromosome 3q that was unique to GD families of Italian origin. In the present study, we used association analysis of single-nucleotide polymorphism (SNPs) at the 3q locus in a cohort of GD patients of Italian origin in order to prioritize the best candidates among the known genes in this locus to choose the one(s) best supported by the association. DNA samples were genotyped using the Illumina GoldenGate genotyping assay analyzing 690 SNP in the linked 3q locus covering all 124 linkage disequilibrium blocks in this locus. Candidate non-HLA (human-leukocyte-antigen) genes previously reported to be associated with GD and/or other autoimmune disorders were analyzed separately. Three SNPs in the 3q locus showed a nominal association (p < 0.05): rs13097181, rs763313, and rs6792646. Albeit these could not be further validated by multiple comparison correction, we were prioritizing candidate genes at a locus already known to harbor a GD-related gene, not hypothesis testing. Moreover, we found significant associations with the thyroid-stimulating hormone receptor (TSHR) gene, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene, and the thyroglobulin (TG) gene. In conclusion, we identified three SNPs on chromosome 3q that may map a new GD susceptibility gene in this region which is unique to the Italian population. Furthermore, we confirmed that the TSHR, the CTLA-4, and the TG genes are associated with GD in Italians. Our findings highlight the influence of ethnicity and geographic variations on the genetic susceptibility to GD. PMID:27014188

  10. In vitro susceptibility of macrophages to porcine reproductive and respiratory syndrome virus varies between genetically diverse lines of pigs.

    PubMed

    Vincent, A L; Thacker, B J; Halbur, P G; Rothschild, M F; Thacker, E L

    2005-01-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be responsible for financial losses in the swine industry worldwide. It remains undetermined whether genetic variability of the host in susceptibility to PRRSV exists and if this variability can be exploited to help control this important disease. The objective of this study was to determine if an in vitro flow cytometry (FACS) assay that detects the percentage of monocyte-derived macrophages (MDM) infected with PRRSV could be utilized to demonstrate genetic variability in the susceptibility between distinct lines of pigs. Over 400 growing pigs from six genetic lines maintained in a single commercial breeding herd were screened using an in vitro FACS assay. From this initial screening, two genetically diverse lines of pigs that were also divergent in their FACS results were selected for further study. An additional 264 pigs from these two lines were subsequently tested for in vitro susceptibility to PRRSV. As in the preliminary screening, the Large White line had significantly higher average percent positive MDM over the Duroc-Pietrain synthetic line. This report suggests a genetic component for susceptibility to PRRSV exists and that the in vitro assay may be useful in predicting the relative susceptibility to PRRSV in large groups of animals. PMID:16212529

  11. Systematic Evaluation of Genes and Genetic Variants Associated with Type 1 Diabetes Susceptibility.

    PubMed

    Ram, Ramesh; Mehta, Munish; Nguyen, Quang T; Larma, Irma; Boehm, Bernhard O; Pociot, Flemming; Concannon, Patrick; Morahan, Grant

    2016-04-01

    Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r(2) > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4(+) and CD8(+) T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes. PMID:26912320

  12. RNAi phenotypes are influenced by the genetic background of the injected strain

    PubMed Central

    2013-01-01

    Background RNA interference (RNAi) is a powerful tool to study gene function in organisms that are not amenable to classical forward genetics. Hence, together with the ease of comprehensively identifying genes by new generation sequencing, RNAi is expanding the scope of animal species and questions that can be addressed in terms of gene function. In the case of genetic mutants, the genetic background of the strains used is known to influence the phenotype while this has not been described for RNAi experiments. Results Here we show in the red flour beetle Tribolium castaneum that RNAi against Tc-importin α1 leads to different phenotypes depending on the injected strain. We rule out off target effects and show that sequence divergence does not account for this difference. By quantitatively comparing phenotypes elicited by RNAi knockdown of four different genes we show that there is no general difference in RNAi sensitivity between these strains. Finally, we show that in case of Tc-importin α1 the difference depends on the maternal genotype. Conclusions These results show that in RNAi experiments strain specific differences have to be considered and that a proper documentation of the injected strain is required. This is especially important for the increasing number of emerging model organisms that are being functionally investigated using RNAi. In addition, our work shows that RNAi is suitable to systematically identify the differences in the gene regulatory networks present in populations of the same species, which will allow novel insights into the evolution of animal diversity. PMID:23324472

  13. Autoimmune type 1 diabetes genetic susceptibility encoded by human leukocyte antigen DRB1 and DQB1 genes in Tunisia.

    PubMed

    Stayoussef, Mouna; Benmansour, Jihen; Al-Irhayim, Abdul-Qader; Said, Hichem B; Rayana, Chiheb B; Mahjoub, Touhami; Almawi, Wassim Y

    2009-08-01

    Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background. PMID:19553558

  14. Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia▿

    PubMed Central

    Stayoussef, Mouna; Benmansour, Jihen; Al-Irhayim, Abdul-Qader; Said, Hichem B.; Rayana, Chiheb B.; Mahjoub, Touhami; Almawi, Wassim Y.

    2009-01-01

    Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background. PMID:19553558

  15. Cardiac teratogenicity in mouse maternal phenylketonuria: defining phenotype parameters and genetic background influences.

    PubMed

    Seagraves, Nikki J; McBride, Kim L

    2012-12-01

    Maternal phenylketonuria (MPKU) is a syndrome including cardiovascular malformations (CVMs), microcephaly, intellectual impairment, and small size for gestational age, caused by in-utero exposure to elevated serum phenylalanine (Phe) due to PKU in the mother. It is becoming a public health concern as more women with PKU reach child bearing age. Although a mouse model of PKU, BTBR Pah(enu2), has been available for 20 years, it has not been well utilized for studying MPKU. We used this model to delineate critical parameters in Phe cardiovascular teratogenicity and study the effect of genetic background. Dosing and timing experiments were performed with the BTBR Pah(enu2) mouse. A dose response curve was noted, with CVM rates at maternal serum Phe levels <360 ?M (control), 360-600 ?M (low), 600-900 ?M (mid), and >900 ?M (high) of 11.86%, 16.67%, 30.86%, and 46.67% respectively. A variety of CVMs were noted on the BTBR background, including double outlet right ventricle (DORV), aortic arch artery (AAA) abnormalities, and ventricular septal defects (VSDs). Timed exposure experiments identified a teratogenic window from embryonic day 8.5-13.5, with higher rates of conotruncal and valve defects occurring in early exposure time and persistent truncus arteriosus (PTA) and aortic arch branching abnormalities occurring with late exposure. Compared to the BTBR strain, N10+ Pah(enu2) congenics on the C3H/HeJ background had higher rates of CVMs in general and propensity to left ventricular outflow tract (LVOT) malformations, while the C57B/L6 background had similar CVM rates but predominately AAA abnormalities. We have delineated key parameters of Phe cardiovascular teratogenicity, demonstrated the utility of this MPKU model on different mouse strains, and shown how genetic background profoundly affects the phenotype. PMID:22951387

  16. Cardiac Teratogenicity in Mouse Maternal Phenylketonuria: Defining phenotype parameters and genetic background influences

    PubMed Central

    Seagraves, Nikki J.; McBride, Kim L.

    2012-01-01

    Maternal phenylketonuria (MPKU) is a syndrome including cardiovascular malformations (CVMs), microcephaly, intellectual impairment, and small for gestational age, caused by in-utero exposure to elevated serum phenylalanine (Phe) due to PKU in the mother. It is becoming a public health concern as more women with PKU reach child bearing age. Although a mouse model of PKU, BTBR Pahenu2, has been available for 20 years, it has not been well utilized for studying MPKU. We used this model to delineate critical parameters in Phe cardiovascular teratogenicity and study the effect of genetic background. Dosing and timing experiments were performed with the BTBR Pahenu2 mouse. A dose response curve was noted, with CVM rates at maternal serum Phe levels <360 μM (control), 360 – 600 μM (low), 600 – 900 μM (mid), and >900μM (high) of 11.86%, 16.67%, 30.86%, and 46.67% respectively. A variety of CVMs were noted on the BTBR background, including double outlet right ventricle (DORV), aortic arch artery (AAA)abnormalities, and ventricular septal defects (VSDs). Timed exposure experiments identified a teratogenic window from embryonic day 8.5-13.5, with higher rates of conotruncal and valve defects occurring in early exposure time and persistent truncus arteriosus (PTA) and aortic arch branching abnormalities occurring with late exposure. Compared to the BTBR strain, N10+ Pahenu2 congenics on the C3H/HeJ background had higher rates of CVMs in general and propensity to left ventricular outflow tract (LVOT) malformations, while the C57B/L6 background had similar CVM rates but predominately AAA abnormalities. We have delineated key parameters of Phe cardiovascular teratogenicity, demonstrated the utility of this MPKU model on different mouse strains, and shown how genetic background profoundly affects the phenotype. PMID:22951387

  17. Interferon-Inducible Transmembrane Protein 3 Genetic Variant rs12252 and Influenza Susceptibility and Severity: A Meta-Analysis

    PubMed Central

    Yang, Xianxian; Tan, Bin; Zhou, Xipeng; Xue, Jian; Zhang, Xian; Wang, Peng; Shao, Chuang; Li, Yingli; Li, Chaorui; Xia, Huiming; Qiu, Jingfu

    2015-01-01

    Background The pandemic influenza A (H1N1) pdm09 virus, avian influenza A (H5N1) virus, and influenza A (H7N9) virus induced severe morbidity and mortality throughout the world. Previous studies suggested a close association between the interferon-induced transmembrane protein-3 (IFITM3) genetic variant rs12252 and influenza. Here, we explored the correlation between the rs12252 and influenza susceptibility and severity using meta-analysis. Methods Relevant studies published before May 22, 2014 were retrieved from PubMed, ISI web of knowledge, EBSCO, and Cochrane central register of controlled trials databases. Association between rs12252 and influenza susceptibility and severity were determined using statistical analysis of odds ratios (ORs). Results A total of four studies consisting of 445 cases and 4180 controls were included in our analysis. Generally, there is increased risk of influenza in subjects carrying rs12252 in the recessive model (CC vs. CT+TT: OR = 2.35, 95% CI: 1.49-3.70, P<0.001), the dominant model (CC+CT vs. TT: OR=1.60, 95% CI: 1.18–2.22, P=0.003), the homozygote comparison (CC vs. TT: OR=4.11, 95% CI: 2.15–7.84, P<0.001), and the allele contrast (C vs. T: OR=1.67, 95% CI: 1.32–2.13, P<0.001). Stratification analysis of ethnicity and severity revealed a significant increase in influenza susceptibility by IFITM3-SNP rs12252 among both Asian and Caucasian population. SNP rs12252 shows significant impact on severe infections (P<0.05), but not on mild influenza. Besides, our result also associated rs12252 with influenza severity (severe vs. mild: OR=2.37, 95% CI: 1.32–4.25, P=0.004), (severe vs. control: OR=2.70, 95% CI: 1.85–3.94, P<0.001). Conclusion Our meta-analysis suggests a significant association between a minor IFITM3 allele (SNP rs12252-C) with severe influenza susceptibility, but not in mild influenza subjects, in both UK Caucasians and Han Chinese population. The rs12252-C allele causes a 23.7% higher chance of infection and also constitutes a risk factor for more severe influenza. PMID:25942469

  18. Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds

    PubMed Central

    Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Scherrer, Alexandra U.; Shilaih, Mohaned; Hinkley, Trevor; Petropoulos, Christos; Bonhoeffer, Sebastian

    2015-01-01

    Transmission of drug-resistant pathogens presents an almost-universal challenge for fighting infectious diseases. Transmitted drug resistance mutations (TDRM) can persist in the absence of drugs for considerable time. It is generally believed that differential TDRM-persistence is caused, at least partially, by variations in TDRM-fitness-costs. However, in vivo epidemiological evidence for the impact of fitness costs on TDRM-persistence is rare. Here, we studied the persistence of TDRM in HIV-1 using longitudinally-sampled nucleotide sequences from the Swiss-HIV-Cohort-Study (SHCS). All treatment-naïve individuals with TDRM at baseline were included. Persistence of TDRM was quantified via reversion rates (RR) determined with interval-censored survival models. Fitness costs of TDRM were estimated in the genetic background in which they occurred using a previously published and validated machine-learning algorithm (based on in vitro replicative capacities) and were included in the survival models as explanatory variables. In 857 sequential samples from 168 treatment-naïve patients, 17 TDRM were analyzed. RR varied substantially and ranged from 174.0/100-person-years;CI=[51.4, 588.8] (for 184V) to 2.7/100-person-years;[0.7, 10.9] (for 215D). RR increased significantly with fitness cost (increase by 1.6[1.3,2.0] per standard deviation of fitness costs). When subdividing fitness costs into the average fitness cost of a given mutation and the deviation from the average fitness cost of a mutation in a given genetic background, we found that both components were significantly associated with reversion-rates. Our results show that the substantial variations of TDRM persistence in the absence of drugs are associated with fitness-cost differences both among mutations and among different genetic backgrounds for the same mutation. PMID:25798934

  19. Genetic analysis of Drosophila melanogaster susceptibility to intestinal Vibrio cholerae infection

    PubMed Central

    Berkey, Cristin D.; Blow, Nathan; Watnick, Paula I.

    2009-01-01

    Summary We previously demonstrated that Vibrio cholerae is able to colonize the intestine of the fly to produce a lethal infection. Here we present the results of a genetic screen undertaken to identify factors that alter susceptibility of the fly to intestinal V. cholerae infection. In this model of infection, the Eiger/Wengen signalling pathway protects the fly against infection. Furthermore, mutations within the IMD signalling pathway increase resistance to intestinal V. cholerae infection and increase programmed cell death within the intestinal epithelium during infection. We propose that programmed cell death protects the intestinal epithelium against V. cholerae infection and therefore that the fly may serve as a useful model in which to study modulation of intestinal epithelial cell survival by commensal and pathogenic intestinal bacteria as well as the pathological processes leading to erosion of the intestinal epithelium and intestinal malignancy. PMID:19046341

  20. Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

    PubMed Central

    Waisberg, Michael; Tarasenko, Tatyana; Vickers, Brandi K.; Scott, Bethany L.; Willcocks, Lisa C.; Molina-Cruz, Alvaro; Pierce, Matthew A.; Huang, Chiung-yu; Torres-Velez, Fernando J.; Smith, Kenneth G. C.; Barillas-Mury, Carolina; Miller, Louis H.; Pierce, Susan K.; Bolland, Silvia

    2011-01-01

    Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease. PMID:21187399

  1. Investigating arsenic susceptibility from a genetic perspective in Drosophila reveals a key role for glutathione synthetase.

    PubMed

    Ortiz, Jorge G Muñiz; Opoka, Robert; Kane, Daniel; Cartwright, Iain L

    2009-02-01

    Chronic exposure to arsenic-contaminated drinking water can lead to a variety of serious pathological outcomes. However, differential responsiveness within human populations suggests that interindividual genetic variation plays an important role. We are using Drosophila to study toxic metal response pathways because of unrivalled access to varied genetic approaches and significant demonstrable overlap with many aspects of mammalian physiology and disease phenotypes. Genetic analysis (via chromosomal segregation and microsatellite marker-based recombination) of various wild-type strains exhibiting relative susceptibility or tolerance to the lethal toxic effects of arsenite identified a limited X-chromosomal region (16D-F) able to confer a differential response phenotype. Using an FRT-based recombination approach, we created lines harboring small, overlapping deficiencies within this region and found that relative arsenite sensitivity arose when the dose of the glutathione synthetase (GS) gene (located at 16F1) was reduced by half. Knockdown of GS expression by RNA interference (RNAi) in cultured S2 cells led to enhanced arsenite sensitivity, while GS RNAi applied to intact organisms dramatically reduced the concentration of food-borne arsenite compatible with successful growth and development. Our analyses, initially guided by observations on naturally occurring variants, provide genetic proof that an optimally functioning two-step glutathione (GSH) biosynthetic pathway is required in vivo for a robust defense against arsenite; the enzymatic implications of this are discussed in the context of GSH supply and demand under arsenite-induced stress. Given an identical pathway for human GSH biosynthesis, we suggest that polymorphisms in GSH biosynthetic genes may be an important contributor to differential arsenic sensitivity and exposure risk in human populations. PMID:18779381

  2. Investigating Arsenic Susceptibility from a Genetic Perspective in Drosophila Reveals a Key Role for Glutathione Synthetase

    PubMed Central

    Muñiz Ortiz, Jorge G.; Opoka, Robert; Kane, Daniel; Cartwright, Iain L.

    2009-01-01

    Chronic exposure to arsenic-contaminated drinking water can lead to a variety of serious pathological outcomes. However, differential responsiveness within human populations suggests that interindividual genetic variation plays an important role. We are using Drosophila to study toxic metal response pathways because of unrivalled access to varied genetic approaches and significant demonstrable overlap with many aspects of mammalian physiology and disease phenotypes. Genetic analysis (via chromosomal segregation and microsatellite marker-based recombination) of various wild-type strains exhibiting relative susceptibility or tolerance to the lethal toxic effects of arsenite identified a limited X-chromosomal region (16D-F) able to confer a differential response phenotype. Using an FRT-based recombination approach, we created lines harboring small, overlapping deficiencies within this region and found that relative arsenite sensitivity arose when the dose of the glutathione synthetase (GS) gene (located at 16F1) was reduced by half. Knockdown of GS expression by RNA interference (RNAi) in cultured S2 cells led to enhanced arsenite sensitivity, while GS RNAi applied to intact organisms dramatically reduced the concentration of food-borne arsenite compatible with successful growth and development. Our analyses, initially guided by observations on naturally occurring variants, provide genetic proof that an optimally functioning two-step glutathione (GSH) biosynthetic pathway is required in vivo for a robust defense against arsenite; the enzymatic implications of this are discussed in the context of GSH supply and demand under arsenite-induced stress. Given an identical pathway for human GSH biosynthesis, we suggest that polymorphisms in GSH biosynthetic genes may be an important contributor to differential arsenic sensitivity and exposure risk in human populations. PMID:18779381

  3. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

    PubMed Central

    Plon, Sharon E.; Eccles, Diana M.; Easton, Douglas; Foulkes, William D.; Genuardi, Maurizio; Greenblatt, Marc S.; Hogervorst, Frans B.L.; Hoogerbrugge, Nicoline; Spurdle, Amanda B.; Tavtigian, Sean

    2011-01-01

    Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology and propose a standardized classification system for application to sequence based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. PMID:18951446

  4. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

    PubMed

    Plon, Sharon E; Eccles, Diana M; Easton, Douglas; Foulkes, William D; Genuardi, Maurizio; Greenblatt, Marc S; Hogervorst, Frans B L; Hoogerbrugge, Nicoline; Spurdle, Amanda B; Tavtigian, Sean V

    2008-11-01

    Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. PMID:18951446

  5. Genetic Susceptibility to Dental Caries Differs between the Sexes: A Family-based Study

    PubMed Central

    Shaffer, John R.; Wang, Xiaojing; McNeil, Daniel W.; Weyant, Robert J.; Crout, Richard; Marazita, Mary L.

    2015-01-01

    Many of the factors affecting susceptibility to dental caries are likely influenced by genetics. In fact, genetics accounts for up to 65% of inter-individual variation in dental caries experience. Sex differences in dental caries experience has been widely reported, with females usually exhibiting higher prevalence and severity of disease across all ages. The cause for this sex bias is currently uncertain, although may be partly explained by the differential effects of genetic factors between the sexes: gene-by-sex interactions. In this family-based study (N=2,663; 740 families; ages 193 years), we assessed dental caries via intra-oral examination and generated six indices of caries experience (DMFS, dfs, and indices of both pit-and-fissure surface caries and smooth surface caries in both primary and permanent dentitions). We used likelihood-based methods to model the variance in caries experience conditional on the expected genetic sharing among relatives in our sample. This modeling framework allowed us to test two lines of evidence for gene-by-sex interactions: (1) whether the magnitude of the cumulative effect of genes differs between the sexes, and (2) whether different genes are involved. We observed significant evidence of gene-by-sex interactions for caries experience in both the primary and permanent dentitions. In the primary dentition, the magnitude of the effect of genes was greater in males than females. In the permanent dentition, different genes may play important roles in each of the sexes. Overall, this study provides the first direct evidence that sex differences in dental caries experiences may be explained, in part, by gene-by-sex interactions. PMID:25612913

  6. Differential Susceptibility: The Genetic Moderation of Peer Pressure on Alcohol Use.

    PubMed

    Griffin, Amanda M; Cleveland, H Harrington; Schlomer, Gabriel L; Vandenbergh, David J; Feinberg, Mark E

    2015-10-01

    Although peer pressure can influence adolescents' alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents' susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n = 414; 58.7% female; 92.8% White). The results revealed significant main effects for antisocial peer pressure, but no main effects for DRD4 genotype on lifetime alcohol use. Adolescent DRD4 genotype moderated the association between peer pressure and lifetime alcohol use. For individuals who carried at least one copy of the DRD4 7-repeat allele (7+), antisocial peer pressure was associated with increased lifetime alcohol use. These findings indicate that genetic sensitivity to peer pressure confers increased alcohol use in late adolescence. PMID:26307243

  7. Differential Susceptibility: The Genetic Moderation of Peer Pressure on Alcohol Use

    PubMed Central

    Cleveland, H. Harrington; Schlomer, Gabriel L.; Vandenbergh, David J.; Feinberg, Mark E.

    2016-01-01

    Although peer pressure can influence adolescents’ alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents’ susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n = 414; 58.7 % female; 92.8 % White). The results revealed significant main effects for antisocial peer pressure, but no main effects for DRD4 genotype on lifetime alcohol use. Adolescent DRD4 genotype moderated the association between peer pressure and lifetime alcohol use. For individuals who carried at least one copy of the DRD4 7-repeat allele (7+), antisocial peer pressure was associated with increased lifetime alcohol use. These findings indicate that genetic sensitivity to peer pressure confers increased alcohol use in late adolescence. PMID:26307243

  8. Specific and natural antibody production during Salmonella typhimurium infection in genetically susceptible and resistant mice.

    PubMed Central

    Matsiota-Bernard, P; Mahana, W; Avrameas, S; Nauciel, C

    1993-01-01

    Genetically susceptible (C57BL/6) and resistant (CBA) mice were infected with an avirulent strain of Salmonella typhimurium and studied over a 35-day period for the production of antibodies directed against bacterial antigens including lipopolysaccharide (LPS) (specific antibodies) and antibodies directed against self antigens [natural antibodies (NAb)]. Antibodies directed against LPS and self antigens were detected by enzyme immunoassay (EIA) and those directed against other bacterial antigens by immunoblotting. We found that serum natural antibody titres in C57BL/6 and CBA mice were similar and correlated with the bacterial load in the spleen and liver. In C57BL/6 mice, anti-LPS antibodies remained polyreactive and of the IgM isotype. In contrast, CBA mice, after an early increase in polyreactive IgM anti-LPS antibodies, mounted a specific anti-LPS IgG antibody response. The immunoblotting results demonstrated that the IgM polyreactive antibodies in the resistant and susceptible mice recognized bacterial antigens of different molecular weights and that CBA, but not C57BL/6 mice, were able to produce IgG antibodies recognizing bacterial components. Our results suggest that the synthesis of antibodies directed against bacterial antigens and natural antibodies follow, at least partially, distinct pathways, but they do not allow us to determine whether these two antibody populations are produced by the same or distinct B-cell subpopulations. Images Figure 3 PMID:8406566

  9. Molecular characterization and genetic susceptibility of sapovirus in children with diarrhea in Burkina Faso.

    PubMed

    Matussek, Andreas; Dienus, Olaf; Djeneba, Ouermi; Simpore, Jacques; Nitiema, Leon; Nordgren, Johan

    2015-06-01

    Sapoviruses (SaVs) are a common cause of gastroenteritis in children. In sub-Saharan Africa, there is a scarcity of information regarding SaV as an etiological agent of diarrhea. Here, we investigated the prevalence, molecular characterization and clinico-epidemiological features of SaV infections in children less than 5years of age with diarrhea in Burkina Faso. We further investigated the role of type 1 histo blood group antigens as susceptibility factors. In total, 309 fecal and 208 saliva samples from diarrheal children in Ouagadougou, Burkina Faso, were collected between May 2009 and March 2010. SaV was detected using real-time PCR, and genogrouped/genotyped by PCR or sequencing. Saliva samples were ABO, Lewis and secretor phenotyped using in house ELISA assays. We found a high prevalence (18%) and large genetic diversity with all 4 human genogroups, and 9 genotypes/genoclusters circulating during the study period. The SaV infections were generally associated with milder symptoms, and neither ABH, Lewis or secretor phenotypes affected susceptibility to SaV infections. PMID:25847694

  10. Hypobaric hypoxia in ascites resistant and susceptible broiler genetic lines influences gut morphology.

    PubMed

    de los, Santos F Solis; Tellez, G; Farnell, M B; Balog, J M; Anthony, N B; Pavlidis, H O; Donoghue, A M

    2005-09-01

    Genetic selection based on rapid growth rates, improved feed conversion, and increased body weights has led to a predisposition to ascites in broiler populations. Sire-family selection was applied to a commercial elite line to produce divergent lines of ascites-resistant (RES) and ascites-susceptible (SUS) broilers by the 8th generation. One objective of this research was to determine the effects of hypobaric hypoxia on gut morphology in these genetic lines. In two separate trials, pedigree broiler chickens were randomly assigned to cages in a hypobaric chamber (simulated 2,900 m above sea level) or a matching local altitude chamber (390 m above sea level). Ascites incidence was characterized by heart enlargement and fluid accumulation in the abdominal cavity. At the end of the study on d 42, all surviving birds were killed and evaluated for the presence of ascites and 2-cm sections from the duodenum and lower ileum were collected from 5 chickens per line, per altitude for each trial for morphometric analysis. At a high altitude, ascites incidence was lower in the RES line (20.9 and 3.7%) than in the SUS line (86.4 and 66.9%, Trials 1 and 2, respectively). No ascites was observed at a local altitude. Under hypoxic conditions, duodenum villus surface area was higher (P < 0.05) in the RES line (181.3 +/- 16.8 and 219 +/- 10.9 microm) compared with the SUS line (130.1 +/- 10.5 and 134.3 +/- 9.3 microm; Trials 1 and 2, respectively). No differences in ileum villus morphology were observed for any of the parameters measured. The reduced surface area in the duodenum of birds selected for ascites susceptibility suggests reduced enteric function and may provide clues as to why these birds have increased incidence of ascites. PMID:16206574

  11. Tumor Necrosis Factor B (TNFB) Genetic Variants and Its Increased Expression Are Associated with Vitiligo Susceptibility

    PubMed Central

    Laddha, Naresh C.; Dwivedi, Mitesh; Gani, Amina R.; Mansuri, Mohmmad Shoab; Begum, Rasheedunnisa

    2013-01-01

    Genetic polymorphisms in TNFB are involved in the regulation of its expression and are found to be associated with various autoimmune diseases. The aim of the present study was to determine whether TNFB +252A/G (rs909253) and exon 3 C/A (rs1041981) polymorphisms are associated with vitiligo susceptibility, and expression of TNFB and ICAM1 affects the disease onset and progression. We have earlier reported the role of TNFA in autoimmune pathogenesis of vitiligo, and we now show the involvement of TNFB in vitiligo pathogenesis. The two polymorphisms investigated in the TNFB were in strong linkage disequilibrium and significantly associated with vitiligo. TNFB and ICAM1 transcripts were significantly increased in patients compared to controls. Active vitiligo patients showed significant increase in TNFB transcripts compared to stable vitiligo. The genotype-phenotype analysis revealed that TNFB expression levels were higher in patients with GG and AA genotypes as compared to controls. Patients with the early age of onset and female patients showed higher TNFB and ICAM1 expression. Overall, our findings suggest that the increased TNFB transcript levels in vitiligo patients could result, at least in part, from variations at the genetic level which in turn leads to increased ICAM1 expression. For the first time, we show that TNFB +252A/G and exon 3 C/A polymorphisms are associated with vitiligo susceptibility and influence the TNFB and ICAM1 expression. Moreover, the study also emphasizes influence of TNFB and ICAM1 on the disease progression, onset and gender bias for developing vitiligo. PMID:24312346

  12. Ozone exposure, vitamin C intake, and genetic susceptibility of asthmatic children in Mexico City: a cohort study

    PubMed Central

    2013-01-01

    Background We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function (FEF25-75) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566). Methods 257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches. Results The change in FEF25-75 per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was −91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF25-75 of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF25-75 did not differ by vitamin C intake. Conclusions Our results provide further evidence that asthmatic children predicted to have compromised antioxidant defense by virtue of genetic susceptibility combined with deficient antioxidant intake may be at increased risk of adverse effects of ozone on pulmonary function. PMID:23379631

  13. Host Genetic Factors Affect Susceptibility to Norovirus Infections in Burkina Faso

    PubMed Central

    Nordgren, Johan; Nitiema, Léon W.; Ouermi, Djeneba; Simpore, Jacques; Svensson, Lennart

    2013-01-01

    Norovirus (NoV) constitutes the second most common viral pathogen causing pediatric diarrhea after rotavirus. In Africa, diarrhea is a major health problem in children, and yet few studies have been performed regarding NoV. The association of histo-blood group antigens (HBGA) and susceptibility to NoV infection is well established in Caucasian populations with non-secretors being resistant to many common NoV strains. No study regarding HBGA and NoV susceptibility has yet been performed in Africa. We collected 309 stool and 208 saliva samples from diarrheal children in Ouagadougou, Burkina Faso; May 2009 to March 2010. NoV was detected using real-time PCR, and genotyped by sequencing. Saliva samples were ABO, Lewis and secretor phenotyped using in house ELISA assays. NoV was detected in 12% (n = 37) of the samples. The genotype diversity was unusually large; overall the 37 positive samples belonged to 14 genotypes. Only children <2 years of age were NoV positive and the GII.4 NoVs were more frequent in the late dry season (Jan-May). NoV infections were observed less in children with the secretor-negative phenotype or blood group A (OR 0.18; p = 0.012 and OR 0.31; p = 0.054; respectively), with two non-secretors infected with genotypes GII.7 and GII.4 respectively. Lewis-negative (Lea−b−) children, representing 32% of the study population, were susceptible to GII, but were not infected with any NoV GI. GII.4 strains preferentially infected children with blood group B whereas secretor-positive children with blood group O were infected with the largest variety of genotypes. This is the first study identifying host genetic factors associated with susceptibility to NoV in an African population, and suggests that while the non-secretor phenotype provides protection; the Lewis b antigen is not necessary for GII infection. PMID:23894502

  14. The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background

    PubMed Central

    Marsh, Sharon; Hu, Junbo; Feng, Wenke

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression.

  15. Complement receptor 1 genetic variants contribute to the susceptibility to gastric cancer in chinese population.

    PubMed

    Zhao, Lina; Zhang, Zhi; Lin, Jia; Cao, Lei; He, Bing; Han, Sugui; Zhang, Xuemei

    2015-01-01

    As the receptor for C3b/C4b, type 1 complement receptor (CR1/CD35) plays an important role in the regulation of complement activity and is further involved in carcinogenesis. This study aimed to elucidate the association of CR1 genetic variants with the susceptibility to gastric cancer in Chinese population. Based on the NCBI database, totally 13 tag single nucleotide polymorphisms (SNPs) were selected by Haploview program and genotyped using iPlex Gold Genotyping Assay and Sequenom MassArray among 500 gastric cancer cases and 500 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression to evaluate the association of each SNP with gastric cancer. Of all selected Tag SNPs , CR1 rs9429942 T > C was found to confer to the risk of developing gastric cancer. Compared with the carriers with rs9429942 TT genotype, those with CT genotype had 88% decreased risk of developing gastric cancer with OR (95%CI) of 0.12 (0.03-0.50). Generalized multifactor dimensionality reduction (GMDR) analysis revealed a significant three-way interaction among rs75422544 C > A, rs10494885 C > T and rs7525160 G > C in the development of gastric cancer with a maximum testing balance accuracy of 56.07% and a cross-validation consistency of 7/10 (P = 0.011). In conclusion, our findings demonstrated the genetic role of CR1 gene in the development of gastric cancer in Chinese population. PMID:26000043

  16. Influenza virus surveillance in Argentina during the 2012 season: antigenic characterization, genetic analysis and antiviral susceptibility.

    PubMed

    Benedetti, E; Daniels, R S; Pontoriero, A; Russo, M; Avaro, M; Czech, A; Campos, A; Periolo, N; Gregory, V; McCauley, J W; Baumeister, E G

    2016-03-01

    The activity and circulation of influenza viruses in Argentina was studied during 2012 as part of the Argentinean Surveillance for Influenza and other Respiratory Viruses, in the context of Global Influenza Surveillance. The antigenicity and molecular characteristics of haemagglutinins (HA) of circulating influenza A and B viruses were analysed to assess the emergence of virus variants. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay and results were backed-up by sequencing of the neuraminidase (NA) genes. During the 2012 season, influenza virus circulation in Argentina was detected from weeks 24 to 51. The HA sequences of the studied A(H1N1)pdm09 subtype viruses segregated in a different genetic group compared to those identified during the 2009 pandemic, although they were still closely related antigenically to the vaccine virus A/California/07/2009. The HA sequences of the A(H3N2) viruses analysed fell into the A/Victoria/208/2009 clade, genetic group 3C. A mixed circulation of virus variants belonging to B/Victoria and B/Yamagata lineages was detected, with B/Victoria being dominant. All viruses tested were sensitive to oseltamivir and zanamivir except one. This isolate, an A(H1N1)pdm09 virus possessing the substitution NA-N295S, showed highly reduced inhibition by oseltamivir and reduced inhibition by zanamivir. Virological and epidemiological surveillance remains critical for detection of evolving influenza viruses. PMID:26345289

  17. Complement Receptor 1 Genetic Variants Contribute to the Susceptibility to Gastric Cancer in Chinese Population

    PubMed Central

    Zhao, Lina; Zhang, Zhi; Lin, Jia; Cao, Lei; He, Bing; Han, Sugui; Zhang, Xuemei

    2015-01-01

    As the receptor for C3b/C4b, type 1 complement receptor (CR1/CD35) plays an important role in the regulation of complement activity and is further involved in carcinogenesis. This study aimed to elucidate the association of CR1 genetic variants with the susceptibility to gastric cancer in Chinese population. Based on the NCBI database, totally 13 tag single nucleotide polymorphisms (SNPs) were selected by Haploview program and genotyped using iPlex Gold Genotyping Assay and Sequenom MassArray among 500 gastric cancer cases and 500 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression to evaluate the association of each SNP with gastric cancer. Of all selected Tag SNPs , CR1 rs9429942 T > C was found to confer to the risk of developing gastric cancer. Compared with the carriers with rs9429942 TT genotype, those with CT genotype had 88% decreased risk of developing gastric cancer with OR (95%CI) of 0.12 (0.03-0.50). Generalized multifactor dimensionality reduction (GMDR) analysis revealed a significant three-way interaction among rs75422544 C > A, rs10494885 C > T and rs7525160 G > C in the development of gastric cancer with a maximum testing balance accuracy of 56.07% and a cross-validation consistency of 7/10 (P = 0.011). In conclusion, our findings demonstrated the genetic role of CR1 gene in the development of gastric cancer in Chinese population. PMID:26000043

  18. Aldehyde dehydrogenase 2 genetic variations may increase susceptibility to Parkinson's disease in Han Chinese population.

    PubMed

    Zhang, Xiong; Ye, Yang-Lie; Wang, Ya-Nan; Liu, Fang-Fang; Liu, Xue-Xia; Hu, Bei-Lei; Zou, Ming; Zhu, Jian-Hong

    2015-09-01

    Genetic variations of ALDH2, encoding aldehyde dehydrogenase-2 which regulates aldehyde oxidation in the brain, have been recently suggested to impact on the association of pesticide exposure with Parkinson's disease (PD). However, the link between ALDH2 polymorphism and PD remains elusive. In the present study, tag-single nucleotide polymorphisms of ALDH2, including rs4767944, rs441, and rs671, were extracted and analyzed in a Chinese cohort consisting of 584 PD patients and 582 controls. Results from genotyping analyses showed that rs4767944 (p = 0.002), but not rs441 and rs671, were associated with PD. The C allele of rs4767944 served a risk factor toward PD. Further analysis presented a significant association between haplotype frequencies and the risk for PD, primarily driven by the preponderance of the C-T-A (p = 0.03) or C-T-G (p = 0.003) haplotype of rs4767944, rs441, and rs671 in PD patients. In conclusion, these novel results suggest an association between PD susceptibility and ALDH2 genetic variations. PMID:26130061

  19. Genetic variation in the DAOA gene complex: Impact on susceptibility for schizophrenia and on cognitive performance

    PubMed Central

    Opgen-Rhein, Carolin; Lencz, Todd; Burdick, Katherine E.; Neuhaus, Andres H; DeRosse, Pamela; Goldberg, Terry E.; Malhotra, Anil K.

    2008-01-01

    Introduction The genetic region coding for D-amino acid oxidase activator (DAOA) is considered an intriguing susceptibility locus for schizophrenia. However, association studies have often resulted in conflicting findings, and the risk conferring variants and their biological impact remain elusive. Our aim in this study was to investigate the relationship between DAOA variation and schizophrenia, and the influence of DAOA on cognitive performance. Methods We analyzed block structure and association patterns of a ~173 kb region on chromosome 13q33, applying genotype data of 55 SNPs derived from Caucasian North American sample (178 cases, 144 healthy controls). Haplotypes were assigned using the program PHASE and frequencies compared between cases and controls. We applied MANOVA to investigate the relationship between the identified risk haplotype on cognitive performance. Results We identified multiple haplotypes within the region containing the DAOA gene. Of these, one was significantly associated with schizophrenia, being over-represented in schizophrenia versus healthy controls. This haplotype was also associated with one aspect of cognitive performance, semantic fluency. Carriers of the risk haplotype showed better semantic fluency than non-carriers. Conclusions We report a significant effect of DAOA variation on risk for schizophrenia. Moreover, we identified a relationship between DAOA genetic variation and specific aspects of neurocognitive function. As the identified DAOA risk haplotype was associated with better performance on a semantic fluency measure, further work is required to identify the mechanism of DAOA action on CNS function, including the possibility of a role for balanced selection at this locus. PMID:18541412

  20. The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus.

    PubMed

    Kaur, Simranjeet; Mirza, Aashiq H; Brorsson, Caroline A; Fløyel, Tina; Størling, Joachim; Mortensen, Henrik B; Pociot, Flemming

    2016-01-01

    The study aimed to explore the role of ERBB3 in type 1 diabetes (T1D). We examined whether genetic variation of ERBB3 (rs2292239) affects residual β-cell function in T1D cases. Furthermore, we examined the expression of ERBB3 in human islets, the effect of ERBB3 knockdown on apoptosis in insulin-producing INS-1E cells and the genetic and regulatory architecture of the ERBB3 locus to provide insights to how rs2292239 may confer disease susceptibility. rs2292239 strongly correlated with residual β-cell function and metabolic control in children with T1D. ERBB3 locus associated lncRNA (NONHSAG011351) was found to be expressed in human islets. ERBB3 was expressed and down-regulated by pro-inflammatory cytokines in human islets and INS-1E cells; knockdown of ERBB3 in INS-1E cells decreased basal and cytokine-induced apoptosis. Our data suggests an important functional role of ERBB3 and its potential regulators in the β-cells and may constitute novel targets to prevent β-cell destruction in T1D. PMID:26450151

  1. Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn’s disease

    PubMed Central

    Gao, Su-Jun; Zhang, Li; Lu, Wei; Wang, Lu; Chen, Lei; Zhu, Zhen; Zhu, Hai-Hang

    2015-01-01

    AIM: To investigate the correlation between interleukin-18 (IL-18) gene polymorphisms and the risk of developing Crohn’s disease (CD). METHODS: The PubMed, CISCOM, CINAHL, Web of Science, EBSCO, Cochrane Library, MEDLINE, EMBASE and CBM databases were searched without any language restrictions using combinations of keywords relating to CD and IL-18 for relevant articles published before November 1st, 2013. Screening of the published studies retrieved from searches was based on our stringent inclusion and exclusion criteria and resulted in seven eligible studies for meta-analysis. A meta-analysis was conducted using a random-effects model with STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95%CI) were calculated. RESULTS: Seven case-control studies, with a total of 1930 CD cases and 1930 healthy subjects, met our inclusion criteria. The results of our meta-analysis indicated that the IL-18 rs1946518 A>C and rs187238 G>C polymorphisms may correlate with an increased risk of CD under five genetic models (all P < 0.05). Furthermore, we observed positive associations between the IL-18 rs360718 A>C polymorphism and CD risk under three genetic models (C allele vs A allele: OR = 2.03, 95%CI: 1.20-3.43, P = 0.008; CC vs AA+AC: OR = 2.39, 95%CI: 1.2-4.43, P = 0.006; CC vs AC: OR = 2.31, 95%CI: 1.22-4.38, P = 0.010). However, such associations were not found for the IL-18 rs917997 C>T, codon 35 A>C and rs1946519 G>T polymorphisms (all P > 0.05). A subgroup analysis was conducted to investigate the effect of ethnicity on an individual’s susceptibility to CD. Our results revealed positive correlations between IL-18 genetic polymorphisms and an increased risk of CD among Asians and Africans (all P < 0.05), but not among Caucasians (all P > 0.05). CONCLUSION: This meta-analysis indicated that the IL-18 rs1946518 A>C, rs187238 G>C and rs360718 A>C polymorphisms may contribute to susceptibility to CD, especially among Asians and Africans. These polymorphisms are known to reduce IL-18 mRNA and protein levels. PMID:26229413

  2. Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century

    SciTech Connect

    Mortensen, Holly M.; Euling, Susan Y.

    2013-09-15

    Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high-throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization of drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment.

  3. Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis.

    PubMed

    McGillicuddy, Fiona C; Roche, Helen M

    2012-07-01

    Atherosclerosis is a progressive disease that starts early in life and is manifested clinically as coronary artery disease (CAD), cerebrovascular disease, or peripheral artery disease. CAD remains the leading cause of morbidity and mortality in Western society despite the great advances made in understanding its underlying pathophysiology. The key risk factors associated with CAD include hypercholesterolemia, hypertension, poor diet, obesity, age, male gender, smoking, and physical inactivity. Genetics also play an important role that may interact with environmental factors, including diet, nutritional status, and physiological parameters. Furthermore, certain chronic inflammatory conditions also predispose to the development of CAD. The spiraling increase in obesity rates worldwide has made it more pertinent than ever before to understand the metabolic perturbations that link over nutrition to enhanced cardiovascular risk. Great breakthroughs have been made at the pharmacological level to manage CAD; statins and aspirin have revolutionized treatment of CAD and prolonged lifespan. Nonetheless, lifestyle intervention prior to clinical presentation of CAD symptoms would negate/delay the need for chronic pharmacotherapy in at-risk individuals which in turn would relieve healthcare systems of a costly burden. Throughout this review, we debate the relative impact of nutrition versus genetics in driving CAD. We will investigate how overnutrition affects adipose tissue biology and drives IR and will discuss the subsequent implications for the cardiovascular system. Furthermore, we will discuss how lifestyle interventions including diet modification and weight loss can improve both IR and metabolic dyslipidemia that is associated with obesity. We will conclude by delving into the concept that nutritional status interacts with genetic susceptibility, such that perhaps a more personalized nutrition approach may be more effective in determining diet-related risk as well as response to nutritional interventions. PMID:22760984

  4. Experimental transmission of U.S. scrapie agent by nasal, peritoneal and conjunctival routes to genetically susceptible sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scrapie is a naturally occurring fatal neurodegenerative disease of sheep and goats. This study documents incubation periods, pathological findings and distribution of abnormal prion proteins (PrP**Sc) by immunohistochemistry in tissues of genetically susceptible sheep inoculated with U.S. sheep scr...

  5. Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility

    PubMed Central

    Zeller, Tanja; Wild, Philipp; Szymczak, Silke; Rotival, Maxime; Schillert, Arne; Castagne, Raphaele; Maouche, Seraya; Germain, Marine; Lackner, Karl; Rossmann, Heidi; Eleftheriadis, Medea; Sinning, Christoph R.; Schnabel, Renate B.; Lubos, Edith; Mennerich, Detlev; Rust, Werner; Perret, Claire; Proust, Carole; Nicaud, Viviane; Loscalzo, Joseph; Hübner, Norbert; Tregouet, David; Münzel, Thomas; Ziegler, Andreas; Tiret, Laurence

    2010-01-01

    Background Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. Methodology/Principal Findings To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78×10−12), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9×10−7), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself. Conclusions/Significance This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment. PMID:20502693

  6. The Association between Carbohydrate-Rich Foods and Risk of Cardiovascular Disease Is Not Modified by Genetic Susceptibility to Dyslipidemia as Determined by 80 Validated Variants

    PubMed Central

    Sonestedt, Emily; Hellstrand, Sophie; Schulz, Christina-Alexandra; Wallström, Peter; Drake, Isabel; Ericson, Ulrika; Gullberg, Bo; Hedblad, Bo; Orho-Melander, Marju

    2015-01-01

    Background It is still unclear whether carbohydrate consumption is associated with cardiovascular disease (CVD) risk. Genetic susceptibility might modify the associations between dietary intakes and disease risk. Objectives The aim was to examine the association between the consumption of carbohydrate-rich foods (vegetables, fruits and berries, juice, potatoes, whole grains, refined grains, cookies and cakes, sugar and sweets, and sugar-sweetened beverages) and the risk of incident ischemic CVD (iCVD; coronary events and ischemic stroke), and whether these associations differ depending on genetic susceptibility to dyslipidemia. Methods Among 26,445 individuals (44–74 years; 62% females) from the Malmö Diet and Cancer Study cohort, 2,921 experienced an iCVD event during a mean follow-up time of 14 years. At baseline, dietary data were collected using a modified diet history method, and clinical risk factors were measured in 4,535 subjects. We combined 80 validated genetic variants associated with triglycerides and HDL-C or LDL-C, into genetic risk scores and examined the interactions between dietary intakes and genetic risk scores on the incidence of iCVD. Results Subjects in the highest intake quintile for whole grains had a 13% (95% CI: 3–23%; p-trend: 0.002) lower risk for iCVD compared to the lowest quintile. A higher consumption of foods rich in added sugar (sugar and sweets, and sugar-sweetened beverages) had a significant cross-sectional association with higher triglyceride concentrations and lower HDL-C concentrations. A stronger positive association between a high consumption of sugar and sweets on iCVD risk was observed among those with low genetic risk score for triglycerides (p-interaction=0.05). Conclusion In this prospective cohort study that examined food sources of carbohydrates, individuals with a high consumption of whole grains had a decreased risk of iCVD. No convincing evidence of an interaction between genetic susceptibility for dyslipidemia, measured as genetic risk scores of dyslipidemia-associated variants, and the consumption of carbohydrate-rich foods on iCVD risk was observed. PMID:25898210

  7. Genetic Variants in GAPDH Confer Susceptibility to Sporadic Parkinsons Disease in a Chinese Han Population

    PubMed Central

    Chen, Chunnuan; Huang, Jinsha; Zhang, Guoxin; Xu, Xiaoyun; Shen, Yan; Lin, Zhicheng; Wang, Tao

    2015-01-01

    Background Accumulating evidence has demonstrated that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a part of Lewy body inclusions and involves the pathogenesis of Parkinsons disease (PD). However, it remains unknown whether or not genetic variation at the GAPDH locus contributes to the risk for PD. Methods A total of 302 sporadic PD patients and 377 control subjects were recruited in our study for assessing two single nucleotide polymorphisms (rs3741918 and rs1060619) in the GAPDH gene. Both allelic association and additive models were used to analyze association between GAPDH variants and risk for PD. Results Both polymorphisms were significantly associated with risk for PD after correction by Bonferroni multiple testing. The minor allele of rs3741918 was associated with decreased risk of sporadic PD (allelic contrast, OR = 0.74, 95% CI: 0.590.93, corrected P = 0.028; additive model, OR = 0.73, 95% CI: 0.580.92, corrected P = 0.018). While for the rs1060619 locus, the minor allele conferred increased risk for PD (allelic contrast, OR = 1.41, 95% CI: 1.141.75, corrected P = 0.007; additive model, OR = 1.43, 95% CI: 1.151.79, corrected P = 0.002). Conclusion Our study indicates that GAPDH variants confer susceptibility to sporadic PD in a Chinese Han population, which is consistent with the role of GAPDH protein in neuronal apoptosis. To our knowledge, this is the first study of genetic association between GAPDH locus and risk for PD in the Chinese population. PMID:26258539

  8. Cytogenetic effects from exposure to mixed pesticides and the influence from genetic susceptibility.

    PubMed Central

    Au, W W; Sierra-Torres, C H; Cajas-Salazar, N; Shipp, B K; Legator, M S

    1999-01-01

    Exposure to pesticides remains a major environmental health problem. Health risk from such exposure needs to be more precisely understood. We conducted three different cytogenetic assays to elucidate the biological effects of exposure to mixed pesticides in 20 Costa Rica farmers (all nonsmokers) compared with 20 matched controls. The farmers were also exposed to dibromochloropropane during the early employment years, and most of them experienced sterility/fertility problems. Our data show that the farmers had consistently higher frequencies of chromosome aberrations, as determined by the standard chromosome aberration assay, and significantly abnormal DNA repair responses (p < 0.05), as determined by the challenge assay, but no statistically significant differences in the tandem-probe fluorescence in situ hybridization (FISH) assay (p > 0.05). Genotype analysis indicates that farmers with certain "unfavorable" versions of polymorphic metabolizing genes (cytochrome P4502E1, the glutathione S-transferases mu and theta, and the paraoxonase genes) had significantly more biological effects, as determined by all three cytogenetic assays, than both the farmers with the "favorable" alleles and the matched controls. A unique observation is that, in individuals who had inherited any of the mentioned "unfavorable" alleles, farmers were consistently underrepresented. In conclusion, the Costa Rican farmers were exposed to genotoxic agents, most likely pesticides, which expressed the induction of biological and adverse health effects. The farmers who had inherited "unfavorable" metabolizing alleles were more susceptible to genotoxic effects than those with "favorable" alleles. Our genotype data suggest that the well-recognized "healthy worker effect" may be influenced by unrecognized occupational selection pressure against genetically susceptible individuals. Images Figure 1 PMID:10339452

  9. VKORC1 and CD-14 genetic polymorphisms associate with susceptibility to cardiovascular and cerebrovascular diseases

    PubMed Central

    Du, Jian; Zhang, Zhiguo; Ge, Yuanyuan; Zhen, Juan; Leng, Jiyan; Wang, Jianmeng

    2015-01-01

    Objective: To investigate the associations of VKORC1 rs2359612 and rs9923231 and CD-14 rs2569190 with susceptibility to cardiovascular and cerebrovascular diseases (CCVD). Methods: A case-control study was conducted with 614 cases of CCVD patients selected at our hospital between January 2011 and June 2012 as case group and 590 healthy individuals participating physical examination during the same period as control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect genotypes of VKORC1 and CD-14 genetic polymorphisms. SHEsis software was used to conduct haplotype analysis and logistic regression analysis was used to identify risk factors for CCVD. Results: The genotype and allele frequencies of VKORC1 rs2359612 and rs9923231 and CD-14 rs2569190 between the case and control groups were statistically different (all P<0.05). Haplotype analysis showed that the frequencies of CAT and TAT haplotypes were significantly higher while the frequencies of TAC and TGC haplotypes were significantly lower in the case group than those in the control group (P = 0.013, 0.029, 0.019 and 0.042, respectively). Logistic regression analysis showed that age, systolic pressure, smoking history and VKORC1 rs2359612 maybe risk factors for CCVD; and body mass index (BMI), diastolic pressure and VKORC1 rs9923231 may be protective factors for CCVD (all P<0.05). Conclusion: VKORC1 rs2359612 and rs9923231, and CD-14 rs2569190 might associate with susceptibility to CCVD. CAT and TAT haplotypes may be risk factors while TAC and TGC haplotype may be protective factors for CCVD. PMID:26884960

  10. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

    PubMed Central

    Antoniou, A C; Cunningham, A P; Peto, J; Evans, D G; Lalloo, F; Narod, S A; Risch, H A; Eyfjord, J E; Hopper, J L; Southey, M C; Olsson, H; Johannsson, O; Borg, A; Passini, B; Radice, P; Manoukian, S; Eccles, D M; Tang, N; Olah, E; Anton-Culver, H; Warner, E; Lubinski, J; Gronwald, J; Gorski, B; Tryggvadottir, L; Syrjakoski, K; Kallioniemi, O-P; Eerola, H; Nevanlinna, H; Pharoah, P D P; Easton, D F

    2008-01-01

    Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 19201929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html). PMID:18349832

  11. Genetic Association Between CDKN1B rs2066827 Polymorphism and Susceptibility to Cancer

    PubMed Central

    Lu, Yongchao; Gao, Kejian; Zhang, Miao; Zhou, Aiyan; Zhou, Xiaoming; Guan, Zhongan; Shi, Xuewen; Ge, Shujian

    2015-01-01

    Abstract Much attention has been directed to the association between cancer risk and rs2066827 polymorphism of the CDKN1B gene. However, the results are indefinitive and inconclusive. This study was devised to evaluate the hypothesis that rs2066827 polymorphism is associated with the risk of cancer. Computer-based databases (EMBASE, PubMed, and CNKI) were used to seek all casecontrol studies evaluating rs2066827 polymorphism and susceptibility to cancer. The genetic risk was assessed by calculating pooled odds ratio (OR) with its corresponding 95% confidence interval (CI). Fixed-effects pooled ORs were calculated by the MantelHaenszel method (Ph?>?0.05), and random-effects pooled ORs were estimated by the DerSimonianLaird method (Ph?susceptibility to cancer, ovarian cancer in particular. PMID:26579796

  12. Disclosing the disclosure: Factors associated with communicating the results of genetic susceptibility testing for Alzheimer’s disease

    PubMed Central

    Ashida, Sato; Koehly, Laura M.; Roberts, J. Scott; Chen, Clara A.; Hiraki, Susan; Green, Robert C.

    2009-01-01

    This study explored the extent to which recipients of genetic susceptibility testing for Alzheimer’s disease (AD) communicated their results to others. It also examined demographic characteristics, along with beliefs about AD, associated with such communication. Participants (N = 271) in a randomized clinical trial involving genetic testing for Apolipoprotein E (APOE) gene variants among first-degree relatives of AD patients reported their communication behaviors 6 weeks after the results disclosure. Information on beliefs about AD and genetic testing was collected at baseline. Eighty-two percent of participants receiving APOE genotype information shared their results with someone. Specifically, 64% shared with family members, 51% with spouse or significant others, 35% with friends, and 12% with health care professionals. Greater AD treatment optimism was associated with communicating results to family (OR=1.43), spouse (OR=1.62), friends (OR =1.81), and health care professionals (OR=2.20). Lower perceived risk (OR=0.98) and higher perceived importance of genetics in the development of AD (OR=1.93) were associated with results communication in general. Lower perceived drawbacks of AD genetic testing was associated with results communication to friends (OR=0.65). Beliefs about AD risks and causes, genetic testing, and development of treatments may partly determine the interpersonal communication patterns of genetic susceptibility test results. PMID:20029710

  13. Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

    PubMed

    Barber, Robert C; Phillips, Nicole R; Tilson, Jeffrey L; Huebinger, Ryan M; Shewale, Shantanu J; Koenig, Jessica L; Mitchel, Jeffrey S; O'Bryant, Sid E; Waring, Stephen C; Diaz-Arrastia, Ramon; Chasse, Scott; Wilhelmsen, Kirk C

    2015-01-01

    Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated. PMID:26625115

  14. Association of Genetic Polymorphisms on Vascular Endothelial Growth Factor and its Receptor Genes with Susceptibility to Coronary Heart Disease

    PubMed Central

    Li, Lei; Pan, Yongquan; Dai, Li; Liu, Bing; Zhang, Dongming

    2016-01-01

    Background Coronary heart disease (CHD) is a cardiovascular disease characterized by high morbidity and mortality. Vascular endothelial growth factor (VEGF) and its receptor, named kinase insert domain-containing receptor (KDR, or VEGFR2), which are involved with angiogenesis and vascular repair, could partly contribute to the development of CHD. The aim of this study, therefore, was to investigate the potential correlations between genetic polymorphisms on VEGF and KDR and susceptibility to CHD, and the integrative role of SNPs combined on susceptibility to CHD were also studied. Material/Methods Venous blood samples gathered from 533 DCM patients and 533 healthy controls were used to genotype tag-SNPs of VEGF (rs699947, rs2010963, and rs3025010) and KDR (rs2071559, rs2305948, and rs1870377) by polymerase chain reaction (PCR) and SNaPshot assay. Investigations of potential haplotypes were conducted on the basis of SHEsis software. The odds ratio (ORs) and relevant 95% confidence intervals (95% CI) were used to estimate associations of SNPs/haplotypes with risk of CHD. Multivariate logistic regression was also performed, taking certain clinical characteristics (e.g., BMI, smoking, alcohol consumption, diabetes, and hypertension) into consideration. All statistical analyses were done with STATA Version 12.0 software. Results Our results suggest that rs699947 (T>C) on KDR are associated with susceptibility to CHD under the dominant model before (OR=1.35, 95% CI: 1.05–1.73, P=0.019) and after (OR=1.33, 95% CI: 1.01–1.76, P=0.044), allowing for clinical characteristics (e.g., BMI, smoking, alcohol consumption, diabetes, and hypertension). rs2305948 (G>A) and rs1870377 (A>T) on VEGF were also found to be associated with risk of CHD under the recessive model after adjustment with multivariate regression analyses (OR=1.21, 95% CI: 1.02–1.43, P=0.029; OR=2.54, 95% CI: 1.13–5.75, P=0.025); OR=2.83, 95% CI: 1.47–5.46, P=0.002, respectively). Additionally, haplotype analyses revealed that integration of 5 SNPs would either raise (e.g. C-C-T-G-T and T-G-T-G-T) or reduce (e.g. C-C-C-G-T, T-C-T-G-A, T-C-T-G-T, and T-G-T-G-A) risk of CHD. Conclusions Genetic polymorphisms on VEGF (rs699947) and KDR (rs2305948and rs1870377), as well as relevant haplotypes, may serve as genetic markers that might be useful in future investigations on the pathogenesis of CHD. PMID:26726843

  15. Hürthle Cells Predict Hypothyroidism in Interferon-γ Transgenic Mice of Different Genetic Backgrounds

    PubMed Central

    Iwama, Shintaro; De Remigis, Alessandra; Bishop, Justin A.; Kimura, Hiroaki J.

    2012-01-01

    Hürthle cells have long been described in Hashimoto thyroiditis but remain of undetermined significance. We have previously shown that Hürthle cells and hypothyroidism develop in C57BL/6J mice expressing interferon-γ (IFNγ) in the thyroid. To assess the influence of genetic backgrounds on Hürthle cell development, we crossed C57BL/6J IFNγ transgenic mice to 14 strains and analyzed thyroid histopathology and function in a cohort of 389 mice (225 transgenic and 164 wild type) using a multiple linear regression model that also included strain, sex, genotype, and major histocompatibility complex haplotype. We then queried the Johns Hopkins surgical pathology electronic archive for “Hashimoto” and/or “thyroiditis” keywords, reviewed the reports, and reexamined the Hashimoto slides. Hürthle cells were markedly affected by the genetic background: they were prominent and associated with hypothyroidism in the C57BL/6J, C57BL/6ByJ, C57BL/10J, C57BLKS/J, C57L/J, C58/J, and BPN/3J IFNγ transgenic strains, whereas they are mild or absent in the BPH/2J, BPL/1J, LP/J, CBA/J, Balb/cJ, DBA/1J, and NOD/ShiLtJ strains. Hürthle cells were the strongest predictor of hypothyroidism after adjusting for all the other covariates in the regression model. Interestingly, transgenic mice of the BPL/1J, DBA/1J, and NOD/ShiLtJ strains developed a marked accumulation of intrathyroidal brown adipocytes that was significantly associated with improved thyroid function. Hürthle cells were mentioned in 23% of the Hashimoto reports but increased to 79% upon our slide review. This study reports a novel association of Hürhtle cells and brown adipocytes on thyroid function that should prompt a reconsideration of their significance and role in pathogenesis of autoimmune thyroiditis. PMID:22719056

  16. SAP modulates B cell functions in a genetic background-dependent manner

    PubMed Central

    Detre, Cynthia; Yigit, Burcu; Keszei, Marton; Castro, Wilson; Magelky, Erica M.; Terhorst, Cox

    2013-01-01

    Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP−/− CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP−/− animals. It is however not well understood whether in XLP patients and SAP−/− mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP−/− mice and in Rag−/− mice into which B cells derived from SAP−/− mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP−/− mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP−/− mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP−/− mice, suggests potentially novel therapeutic interventions in subsets of XLP patients. PMID:23806511

  17. Genetic background of nontraumatic osteonecrosis of the femoral head in the Korean population.

    PubMed

    Chang, Jun-Dong; Hur, Mina; Lee, Sang-Soo; Yoo, Je-Hyun; Lee, Kyu Man

    2008-05-01

    Major thrombophilic mutations have been identified as risk factors for nontraumatic osteonecrosis of the femoral head (ONFH) in Caucasians. We asked whether the genetic background of patients with ONFH in the Korean population was similar. We analyzed factor V G1691A mutation (factor V Leiden), prothrombin G20210A mutation, and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in 71 patients (53 men, 18 women) with ONFH. We classified these patients as 51 alcohol-induced, 18 idiopathic, one steroid-induced, and one dysbaric. We recruited 200 normal control subjects (128 men, 72 women). We used multiplex PCR/restriction fragment length polymorphism for each genotyping. We observed neither factor V Leiden nor prothrombin G20210A mutation. Although methylenetetrahydrofolate reductase A1298C genotypes were not associated with osteonecrosis, methylenetetrahydrofolate reductase C677T variant genotypes increased the risk of ONFH compared with 677CC. Odds ratios of 677CT and 677CT+TT were 2.00 (95% confidence interval, 1.05-3.81) and 1.96 (95% confidence interval, 1.07-3.59), respectively, compared with 677CC. Our data suggest methylenetetrahydrofolate reductase C677T polymorphism plays a role in the pathogenesis of osteonecrosis in the Korean population. It also implies the genetic risk profile of ONFH may differ among ethnic populations. PMID:18350352

  18. Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions

    PubMed Central

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra; Dunning, Alison M.; Milne, Roger L.; Bojesen, Stig E.; Swerdlow, Anthony; Andrulis, Irene; Brenner, Hermann; Behrens, Sabine; Orr, Nicholas; Jones, Michael; Ashworth, Alan; Li, Jingmei; Cramp, Helen; Connley, Dan; Czene, Kamila; Darabi, Hatef; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Knight, Julia; Glendon, Gord; Mulligan, Anna M.; Dumont, Martine; Severi, Gianluca; Baglietto, Laura; Olson, Janet; Vachon, Celine; Purrington, Kristen; Moisse, Matthieu; Neven, Patrick; Wildiers, Hans; Spurdle, Amanda; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Hamann, Ute; Ko, Yon-Dschun; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Malats, Núria; Arias Perez, JoséI.; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G.; Truong, Théresè; Cordina-Duverger, Emilie; Menegaux, Florence; Silva, Isabel dos Santos; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Cox, Angela; Simard, Jacques; Giles, Graham G.; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A.; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Hall, Per; Easton, Douglas F.; Chang-Claude, Jenny

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci. PMID:24248812

  19. A functional lncRNA HOTAIR genetic variant contributes to gastric cancer susceptibility.

    PubMed

    Pan, Wenting; Liu, Lisheng; Wei, Jinyu; Ge, Yunxia; Zhang, Jingfeng; Chen, Hongwei; Zhou, Liqing; Yuan, Qipeng; Zhou, Changchun; Yang, Ming

    2016-01-01

    Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) acts as an oncogene in gastric cancer development. HOTAIR could induce genome-wide retargeting of polycomb-repressive complex 2, trimethylates histone H3 lysine-27 (H3K27me3) and deregulation of multiple downstream genes. Additionally, as the ceRNA of miR-331-3p, HOTAIR may modulate HER2 deregulation in gastric cancer cells. We hypothesized that the functional single nucleotide polymorphisms (SNP) in HOTAIR may affect HOTAIR expression and/or its function and, thus, gastric cancer risk. We examined the association between three haplotype-tagging SNPs (htSNP) across the whole HOTAIR locus and gastric cancer risk as well as the functional relevance of a gastric cancer susceptibility SNP rs920778. Genotypes were determined in two independent hospital-based case-control sets that consisted of 800 gastric cancer patients and 1600 controls. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was examined in vitro and in vivo. We found that the HOTAIR rs920778 TT carriers had a 1.66- and 1.87-fold increased gastric cancer risk in Jinan and Huaian populations compared with the CC carriers (P = 4.2 × 10(-4) and 6.5 × 10(-5) ). During inspecting functional relevance of the rs920778 SNP, we observed an allelic regulation of rs920778 on HOTAIR expression in both gastric cancer cell lines and tissue samples, with higher HOTAIR expression among T allele carriers. These findings elucidate that functional genetic variants influencing lncRNA expression may explain a portion of gastric cancer genetic basis. © 2015 Wiley Periodicals, Inc. PMID:25640751

  20. Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.

    PubMed

    Dai, Wei; Zheng, Hong; Cheung, Arthur Kwok Leung; Tang, Clara Sze-Man; Ko, Josephine Mun Yee; Wong, Bonnie Wing Yan; Leong, Merrin Man Long; Sham, Pak Chung; Cheung, Florence; Kwong, Dora Lai-Wan; Ngan, Roger Kai Cheong; Ng, Wai Tong; Yau, Chun Chung; Pan, Jianji; Peng, Xun; Tung, Stewart; Zhang, Zengfeng; Ji, Mingfang; Chiang, Alan Kwok-Shing; Lee, Anne Wing-Mui; Lee, Victor Ho-Fun; Lam, Ka-On; Au, Kwok Hung; Cheng, Hoi Ching; Yiu, Harry Ho-Yin; Lung, Maria Li

    2016-03-22

    Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying theMST1Rpathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating thatMST1Rgerm-line variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, fiveMST1Rmissense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%,P= 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that theMST1Rvariant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0).MST1Ris predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation ofMST1Rwas identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation atMST1Rwere often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways. PMID:26951679

  1. Depression from childhood into late adolescence: Influence of gender, development, genetic susceptibility, and peer stress.

    PubMed

    Hankin, Benjamin L; Young, Jami F; Abela, John R Z; Smolen, Andrew; Jenness, Jessica L; Gulley, Lauren D; Technow, Jessica R; Gottlieb, Andrea Barrocas; Cohen, Joseph R; Oppenheimer, Caroline W

    2015-11-01

    Depression is a debilitating mental illness with clear developmental patterns from childhood through late adolescence. Here, we present data from the Gene Environment Mood (GEM) study, which used an accelerated longitudinal cohort design with youth (N = 665) starting in 3rd, 6th, and 9th grades, and a caretaker, who were recruited from the general community, and were then assessed repeatedly through semistructured diagnostic interviews every 6 months over 3 years (7 waves of data) to establish and then predict trajectories of depression from age 8 to 18. First, we demonstrated that overall prevalence rates of depression over time, by age, gender, and pubertal status, in the GEM study closely match those trajectories previously obtained in past developmental epidemiological research. Second, we tested whether a genetic vulnerability-stress model involving 5-HTTLPR and chronic peer stress was moderated by developmental factors. Results showed that older aged adolescents with SS/SL genotype, who experienced higher peer chronic stress over 3 years, were the most likely to be diagnosed with a depressive episode over time. Girls experiencing greater peer chronic stress were the most likely to develop depression. This study used repeated assessments of diagnostic interviewing in a moderately large sample of youth over 3 years to show that depression rates increase in middle to late adolescence, or postpubertally, and that the gender difference in depression emerges earlier in adolescence (age 12.5), or postpubertally. Additionally, genetically susceptible older adolescents who experience chronic peer stress were the most likely to become depressed over time. PMID:26595469

  2. Genetic Variation in CLDN1 and Susceptibility to Hepatitis C Virus Infection

    PubMed Central

    Bekker, Vincent; Chanock, Stephen J.; Yeager, Meredith; Hutchinson, Amy A.; von Hahn, Thomas; Chen, Sabrina; Xiao, Nianqing; Dotrang, Myhanh; Brown, Merideth; Busch, Michael P.; Edlin, Brian R.; Rice, Charles M.; O'Brien, Thomas R.

    2010-01-01

    Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 (CLDN1) could play a role in HCV infection, we conducted a ‘whole gene association study’ among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV (n=658) to those in IDUs who had cleared HCV (n=199) or remained HCV-uninfected (n=68). Analyses were controlled for racial ancestry (African American or European American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs -15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00-2.94; p=0.048], -7153A (OR, 2.13; 95% CI, 1.25-3.62; p=0.006) and -5414C (OR, 1.78; 95% CI, 1.06-3.00; p=0.03). HCV-uninfected participants less often carried CLDN1 IVS1-2983C (OR, 0.55; 95% CI, 0.31-0.97; p=0.04), which lies in intron 1. CLDN1 -15312C, -7153A and -5414C formed a haplotype in both the African American and European American participants and a haplotype analysis supported the association of CLDN1 -7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection. PMID:19674288

  3. Unifying Genetic Canalization, Genetic Constraint, and Genotype-by-Environment Interaction: QTL by Genomic Background by Environment Interaction of Flowering Time in Boechera stricta

    PubMed Central

    Lee, Cheng-Ruei; Anderson, Jill T.; Mitchell-Olds, Thomas

    2014-01-01

    Natural populations exhibit substantial variation in quantitative traits. A quantitative trait is typically defined by its mean and variance, and to date most genetic mapping studies focus on loci altering trait means but not (co)variances. For single traits, the control of trait variance across genetic backgrounds is referred to as genetic canalization. With multiple traits, the genetic covariance among different traits in the same environment indicates the magnitude of potential genetic constraint, while genotype-by-environment interaction (GxE) concerns the same trait across different environments. While some have suggested that these three attributes of quantitative traits are different views of similar concepts, it is not yet clear, however, whether they have the same underlying genetic mechanism. Here, we detect quantitative trait loci (QTL) influencing the (co)variance of phenological traits in six distinct environments in Boechera stricta, a close relative of Arabidopsis. We identified nFT as the QTL altering the magnitude of phenological trait canalization, genetic constraint, and GxE. Both the magnitude and direction of nFT's canalization effects depend on the environment, and to our knowledge, this reversibility of canalization across environments has not been reported previously. nFT's effects on trait covariance structure (genetic constraint and GxE) likely result from the variable and reversible canalization effects across different traits and environments, which can be explained by the interaction among nFT, genomic backgrounds, and environmental stimuli. This view is supported by experiments demonstrating significant nFT by genomic background epistatic interactions affecting phenological traits and expression of the candidate gene, FT. In contrast to the well-known canalization gene Hsp90, the case of nFT may exemplify an alternative mechanism: Our results suggest that (at least in traits with major signal integrators such as flowering time) genetic canalization, genetic constraint, and GxE may have related genetic mechanisms resulting from interactions among major QTL, genomic backgrounds, and environments. PMID:25340779

  4. Genetic Anthropology of the Colorectal Cancer–Susceptibility Allele APC I1307K: Evidence of Genetic Drift within the Ashkenazim

    PubMed Central

    Niell, Bethany L.; Long, Jeffrey C.; Rennert, Gad; Gruber, Stephen B.

    2003-01-01

    The adenomatous polyposis coli (APC) I1307K allele is found in 6% of the Ashkenazi Jewish population and in 1%–2% of Sephardi Jews; it confers a relative risk of 1.5–2.0 for colorectal cancer (CRC) on all carriers. Within the Ashkenazim, the existence of numerous high-prevalence mutations, including I1307K, has sparked controversy over whether genetic drift or selection is the underlying cause. For the present population-based case-control study of CRC in Israel, we tested whether selection has operated at I1307K. We also estimated the age of the I1307K allele, to understand its origin in the context of the Jewish diasporas and subsequent founder events. We genotyped 83 matched pairs, in which one or both members of the pair carried I1307K, at three microsatellites and two SNPs. Haplotypes were statistically constructed using PHASE software. Single-marker age estimates for I1307K were calculated using the approach described by Risch et al. A common progenitor haplotype spanned across APC I1307K from the centromeric marker D5S135 to the telomeric marker D5S346 and was observed in individuals of Ashkenazi, Sephardi, and Arab descent. The ancestor of modern I1307K alleles existed 87.9–118 generations ago (∼2,200–2,950 years ago). This age estimate indicates that I1307K existed at about the time of the beginning of the Jewish diaspora, explaining its presence in non-Ashkenazi populations. Our data do not indicate that selection operated at I1307K (D5S346, P=.114; D5S135, P=.373), providing compelling evidence that the high frequency of disease-susceptibility alleles in the Ashkenazim is due to genetic drift, not selection. This research underscores the importance of the migratory patterns of ancestral populations in the ethnic and geographic distribution of APC I1307K. PMID:14624392

  5. Genetic background and GxE interactions modulate the penetrance of a naturally occurring wing mutation in Drosophila melanogaster.

    PubMed

    Lachance, Joseph; Jung, Lawrence; True, John R

    2013-11-01

    Many genes involved in producing complex traits are incompletely penetrant. One such example is vesiculated, an X-linked gene in Drosophila melanogaster that results in wing defects. To examine the genetic architecture of a complex trait (wings containing vesicles), we placed a naturally occurring variant into multiple autosomal backgrounds and quantified penetrance and expressivity at a range of developmental temperatures. We found significant epistasis, genotype-by-environment interactions, and maternal effects. Sex and temperature effects were modulated by genetic background. The severity of wing phenotypes also varied across different genetic backgrounds, and expressivity was positively correlated with penetrance. We also found evidence of naturally segregating suppressors of vesiculated. These suppressors were present on both the second and third chromosomes, and complex interactions were observed. Taken together, these findings indicate that multiple genetic and environmental factors modulate the phenotypic effects of a naturally occurring vesiculated allele. PMID:24002866

  6. MeCP2 Related Studies Benefit from the Use of CD1 as Genetic Background.

    PubMed

    Cobolli Gigli, Clementina; Scaramuzza, Linda; Gandaglia, Anna; Bellini, Elisa; Gabaglio, Marina; Parolaro, Daniela; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta; Bedogni, Francesco

    2016-01-01

    MECP2 mutations cause a number of neurological disorders of which Rett syndrome (RTT) represents the most thoroughly analysed condition. Many Mecp2 mouse models have been generated through the years; their validity is demonstrated by the presence of a broad spectrum of phenotypes largely mimicking those manifested by RTT patients. These mouse models, between which the C57BL/6 Mecp2tm1.1Bird strain probably represents the most used, enabled to disclose much of the roles of Mecp2. However, small litters with little viability and poor maternal care hamper the maintenance of the colony, thus limiting research on such animals. For this reason, past studies often used Mecp2 mouse models on mixed genetic backgrounds, thus opening questions on whether modifier genes could be responsible for at least part of the described effects. To verify this possibility, and facilitate the maintenance of the Mecp2 colony, we transferred the Mecp2tm1.1Bird allele on the stronger CD1 background. The CD1 strain is easier to maintain and largely recapitulates the phenotypes already described in Mecp2-null mice. We believe that this mouse model will foster the research on RTT. PMID:27097329

  7. MeCP2 Related Studies Benefit from the Use of CD1 as Genetic Background

    PubMed Central

    Cobolli Gigli, Clementina; Scaramuzza, Linda; Gandaglia, Anna; Bellini, Elisa; Gabaglio, Marina; Parolaro, Daniela; Kilstrup-Nielsen, Charlotte; Bedogni, Francesco

    2016-01-01

    MECP2 mutations cause a number of neurological disorders of which Rett syndrome (RTT) represents the most thoroughly analysed condition. Many Mecp2 mouse models have been generated through the years; their validity is demonstrated by the presence of a broad spectrum of phenotypes largely mimicking those manifested by RTT patients. These mouse models, between which the C57BL/6 Mecp2tm1.1Bird strain probably represents the most used, enabled to disclose much of the roles of Mecp2. However, small litters with little viability and poor maternal care hamper the maintenance of the colony, thus limiting research on such animals. For this reason, past studies often used Mecp2 mouse models on mixed genetic backgrounds, thus opening questions on whether modifier genes could be responsible for at least part of the described effects. To verify this possibility, and facilitate the maintenance of the Mecp2 colony, we transferred the Mecp2tm1.1Bird allele on the stronger CD1 background. The CD1 strain is easier to maintain and largely recapitulates the phenotypes already described in Mecp2-null mice. We believe that this mouse model will foster the research on RTT. PMID:27097329

  8. Genetic associations of FCRL3 polymorphisms with the susceptibility of Graves ophthalmopathy in a Chinese population

    PubMed Central

    Wu, Shanshan; Cai, Ting; Chen, Feng; He, Xuefei; Cui, Zhihua

    2015-01-01

    Background: Graves ophthalmopathy (GO) is a form of autoimmune thyroid disease commonly found in approximately 25-50% patients with Graves’ disease. Both the thyroid-specific genes and immune-modulating genes are involved in susceptibility to GO. However, even though FCRL3 polymorphisms were also autoimmune-associated genes, no study has been performed regarding the association of FCRL3 with GO. Therefore, the objective of the current study was to conduct a basic case-control study in a Chinese population. Methods and materials: Seven SNPs were selected in this case-control study and 577 GD patients and 608 controls were recruited. Odds ratio and 95% confidence interval were used to assess the association between susceptibility of GO and FCRL3 polymorphisms with Stata software (Version 11.0, Stata Corp LP, USA). Results: The case-control analysis showed that three polymorphisms, FCRL3_3C, FCRL3_5C, FCRL3_6A, were significantly associated with raised risk of GO in a Chinese Han population in the allelic model [OR = 1.28, 95% CI: 1.09-1.51, P = 0.003; OR = 1.26, 95% CI: 1.07-1.48, P = 0.005; OR = 1.25, 95% CI: 1.06-1.47, P = 0.007]. Conclusions: This case-control analysis confirmed that the FCRL3_3, FCRL3_5 and FCRL3_6 polymorphisms were associated with significantly increased risk of GO in a Chinese population. PMID:26629249

  9. Correlation between genetic susceptibility of tuberculosis and macrophage migration inhibitory factor.

    PubMed

    Wang, Y L; Zhang, C X; Shi, G C; Zhang, Q Y; Liu, W G

    2016-01-01

    This paper aims to study the relationship between genetic susceptibility of tuberculosis and macrophage migration inhibitory factor (MIF) and provide theoretical basis and foundation for further studies on pathogenesis and treatment of tuberculosis. Enzyme Linked Immuno Sorbent Assay (ELISA) was applied to detect the difference of MIF protein expression level in peripheral serum of the test subjects, and analyze the difference of MIF protein expression levels of different genotypes and alleles at -794CATT locus and -173G/C locus. The results showed that MIF protein expression level in serum of patients in the tuberculosis group was higher than that of the healthy control group (p less than 0.05). The MIF protein expression level of genotype (5/5+5/6+6/6) and (7/X+8/X) at -794CATT locus of the tuberculosis group was higher than that of the healthy control group (p less than 0.05), and MIF protein expression level of genotype GG and (GC+CC) at -173G/C locus of the tuberculosis group was higher than that of the healthy control group (p less than 0.05). Therefore, macrophage migration inhibitory factor is an important cell factor which plays a regulating role in the immune system, as it can inhibit macrophage migration and promote the gathering, infiltration and proliferation of macrophages at inflammatory sites. Furthermore, it can secrete some cell factors which play a central role in immunological regulation. PMID:27049098

  10. Glutamate carboxypeptidase II (GCPII) genetic variants as determinants of hyperhomocysteinemia: implications in stroke susceptibility.

    PubMed

    Divyya, Shree; Naushad, Shaik Mohammad; Kaul, Subhash; Anusha, Vuppala; Subbarao, Sreedhar Amere; Kutala, Vijay Kumar

    2012-10-01

    The rationale of this case-control study is to ascertain whether glutamate carboxypeptidase II (GCPII) variants serve as determinants of hyperhomocysteinemia and contribute to the etiology of stroke. Hyperhomocysteinemia was observed in stroke cases compared to controls (14.09 +/- 7.62 micromol/L vs. 8.71 +/- 4.35, P < 0.0001). GCPII sequencing revealed two known variants (R190W and H475Y) and six novel variants (V108A, P160S, Y176H, G206R, G245S and D520E). Among the haplotypes of GCPII, all wild-haplotype H0 showed independent association with stroke risk (OR: 9.89, 95% CI: 4.13-23.68), while H2 representing P160S variant showed reduced risk (OR: 0.17, 95% CI: 0.06-0.50). When compared to subjects with H2 haplotype, H0 haplotype showed elevated homocysteine levels (18.26 +/- 4.31 micromol/L vs. 13.66 +/- 3.72 micromol/L, P = 0.002) and reduced plasma folate levels (7.09 +/- 1.19 ng/ml vs. 8.21 +/- 1.14 ng/ml, P = 0.007). Using GCPII genetic variants, dietary folate and gender as predictor variables and homocysteine as outcome variable, a multiple linear regression model was developed. This model explained 36% variability in plasma homocysteine levels. To conclude, GCPII haplotypes influenced susceptibility to stroke by influencing homocysteine levels. PMID:23259322

  11. Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population

    PubMed Central

    Villanueva, Pia; Newbury, Dianne F; Jara, Lilian; De Barbieri, Zulema; Mirza, Ghazala; Palomino, Hernán M; Fernández, María Angélica; Cazier, Jean-Baptiste; Monaco, Anthony P; Palomino, Hernán

    2011-01-01

    Specific language impairment (SLI) is an unexpected deficit in the acquisition of language skills and affects between 5 and 8% of pre-school children. Despite its prevalence and high heritability, our understanding of the aetiology of this disorder is only emerging. In this paper, we apply genome-wide techniques to investigate an isolated Chilean population who exhibit an increased frequency of SLI. Loss of heterozygosity (LOH) mapping and parametric and non-parametric linkage analyses indicate that complex genetic factors are likely to underlie susceptibility to SLI in this population. Across all analyses performed, the most consistently implicated locus was on chromosome 7q. This locus achieved highly significant linkage under all three non-parametric models (max NPL=6.73, P=4.0 × 10−11). In addition, it yielded a HLOD of 1.24 in the recessive parametric linkage analyses and contained a segment that was homozygous in two affected individuals. Further, investigation of this region identified a two-SNP haplotype that occurs at an increased frequency in language-impaired individuals (P=0.008). We hypothesise that the linkage regions identified here, in particular that on chromosome 7, may contain variants that underlie the high prevalence of SLI observed in this isolated population and may be of relevance to other populations affected by language impairments. PMID:21248734

  12. Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study.

    PubMed

    Ribasés, M; Ramos-Quiroga, J A; Sánchez-Mora, C; Bosch, R; Richarte, V; Palomar, G; Gastaminza, X; Bielsa, A; Arcos-Burgos, M; Muenke, M; Castellanos, F X; Cormand, B; Bayés, M; Casas, M

    2011-03-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable developmental disorder characterized by a persistent impairing pattern of inattention and/or hyperactivity-impulsivity. Using families from a genetic isolate, the Paisa population from Colombia, and five independent datasets from four different populations (United States, Germany, Norway and Spain), a highly consistent association was recently reported between ADHD and the latrophilin 3 (LPHN3) gene, a brain-specific member of the LPHN subfamily of G-protein-coupled receptors that is expressed in ADHD-related regions, such as amygdala, caudate nucleus, cerebellum and cerebral cortex. To replicate the association between LPHN3 and ADHD in adults, we undertook a case-control association study in 334 adult patients with ADHD and 334 controls with 43 single nucleotide polymorphisms (SNPs) covering the LPNH3 gene. Single- and multiple-marker analyses showed additional evidence of association between LPHN3 and combined type ADHD in adulthood [P = 0.0019; df = 1; odds ratio (OR) = 1.82 (1.25-2.70) and P = 5.1e-05; df = 1; OR = 2.25 (1.52-3.34), respectively]. These results further support the LPHN3 contribution to combined type ADHD, and specifically to the persistent form of the disorder, and point at this new neuronal pathway as a common susceptibility factor for ADHD throughout the lifespan. PMID:21040458

  13. HLA-A*31 as a marker of genetic susceptibility to sepsis

    PubMed Central

    da Silva, Fabiano Pinheiro; Preuhs Filho, Germano; Finger, Eduardo; Barbeiro, Hermes Vieira; Zampieri, Fernando Godinho; Goulart, Alessandra Carvalho; Torggler Filho, Francisco; Panajotopoulos, Nicolas; Velasco, Irineu Tadeu; Kalil, Jorge; de Souza, Heraldo Possolo; da Cruz Neto, Luiz Monteiro; Rodrigues, Hélcio

    2013-01-01

    Objective The HLA haplotype has been associated with many autoimmune diseases, but no associations have been described in sepsis. This study aims to investigate the HLA system as a possible marker of genetic sepsis susceptibility. Methods This is a prospective cohort study including patients admitted to an intensive care unit and healthy controls from a list of renal transplant donors. Patients with less 18 years of age; pregnant or HIV positive patients; those with metastatic malignancies or receiving chemotherapy; or with advanced liver disease; or with end-of-life conditions were excluded. The DNA was extracted from the whole blood and HLA haplotypes determined using MiliPlex® technology. Results From October 2010 to October 2012, 1,121 patients were included (1,078 kidney donors, 20 patients admitted with severe sepsis and 23 with septic shock). HLA-A*31 positive subjects had increased risk of developing sepsis (OR 2.36, 95%CI 1.26-5.35). Considering a p value <0.01, no other significant association was identified. Conclusion HLA-A*31 expression is associated to risk of developing sepsis. PMID:24553509

  14. An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation.

    PubMed

    Xue, Jing; Ideraabdullah, Folami Y

    2016-04-01

    In recent years, the etiology of human disease has greatly improved with the inclusion of epigenetic mechanisms, in particular as a common link between environment and disease. However, for most diseases we lack a detailed interpretation of the epigenetic regulatory pathways perturbed by environment and causal mechanisms. Here, we focus on recent findings elucidating nutrient-related epigenetic changes linked to obesity. We highlight studies demonstrating that obesity is a complex disease linked to disruption of epigenetically regulated metabolic pathways in the brain, adipose tissue and liver. These pathways regulate (1) homeostatic and hedonic eating behaviors, (2) adipocyte differentiation and fat accumulation, and (3) energy expenditure. By compiling these data, we illustrate that obesity-related phenotypes are repeatedly linked to disruption of critical epigenetic mechanisms that regulate key metabolic genes. These data are supported by genetic mutation of key epigenetic regulators, and many of the diet-induced epigenetic mechanisms of obesity are also perturbed by exposure to environmental toxicants. Identifying similarly perturbed epigenetic mechanisms in multiple experimental models of obesity strengthens the translational applications of these findings. We also discuss many of the ongoing challenges to understanding the role of environmentally induced epigenetic pathways in obesity and suggest future studies to elucidate these roles. This assessment illustrates our current understanding of molecular pathways of obesity that are susceptible to environmental perturbation via epigenetic mechanisms. Thus, it lays the groundwork for dissecting the complex interactions between diet, genes and toxicants that contribute to obesity and obesity-related phenotypes. PMID:27012616

  15. A QTL for rice grain yield in aerobic environments with large effects in three genetic backgrounds.

    PubMed

    Venuprasad, R; Bool, M E; Quiatchon, L; Atlin, G N

    2012-02-01

    A large-effect QTL associated with grain yield in aerobic environments was identified in three genetic backgrounds, Apo/(2)*Swarna, Apo/(2)*IR72, and Vandana/(2)*IR72, using bulk-segregant analysis (BSA). Apo and Vandana are drought-tolerant aerobic-adapted varieties, while Swarna and IR72 are important lowland rice varieties grown on millions of hectares in Asia but perform poorly in aerobic conditions. Two closely linked rice microsatellite (RM) markers, RM510 and RM19367, located on chromosome 6, were found to be associated with yield under aerobic soil conditions in all three backgrounds. The QTL linked to this marker, qDTY6.1 (DTY, grain yield under drought), was mapped to a 2.2 cM region between RM19367 and RM3805 at a peak LOD score of 32 in the Apo/(2)*Swarna population. The effect of qDTY6.1 was tested in a total of 20 hydrological environments over a period of five seasons and in five populations in the three genetic backgrounds. In the Apo/(2)*Swarna population, qDTY6.1 had a large effect on grain yield under favorable aerobic (R (2) ≤ 66%) and irrigated lowland (R (2) < 39%) conditions but not under drought stress; Apo contributed the favorable allele in all the conditions where an effect was observed. In the Apo/IR72 cross, Apo contributed the favorable allele in almost all the aerobic environments in RIL and BC(1)-derived populations. In the Vandana/IR72 RIL and BC(1)-derived populations, qDTY6.1 had a strong effect on yield in aerobic drought stress, aerobic non-stress, and irrigated lowland conditions; the Vandana allele was favorable in aerobic environments and the IR72 allele was favorable in irrigated lowland environments. We conclude that qDTY6.1 is a large-effect QTL for rice grain yield under aerobic environments and could potentially be used in molecular breeding of rice for aerobic environments. PMID:21938473

  16. iGWAS: Integrative Genome-Wide Association Studies of Genetic and Genomic Data for Disease Susceptibility Using Mediation Analysis.

    PubMed

    Huang, Yen-Tsung; Liang, Liming; Moffatt, Miriam F; Cookson, William O C M; Lin, Xihong

    2015-07-01

    Genome-wide association studies (GWAS) have been a standard practice in identifying single nucleotide polymorphisms (SNPs) for disease susceptibility. We propose a new approach, termed integrative GWAS (iGWAS) that exploits the information of gene expressions to investigate the mechanisms of the association of SNPs with a disease phenotype, and to incorporate the family-based design for genetic association studies. Specifically, the relations among SNPs, gene expression, and disease are modeled within the mediation analysis framework, which allows us to disentangle the genetic effect on a disease phenotype into two parts: an effect mediated through a gene expression (mediation effect, ME) and an effect through other biological mechanisms or environment-mediated mechanisms (alternative effect, AE). We develop omnibus tests for the ME and AE that are robust to underlying true disease models. Numerical studies show that the iGWAS approach is able to facilitate discovering genetic association mechanisms, and outperforms the SNP-only method for testing genetic associations. We conduct a family-based iGWAS of childhood asthma that integrates genetic and genomic data. The iGWAS approach identifies six novel susceptibility genes (MANEA, MRPL53, LYCAT, ST8SIA4, NDFIP1, and PTCH1) using the omnibus test with false discovery rate less than 1%, whereas no gene using SNP-only analyses survives with the same cut-off. The iGWAS analyses further characterize that genetic effects of these genes are mostly mediated through their gene expressions. In summary, the iGWAS approach provides a new analytic framework to investigate the mechanism of genetic etiology, and identifies novel susceptibility genes of childhood asthma that were biologically meaningful. PMID:25997986

  17. Mouse genetic background impacts both on iron and non-iron metals parameters and on their relationships.

    PubMed

    Cavey, Thibault; Ropert, Martine; de Tayrac, Marie; Bardou-Jacquet, Edouard; Island, Marie-Laure; Leroyer, Patricia; Bendavid, Claude; Brissot, Pierre; Loréal, Olivier

    2015-08-01

    Iron is reported to interact with other metals. In addition, it has been shown that genetic background may impact iron metabolism. Our objective was to characterize, in mice of three genetic backgrounds, the links between iron and several non-iron metals. Thirty normal mice (C57BL/6, Balb/c and DBA/2; n = 10 for each group), fed with the same diet, were studied. Quantification of iron, zinc, cobalt, copper, manganese, magnesium and rubidium was performed by ICP/MS in plasma, erythrocytes, liver and spleen. Transferrin saturation was determined. Hepatic hepcidin1 mRNA level was evaluated by quantitative RT-PCR. As previously reported, iron parameters were modulated by genetic background with significantly higher values for plasma iron parameters and liver iron concentration in DBA/2 and Balb/c strains. Hepatic hepcidin1 mRNA level was lower in DBA/2 mice. No iron parameter was correlated with hepcidin1 mRNA levels. Principal component analysis of the data obtained for non-iron metals indicated that metals parameters stratified the mice according to their genetic background. Plasma and tissue metals parameters that are dependent or independent of genetic background were identified. Moreover, relationships were found between plasma and tissue content of iron and some other metals parameters. Our data: (i) confirms the impact of the genetic background on iron parameters, (ii) shows that genetic background may also play a role in the metabolism of non-iron metals, (iii) identifies links between iron and other metals parameters which may have implications in the understanding and, potentially, the modulation of iron metabolism. PMID:26041486

  18. Reversal of Refractory Ulcerative Colitis and Severe Chronic Fatigue Syndrome Symptoms Arising from Immune Disturbance in an HLA-DR/DQ Genetically Susceptible Individual with Multiple Biotoxin Exposures.

    PubMed

    Gunn, Shelly R; Gunn, G Gibson; Mueller, Francis W

    2016-01-01

    BACKGROUND Patients with multisymptom chronic conditions, such as refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS), present diagnostic and management challenges for clinicians, as well as the opportunity to recognize and treat emerging disease entities. In the current case we report reversal of co-existing RUC and CFS symptoms arising from biotoxin exposures in a genetically susceptible individual. CASE REPORT A 25-year-old previously healthy male with new-onset refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS) tested negative for autoimmune disease biomarkers. However, urine mycotoxin panel testing was positive for trichothecene group and air filter testing from the patient's water-damaged rental house identified the toxic mold Stachybotrys chartarum. HLA-DR/DQ testing revealed a multisusceptible haplotype for development of chronic inflammation, and serum chronic inflammatory response syndrome (CIRS) biomarker testing was positive for highly elevated TGF-beta and a clinically undetectable level of vasoactive intestinal peptide (VIP). Following elimination of biotoxin exposures, VIP replacement therapy, dental extractions, and implementation of a mind body intervention-relaxation response (MBI-RR) program, the patient's symptoms resolved. He is off medications, back to work, and resuming normal exercise. CONCLUSIONS This constellation of RUC and CFS symptoms in an HLA-DR/DQ genetically susceptible individual with biotoxin exposures is consistent with the recently described CIRS disease pathophysiology. Chronic immune disturbance (turbatio immuno) can be identified with clinically available CIRS biomarkers and may represent a treatable underlying disease etiology in a subset of genetically susceptible patients with RUC, CFS, and other immune disorders. PMID:27165859

  19. Comparative analysis of genetic background in eight near-isogenic wheat lines with different H genes conferring resistance to Hessian fly.

    PubMed

    Xu, S S; Chu, C G; Harris, M O; Williams, C E

    2011-01-01

    Near-isogenic lines (NILs) are useful for plant genetic and genomic studies. However, the strength of conclusions from such studies depends on the similarity of the NILs' genetic backgrounds. In this study, we investigated the genetic similarity for a set of NILs developed in the 1990s to study gene-for-gene interactions between wheat (Triticum aestivum L.) and the Hessian fly (Mayetiola destructor (Say)), an important pest of wheat. Each of the eight NILs carries a single H resistance gene and was created by successive backcrossing for two to six generations to susceptible T. aestivum 'Newton'. We generated 256 target region amplification polymorphism (TRAP) markers and used them to calculate genetic similarity, expressed by the Nei and Li (NL) coefficient. Six of the NILs (H3, H5, H6, H9, H11, and H13) had the highly uniform genetic background of Newton, with NL coefficients from 0.97 to 0.99. However, genotypes with H10 or H12 were less similar to Newton, with NL coefficients of 0.86 and 0.93, respectively. Cluster analysis based on NL coefficients and pedigree analysis showed that the genetic similarity between each of the NILs and Newton was affected by both the number of backcrosses and the genetic similarity between Newton and the H gene donors. We thus generated an equation to predict the number of required backcrosses, given varying similarity of donor and recurrent parent. We also investigated whether the genetic residues of the donor parents that remained in the NILs were related to linkage drag. By using a complete set of 'Chinese Spring' nullisomic-tetrasomic lines, one third of the TRAP markers that showed polymorphism between the NILs and Newton were assigned to a specific chromosome. All of the assigned markers were located on chromosomes other than the chromosome carrying the H gene, suggesting that the genetic residues detected in this study were not due to linkage drag. Results will aid in the development and use of near-isogenic lines for studies of the functional genomics of wheat. PMID:21217808

  20. Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery

    PubMed Central

    2014-01-01

    Background Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors. Methods In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies. Results We identify 1 coexpression module associated with innominate artery atherosclerosis that is also enriched for inflammatory and macrophage gene signatures. Using a series of bioinformatics analysis, we further prioritize the genes in this pathway and identify Cd44 as a critical mediator of the atherosclerosis. We validate our predictions generated by the network analysis using Cd44 knockout mice. Conclusion These results indicate that alterations in Cd44 expression mediate inflammation through a complex transcriptional network involving a number of previously uncharacterized genes. PMID:25115202

  1. Testing an 'aging gene' in long-lived drosophila strains: increased longevity depends on sex and genetic background.

    PubMed

    Spencer, Christine C; Howell, Christine E; Wright, Amber R; Promislow, Daniel E L

    2003-04-01

    Molecular advances of the past decade have led to the discovery of a myriad of 'aging genes' (methuselah, Indy, InR, Chico, superoxide dismutase) that extend Drosophila lifespan by up to 85%. Despite this life extension, these mutants are no longer lived than at least some recently wild-caught strains. Typically, long-lived mutants are identified in relatively short-lived genetic backgrounds, and their effects are rarely tested in genetic backgrounds other than the one in which they were isolated or derived. However, the mutant's high-longevity phenotype may be dependent on interactions with alleles that are common in short-lived laboratory strains. Here we set out to determine whether one particular mutant could extend lifespan in long-lived genetic backgrounds in the fruit fly, Drosophila melanogaster. We measured longevity and resistance to thermal stress in flies that were transgenically altered to overexpress human superoxide dismutase (SOD) in the motorneurones in each of 10 genotypes. Each genotype carried the genetic background from a different naturally long-lived wild-caught Drosophila strain. While SOD increased lifespan on average, the effect was genotype- and sex-specific. Our results indicate that naturally segregating genes interact epistatically with the aging gene superoxide dismutase to modify its ability to extend longevity. This study points to the need to identify mutants that increase longevity not only in the lab strain of origin but also in naturally long-lived genetic backgrounds. PMID:12882325

  2. Antibiotic Resistance, Virulence, and Genetic Background of Community-Acquired Uropathogenic Escherichia coli from Algeria.

    PubMed

    Yahiaoui, Merzouk; Robin, Frédéric; Bakour, Rabah; Hamidi, Moufida; Bonnet, Richard; Messai, Yamina

    2015-10-01

    The aim of the study was to investigate antibiotic resistance mechanisms, virulence traits, and genetic background of 150 nonrepetitive community-acquired uropathogenic Escherichia coli (CA-UPEC) from Algeria. A rate of 46.7% of isolates was multidrug resistant. bla genes detected were blaTEM (96.8% of amoxicillin-resistant isolates), blaCTX-M-15 (4%), overexpressed blaAmpC (4%), blaSHV-2a, blaTEM-4, blaTEM-31, and blaTEM-35 (0.7%). All tetracycline-resistant isolates (51.3%) had tetA and/or tetB genes. Sulfonamides and trimethoprim resistance genes were sul2 (60.8%), sul1 (45.9%), sul3 (6.7%), dfrA14 (25.4%), dfrA1 (18.2%), dfrA12 (16.3%), and dfrA25 (5.4%). High-level fluoroquinolone resistance (22.7%) was mediated by mutations in gyrA (S83L-D87N) and parC (S80I-E84G/V or S80I) genes. qnrB5, qnrS1, and aac(6')-Ib-cr were rare (5.3%). Class 1 and/or class 2 integrons were detected (40.7%). Isolates belonged to phylogroups B2+D (50%), A+B1 (36%), and F+C+Clade I (13%). Most of D (72.2%) and 38.6% of B2 isolates were multidrug resistant; they belong to 14 different sequence types, including international successful ST131, ST73, and ST69, reported for the first time in the community in Algeria and new ST4494 and ST4529 described in this study. Besides multidrug resistance, B2 and D isolates possessed virulence factors of colonization, invasion, and long-term persistence. The study highlighted multidrug-resistant CA-UPEC with high virulence traits and an epidemic genetic background. PMID:26430940

  3. Eimeria Species and Genetic Background Influence the Serum Protein Profile of Broilers with Coccidiosis

    PubMed Central

    Gilbert, Elizabeth R.; Cox, Chasity M.; Williams, Patricia M.; McElroy, Audrey P.; Dalloul, Rami A.; Ray, W. Keith; Barri, Adriana; Emmerson, Derek A.; Wong, Eric A.; Webb, Kenneth E.

    2011-01-01

    Background Coccidiosis is an intestinal disease caused by protozoal parasites of the genus Eimeria. Despite the advent of anti-coccidial drugs and vaccines, the disease continues to result in substantial annual economic losses to the poultry industry. There is still much unknown about the host response to infection and to date there are no reports of protein profiles in the blood of Eimeria-infected animals. The objective of this study was to evaluate the serum proteome of two genetic lines of broiler chickens after infection with one of three species of Eimeria. Methodology/Principal Findings Birds from lines A and B were either not infected or inoculated with sporulated oocysts from one of the three Eimeria strains at 15 d post-hatch. At 21 d (6 d post-infection), whole blood was collected and lesion scoring was performed. Serum was harvested and used for 2-dimensional gel electrophoresis. A total of 1,266 spots were quantitatively assessed by densitometry. Protein spots showing a significant effect of coccidia strain and/or broiler genetic line on density at P<0.05−0.01 (250 spots), P<0.01−0.001 (248 spots), and P<0.001 (314 spots) were excised and analyzed by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. Proteins were identified in 172 spots. A total of 46 different proteins were identified. Of the spots with a corresponding protein identification, 57 showed a main effect of coccidia infection and/or 2-way interaction of coccidia infection×broiler genetic line at P<0.001. Conclusions/Significance Several of the metabolic enzymes identified in this study are potential candidates for early diagnostic markers of E. acervulina infection including malate dehydrogenase 2, NADH dehydrogenase 1 alpha subcomplex 9, and an ATP synthase. These proteins were detected only in Line A birds that were inoculated with E. acervulina. Results from this study provide a basic framework for future research aimed at uncovering the complex biochemical mechanisms involved in host response to Eimeria infection and in identifying molecular targets for diagnostic screening and development of alternative preventative and therapeutic methods. PMID:21297942

  4. The genetic tumor background is an important determinant for heterogeneous MYCN-amplified neuroblastoma.

    PubMed

    Bogen, Dominik; Brunner, Clemens; Walder, Diana; Ziegler, Andrea; Abbasi, Reza; Ladenstein, Ruth L; Noguera, Rosa; Martinsson, Tommy; Amann, Gabriele; Schilling, Freimut H; Ussowicz, Marek; Benesch, Martin; Ambros, Peter F; Ambros, Inge M

    2016-07-01

    Amplification of MYCN is the signature genetic aberration of 20-25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN-FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di- or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di- or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment. PMID:26910568

  5. Behavioral deficits in an Angelman syndrome model: Effects of genetic background and age

    PubMed Central

    Huang, Hsien-Sung; Burns, Andrew J.; Nonneman, Randal J.; Baker, Lorinda K.; Riddick, Natallia V.; Nikolova, Viktoriya D.; Riday, Thorfinn T.; Yashiro, Koji; Philpot, Benjamin D.; Moy, Sheryl S.

    2013-01-01

    Angelman syndrome (AS) is a severe neurodevelopmental disorder associated with disruption of maternally inherited UBE3A (ubiquitin protein ligase E3A) expression. At the present time, there is no effective treatment for AS. Mouse lines with loss of maternal Ube3a (Ube3am/p+) recapitulate multiple aspects of the clinical AS profile, including impaired motor coordination, learning deficits, and seizures. Thus, these genetic mouse models could serve as behavioral screens for preclinical efficacy testing, a critical component of drug discovery for AS intervention. However, the severity and consistency of abnormal phenotypes reported in Ube3am/p+ mice can vary, dependent upon age and background strain, which is problematic for the detection of beneficial drug effects. As part of an ongoing AS drug discovery initiative, we characterized Ube3am/p+ mice on either a 129S7/SvEvBrd-Hprtb-m2 (129) or C57BL/6J (B6) background across a range of functional domains and ages to identify reproducible and sufficiently large phenotypes suitable for screening therapeutic compounds. The results from the study showed that Ube3am/p+ mice have significant deficits in acquisition and reversal learning in the Morris water maze. The findings also demonstrated that Ube3am/p+ mice exhibit motor impairment in a rotarod task, hypoactivity, reduced rearing and marble-burying, and deficient fear conditioning. Overall, these profiles of abnormal phenotypes can provide behavioral targets for evaluating effects of novel therapeutic strategies relevant to AS. PMID:23295389

  6. Evaluation of genetic damage in Brazilian footwear-workers: biomarkers of exposure, effect, and susceptibility.

    PubMed

    Heuser, Vanina Dahlström; Erdtmann, Bernardo; Kvitko, Kátia; Rohr, Paula; da Silva, Juliana

    2007-04-11

    Employees in the footwear manufacturing industry are routinely exposed to complex mixtures of solvents used in cleaning and as diluents in glues, primers, and degreasers. The objective of this study was to determine the genotoxic effects in a group of footwear-workers occupationally exposed to solvent-based adhesive and solutions containing organic solvents, mainly toluene. Peripheral blood and buccal cells samples were collected from 39 footwear-workers (31 males and 8 females) and 55 controls (44 males and 11 females). As biomarker of exposure, we obtained data on hippuric acid (HA), the main metabolite of toluene in urine, and DNA damage detected by the Comet assay in blood cells. Micronucleus frequencies in binucleated lymphocytes (BNMN) and in epithelial buccal cells (EBCMN) were analyzed as biomarkers of effect, while polymorphisms in genes GSTT1, GSTM1, GSTP1, CYP1A1, and CYP2E1 were used as susceptibility biomarkers. Results of HA and Comet assay showed statistical increased values amongst footwear-workers relative to controls (P < or = 0.001). No differences were observed in BNMN and EBCMN frequencies between the groups, but a correlation test revealed that age was significantly associated with BNMN frequency in both control (r(s)=0.290; P < or = 0.05) and exposed groups (r(s)=0.674; P < or = 0.001). Regarding the results on genetic polymorphisms, GSTM1 null subjects from the control group showed a significant increase in EBCMN frequency relative to GSTM1 non-null subjects (P < or = 0.05). A significant increase in DNA damage detected by Comet assay in leukocytes was obtained for GSTP1 Ile/Val or Val/Val individuals from the exposed group relative to those with GSTP1 Ile/Ile (P < or = 0.05), especially in younger subjects (P < or = 0.01), and a suggestion of interaction with CYP2E1 polymorphism was found. In confirmation of these data, stepwise multiple regression analyses for selecting between the different independent variables showed that about 25% of levels of the DNA damage in footwear-worker can be associated with genetic polymorphisms in GSTP1 and CYP2E1 (P=0.006, F=5.876). PMID:17292523

  7. Personal history of diabetes, genetic susceptibility to diabetes, and risk of brain glioma: a pooled analysis of observational studies

    PubMed Central

    Kitahara, Cari M.; Linet, Martha S.; Brenner, Alina V.; Wang, Sophia S.; Melin, Beatrice S.; Wang, Zhaoming; Inskip, Peter D.; Beane Freeman, Laura E.; Braganza, Melissa Z.; Carreón, Tania; Feychting, Maria; Gaziano, J. Michael; Peters, Ulrike; Purdue, Mark P.; Ruder, Avima M.; Sesso, Howard D.; Shu, Xiao-Ou; Waters, Martha A.; White, Emily; Zheng, Wei; Hoover, Robert N.; Fraumeni, Joseph F.; Chatterjee, Nilanjan; Yeager, Meredith; Chanock, Stephen J.; Hartge, Patricia; Rajaraman, Preetha

    2013-01-01

    Background Brain glioma is a relatively rare and fatal malignancy in adulthood with few known risk factors. Some observational studies have reported inverse associations between diabetes and subsequent glioma risk, but possible mechanisms are unclear. Methods We conducted a pooled analysis of original data from five nested case-control studies and two case-control studies from the U.S. and China that included 962 glioma cases and 2,195 controls. We examined self-reported diabetes history in relation to glioma risk, as well as effect modification by seven glioma risk-associated single-nucleotide polymorphisms (SNPs). We also examined the associations between 13 diabetes risk-associated SNPs, identified from genome-wide association studies, and glioma risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression models. Results We observed a 42% reduced risk of glioma for individuals with a history of diabetes (OR=0.58, 95% CI: 0.40–0.84). The association did not differ by sex, study design, or after restricting to glioblastoma, the most common histological sub-type. We did not observe any significant per-allele trends among the 13 diabetes-related SNPs examined in relation to glioma risk. Conclusion These results support an inverse association between diabetes history and glioma risk. The role of genetic susceptibility to diabetes cannot be excluded, and should be pursued in future studies together with other factors that might be responsible for the diabetes-glioma association. Impact These data suggest the need for studies that can evaluate, separately, the association between type 1 and type 2 diabetes and subsequent risk of adult glioma. PMID:24220915

  8. HLA-B*1301 as a Biomarker for Genetic Susceptibility to Hypersensitivity Dermatitis Induced by Trichloroethylene among Workers in China

    PubMed Central

    Li, Haishan; Dai, Yufei; Huang, Hanlin; Li, Laiyu; Leng, Shuguang; Cheng, Juan; Niu, Yong; Duan, Huawei; Liu, Qingjun; Zhang, Xing; Huang, Xianqing; Xie, Jinxin; Feng, Zhiming; Wang, Juncai; He, Jiaxi; Zheng, Yuxin

    2007-01-01

    Background Trichloroethylene (TCE) is used extensively as an industrial solvent and has been recognized as one of the major environmental pollutants. To date, > 200 cases of TCE-induced hypersensitivity dermatitis among exposed workers have been reported worldwide, and TCE exposure has become one of the critical occupational health issues in Asia. Objectives The study aimed to identify genetic susceptible biomarkers associated with the TCE-induced hypersensitivity dermatitis in genes located in the human leukocyte antigen (HLA) region. Methods From 1998 to 2006, 121 cases with TCE-induced hypersensitivity dermatitis and 142 tolerant controls were recruited into the population-based case–control study. We determined HLA alleles B, DRB1, DQA1, and DQB1, by sequence-based typing. p-Values were corrected for comparisons of multiple HLA alleles. In addition, we compared and analyzed the structure character of amino acid residues of HLA molecules found in participants. Results We obtained complete genotyping data of 113 cases and 142 controls. The allele HLA-B*1301 was present in 83 (73.5%) of 113 patients compared with 13 (9.2%) of 142 tolerant workers (odds ratio = 27.5; 95% confidence interval, 13.5–55.7; corrected p = 1.48 × 10−21). In addition, the HLA-B*44 alleles were present in 6.2% (7/113) of patients, but were absent in TCE-tolerant workers. Residue 95 shared by HLA-B*1301 and HLA-B*44 molecules formed a different pocket F than other residues. Conclusions The allele HLA-B*1301 is strongly associated with TCE-induced hypersensitivity dermatitis among exposed workers and might be used as a biomarker to predict high risk individuals to TCE. PMID:18007983

  9. Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population

    PubMed Central

    Ban, Yoshiyuki; Taniyama, Matsuo; Yanagawa, Tatsuo; Yamada, Satoru; Maruyama, Taro; Kasuga, Akira; Ban, Yoshio

    2001-01-01

    Background Vitamin D has been shown to exert manifold immunomodulatory effects. Type 1 diabetes mellitus (T1DM) is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse. We studied the association between T1DM and the initiation codon polymorphism in exon 2 of the vitamin D receptor gene in a Japanese population. We also investigated associations between the vitamin D receptor polymorphism and GAD65-antibody (Ab) positivity. We carried out polymerase chain reaction-restriction fragment length polymorphism analysis in 110 Japanese T1DM patients and 250 control subjects. GAD65 antibodies were assessed in 78 patients with T1DM. Results We found a significantly higher prevalence of the F allele / the FF genotype in the patients compared to the controls (P = 0.0069 and P = 0.014, respectively). Genotype and allele frequencies differed significantly between GAD65-Ab-positive patients and controls (P = 0.017 and P = 0.012, respectively), but neither between GAD65-Ab-negative patients and controls (P = 0.68 and P = 0.66, respectively) nor between GAD65-Ab-positive and -negative patients (P = 0.19 and P = 0.16, respectively). Conclusions Our findings suggest that the vitamin D receptor initiation codon polymorphism influences genetic susceptibility to T1DM among the Japanese. This polymorphism is also associated with GAD65-Ab-positive T1DM, although the absence of a significant difference between GAD65-Ab-negative patients and controls might be simply due to the small sample size of patients tested for GAD65 antibodies. PMID:11445000

  10. The impact of the genetic background in the Noonan syndrome phenotype induced by K-RasV14I

    PubMed Central

    Hernández-Porras, Isabel; Jiménez-Catalán, Beatriz; Schuhmacher, Alberto J; Guerra, Carmen

    2015-01-01

    Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant fraction of NS-patients also develop myeloproliferative disorders. The penetrance of these defects varies considerably among patients. In this study, we have examined the effect of 2 genetic backgrounds (C57BL/6J.OlaHsd and 129S2/SvPasCrl) on the phenotypes displayed by a mouse model of NS induced by germline expression of the mutated K-RasV14I allele, one of the most frequent NS-KRAS mutations. Our results suggest the presence of genetic modifiers associated to the genetic background that are essential for heart development and function at early stages of postnatal life as well as in the severity of the haematopoietic alterations. PMID:26458870

  11. Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans

    PubMed Central

    Chen, Fang; Chen, Gary K.; Millikan, Robert C.; John, Esther M.; Ambrosone, Christine B.; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J.; Ziegler, Regina G.; Deming, Sandra L.; Bandera, Elisa V.; Nyante, Sarah; Palmer, Julie R.; Rebbeck, Timothy R.; Ingles, Sue A.; Press, Michael F.; Rodriguez-Gil, Jorge L.; Chanock, Stephen J.; Le Marchand, Loïc; Kolonel, Laurence N.; Henderson, Brian E.; Stram, Daniel O.; Haiman, Christopher A.

    2011-01-01

    Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) = 1.18, P = 2.8 × 10−24 versus OR = 1.04, P = 6.1 × 10−5]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry. PMID:21852243

  12. Association of Environmental Arsenic Exposure, Genetic Polymorphisms of Susceptible Genes, and Skin Cancers in Taiwan

    PubMed Central

    Hsu, Ling-I; Wu, Meei-Maan; Wang, Yuan-Hung; Lee, Cheng-Yeh; Yang, Tse-Yen; Hsiao, Bo-Yu; Chen, Chien-Jen

    2015-01-01

    Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1), reactive oxygen species (ROS) related metabolic genes (NQO1, EPHX1, and HO-1), and DNA repair genes (XRCC1, XPD, hOGG1, and ATM) together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR) and 95% confidence interval (CI) using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01–8.83; OR = 2.04, 95% CI = 0.99–4.27; OR = 1.74, 95% CI = 1.00–3.02, resp.). However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated. PMID:26295053

  13. Effects of Vendor and Genetic Background on the Composition of the Fecal Microbiota of Inbred Mice

    PubMed Central

    Ericsson, Aaron C.; Davis, J. Wade; Spollen, William; Bivens, Nathan; Givan, Scott; Hagan, Catherine E.; McIntosh, Mark; Franklin, Craig L.

    2015-01-01

    The commensal gut microbiota has been implicated as a determinant in several human diseases and conditions. There is mounting evidence that the gut microbiota of laboratory mice (Mus musculus) similarly modulates the phenotype of mouse models used to study human disease and development. While differing model phenotypes have been reported using mice purchased from different vendors, the composition and uniformity of the fecal microbiota in mice of various genetic backgrounds from different vendors is unclear. Using culture-independent methods and robust statistical analysis, we demonstrate significant differences in the richness and diversity of fecal microbial populations in mice purchased from two large commercial vendors. Moreover, the abundance of many operational taxonomic units, often identified to the species level, as well as several higher taxa, differed in vendor- and strain-dependent manners. Such differences were evident in the fecal microbiota of weanling mice and persisted throughout the study, to twenty-four weeks of age. These data provide the first in-depth analysis of the developmental trajectory of the fecal microbiota in mice from different vendors, and a starting point from which researchers may be able to refine animal models affected by differences in the gut microbiota and thus possibly reduce the number of animals required to perform studies with sufficient statistical power. PMID:25675094

  14. Fitness cost due to herbicide resistance may trigger genetic background evolution.

    PubMed

    Darmency, Henri; Menchari, Yosra; Le Corre, Valérie; Délye, Christophe

    2015-01-01

    This article investigates the possible existence of mechanisms counterbalancing the negative pleiotropic effects on development and reproduction that are conferred by alleles responsible for herbicide resistance in the weed Alopecurus myosuroides. We considered three herbicide-resistant, mutant acetyl-coenzyme A carboxylase (ACCase) alleles, Leu1781, Asn2041, and Gly2078, found in eight resistant populations. Of these, Gly2078 is the only allele with a known fitness cost. We compared plants homozygous for wild-type ACCase alleles that were siblings of plants carrying a given mutant resistant ACCase allele with plants from three populations where resistance did not evolve. In each of two series of experiments, we measured germination dynamics, seedling vigor, plant height, vegetative biomass, and seed production. The wild-type siblings of plants carrying Gly2078 performed better in the field, on average, than wild-type plants that were sibling of plants carrying other mutant ACCase alleles, and particularly those carrying Leu1781. We propose that rapid evolution of the genetic background of plants from the populations where the Gly2078 allele originally arose could partially counterbalance Gly2078 fitness cost, enhancing the spread of the resistant genotypes. PMID:25255698

  15. Effects of vendor and genetic background on the composition of the fecal microbiota of inbred mice.

    PubMed

    Ericsson, Aaron C; Davis, J Wade; Spollen, William; Bivens, Nathan; Givan, Scott; Hagan, Catherine E; McIntosh, Mark; Franklin, Craig L

    2015-01-01

    The commensal gut microbiota has been implicated as a determinant in several human diseases and conditions. There is mounting evidence that the gut microbiota of laboratory mice (Mus musculus) similarly modulates the phenotype of mouse models used to study human disease and development. While differing model phenotypes have been reported using mice purchased from different vendors, the composition and uniformity of the fecal microbiota in mice of various genetic backgrounds from different vendors is unclear. Using culture-independent methods and robust statistical analysis, we demonstrate significant differences in the richness and diversity of fecal microbial populations in mice purchased from two large commercial vendors. Moreover, the abundance of many operational taxonomic units, often identified to the species level, as well as several higher taxa, differed in vendor- and strain-dependent manners. Such differences were evident in the fecal microbiota of weanling mice and persisted throughout the study, to twenty-four weeks of age. These data provide the first in-depth analysis of the developmental trajectory of the fecal microbiota in mice from different vendors, and a starting point from which researchers may be able to refine animal models affected by differences in the gut microbiota and thus possibly reduce the number of animals required to perform studies with sufficient statistical power. PMID:25675094

  16. Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation

    DOE PAGESBeta

    Tang, Jonathan; Huang, Yurong; Nguyen, David H.; Costes, Sylvain V.; Snijders, Antoine M.; Mao, Jian-Hua

    2015-01-01

    Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed aftermore » LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.« less

  17. Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation.

    PubMed

    Tang, Jonathan; Huang, Yurong; Nguyen, David H; Costes, Sylvain V; Snijders, Antoine M; Mao, Jian-Hua

    2015-01-01

    Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed after LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs. PMID:25802832

  18. Genetic Background Modulates lncRNA-Coordinated Tissue Response to Low Dose Ionizing Radiation

    PubMed Central

    Tang, Jonathan; Huang, Yurong; Nguyen, David H.; Costes, Sylvain V.; Snijders, Antoine M.; Mao, Jian-Hua

    2015-01-01

    Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed after LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs. PMID:25802832

  19. Genetic modifiers of Lepr{sup fa} associated with variability in insulin production and susceptibility to NIDDM

    SciTech Connect

    Chung, W.K.; Zheng, M.; Chua, M.

    1997-05-01

    In an attempt to identify the genetic basis for susceptibility to non-insulin-dependent diabetes mellitus within the context of obesity, we generated 401 genetically obese Lepr{sup fa}/Lepr{sup fa} F2 WKY13M intercross rats that demonstrated wide variation in multiple phenotypic measures related to diabetes, including plasma glucose concentration, percentage of glycosylated hemoglobin, plasma insulin concentration, and pancreatic islet morphology. Using selective genotyping genome scanning approaches, we have identified three quantitative trait loci (QTLs) on Chr. 1 (LOD 7.1 for pancreatic morpholology), Chr. 12 (LOD 5.1 for body mass index and LOD 3.4 for plasma glucose concentration), and Chr. 16 (P < 0.001 for genotype effect on plasma glucose concentration). The obese F2 progeny demonstrated sexual dimorphism for these traits, with increased diabetes susceptibility in the males appearing at approximately 6 weeks of age, as sexual maturation occurred. For each of the QTLs, the linked phenotypes demonstrated sexual dimorphism (more severe affection in males). The QTL on Chr. 1 maps to a region vicinal to that previously linked to adiposity in studies of diabetes susceptibility in the nonobese Goto-Kakizaki rat, which is genetically closely related to the Wistar counterstrain we employed. Several candidate genes, including tubby (tub), multigenic obesity 1 (Mob1), adult obesity and diabetes (Ad), and insulin-like growth factor-2 (Igf2), map to murine regions homologous to the QTL region identified on rat Chr. 1. 60 refs., 5 figs., 4 tabs.

  20. Protection from Severe Influenza Virus Infections in Mice Carrying the Mx1 Influenza Virus Resistance Gene Strongly Depends on Genetic Background

    PubMed Central

    Shin, Dai-Lun; Hatesuer, Bastian; Bergmann, Silke; Nedelko, Tatiana

    2015-01-01

    ABSTRACT Influenza virus infections represent a serious threat to human health. Both extrinsic and intrinsic factors determine the severity of influenza. The MX dynamin-like GTPase 1 (Mx1) gene has been shown to confer strong resistance to influenza A virus infections in mice. Most laboratory mouse strains, including C57BL/6J, carry nonsense or deletion mutations in Mx1 and thus a nonfunctional allele, whereas wild-derived mouse strains carry a wild-type Mx1 allele. Congenic C57BL/6J (B6-Mx1r/r) mice expressing a wild-type allele from the A2G mouse strain are highly resistant to influenza A virus infections, to both mono- and polybasic subtypes. Furthermore, in genetic mapping studies, Mx1 was identified as the major locus of resistance to influenza virus infections. Here, we investigated whether the Mx1 protective function is influenced by the genetic background. For this, we generated a congenic mouse strain carrying the A2G wild-type Mx1 resistance allele on a DBA/2J background (D2-Mx1r/r). Most remarkably, congenic D2-Mx1r/r mice expressing a functional Mx1 wild-type allele are still highly susceptible to H1N1 virus. However, pretreatment of D2-Mx1r/r mice with alpha interferon protected them from lethal infections. Our results showed, for the first time, that the presence of an Mx1 wild-type allele from A2G as such does not fully protect mice from lethal influenza A virus infections. These observations are also highly relevant for susceptibility to influenza virus infections in humans. IMPORTANCE Influenza A virus represents a major health threat to humans. Seasonal influenza epidemics cause high economic loss, morbidity, and deaths each year. Genetic factors of the host strongly influence susceptibility and resistance to virus infections. The Mx1 (MX dynamin-like GTPase 1) gene has been described as a major resistance gene in mice and humans. Most inbred laboratory mouse strains are deficient in Mx1, but congenic B6-Mx1r/r mice that carry the wild-type Mx1 gene from the A2G mouse strain are highly resistant. Here, we show that, very unexpectedly, congenic D2-Mx1r/r mice carrying the wild-type Mx1 gene from the A2G strain are not fully protected against lethal influenza virus infections. These observations demonstrate that the genetic background is very important for the protective function of the Mx1 resistance gene. Our results are also highly relevant for understanding genetic susceptibility to influenza virus infections in humans. PMID:26202236

  1. Adsorption of Rous sarcoma virus to genetically susceptible and resistant chicken cells studied by laser flow cytometry.

    PubMed Central

    Notter, M F; Leary, J F; Balduzzi, P C

    1982-01-01

    Quantitative binding of Rous sarcoma virus (RSV) of different antigenic subgroups to chicken cells was examined by using a laser flow cytometer/cell sorter. RSV of subgroups A, C, and E, labeled with the fluorescent membrane probe rhodamine-18, bound 2 to 10 times more to genetically susceptible chicken embryo fibroblasts than to resistant cells, as measured by flow cytometry on a single-cell basis. This suggested that susceptible cells possess both specific and nonspecific receptors for virus adsorption, whereas resistant cells bind virus only by means of nonspecific sites. Polybrene at low concentration increased eightfold the binding of virus. Higher levels of Polybrene inhibited adsorption. Cell binding sites were saturable, and attachment of labeled virus could be partially blocked by preexposure of cells to unlabeled RSV. Virus surface glycoproteins played an important role in adsorption, since their removal with bromelain decreased binding of virus to susceptible cells. Maximal binding of RSV to both susceptible and resistant cells occurred within 10 min, although the level of binding was up to 10-fold higher for susceptible cells. Binding to all cell types showed a broad distribution. This implies that there are considerable differences in the number of virions bound per cell. PMID:6284984

  2. PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes

    PubMed Central

    Huen, Karen; Yousefi, Paul; Street, Kelly; Eskenazi, Brenda; Holland, Nina

    2016-01-01

    Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1−108, was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (β(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1−108 genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1. PMID:26913202

  3. The role of CD1d-restricted NKT cells in the clearance of Pseudomonas aeruginosa from the lung is dependent on the host genetic background.

    PubMed

    Benoit, Patrick; Sigounas, Vaia Yioula; Thompson, Jenna L; van Rooijen, Nico; Poynter, Matthew E; Wargo, Matthew J; Boyson, Jonathan E

    2015-06-01

    Pseudomonas aeruginosa is an important human opportunistic pathogen, accounting for a significant fraction of hospital-acquired lung infections. CD1d-restricted NKT cells comprise an unusual innate-like T cell subset that plays important roles in both bacterial and viral infections. Previous reports have differed in their conclusions regarding the role of NKT cells in clearance of P. aeruginosa from the lung. Since there is significant strain-dependent variation in NKT cell number and function among different inbred strains of mice, we investigated whether the role of NKT cells was dependent on the host genetic background. We found that NKT cells did indeed play a critical role in the clearance of P. aeruginosa from the lungs of BALB/c mice but that they played no discernible role in clearance from the lungs of C57BL/6 mice. We found that the strain-dependent role of NKT cells was associated with significant strain-dependent differences in cytokine production by lung NKT cells and that impaired clearance of P. aeruginosa in BALB/c CD1d(-/-) mice was associated with an increase in neutrophil influx to the lung and increased levels of proinflammatory cytokines and chemokines after infection. Finally, we found that the role of alveolar macrophages was also dependent on the genetic background. These data provide further support for a model in which the unusually high level of variability in NKT cell number and function among different genetic backgrounds may be an important contributor to infectious-disease susceptibility and pathology. PMID:25870224

  4. The Role of CD1d-Restricted NKT Cells in the Clearance of Pseudomonas aeruginosa from the Lung Is Dependent on the Host Genetic Background

    PubMed Central

    Benoit, Patrick; Sigounas, Vaia Yioula; Thompson, Jenna L.; van Rooijen, Nico; Poynter, Matthew E.; Wargo, Matthew J.

    2015-01-01

    Pseudomonas aeruginosa is an important human opportunistic pathogen, accounting for a significant fraction of hospital-acquired lung infections. CD1d-restricted NKT cells comprise an unusual innate-like T cell subset that plays important roles in both bacterial and viral infections. Previous reports have differed in their conclusions regarding the role of NKT cells in clearance of P. aeruginosa from the lung. Since there is significant strain-dependent variation in NKT cell number and function among different inbred strains of mice, we investigated whether the role of NKT cells was dependent on the host genetic background. We found that NKT cells did indeed play a critical role in the clearance of P. aeruginosa from the lungs of BALB/c mice but that they played no discernible role in clearance from the lungs of C57BL/6 mice. We found that the strain-dependent role of NKT cells was associated with significant strain-dependent differences in cytokine production by lung NKT cells and that impaired clearance of P. aeruginosa in BALB/c CD1d−/− mice was associated with an increase in neutrophil influx to the lung and increased levels of proinflammatory cytokines and chemokines after infection. Finally, we found that the role of alveolar macrophages was also dependent on the genetic background. These data provide further support for a model in which the unusually high level of variability in NKT cell number and function among different genetic backgrounds may be an important contributor to infectious-disease susceptibility and pathology. PMID:25870224

  5. Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes.

    PubMed

    Mueller, Patricia W; Rogus, John J; Cleary, Patricia A; Zhao, Yuan; Smiles, Adam M; Steffes, Michael W; Bucksa, Jean; Gibson, Therese B; Cordovado, Suzanne K; Krolewski, Andrzej S; Nierras, Concepcion R; Warram, James H

    2006-07-01

    The Genetics of Kidneys in Diabetes (GoKinD) study is an initiative that aims to identify genes that are involved in diabetic nephropathy. A large number of individuals with type 1 diabetes were screened to identify two subsets, one with clear-cut kidney disease and another with normal renal status despite long-term diabetes. Those who met additional entry criteria and consented to participate were enrolled. When possible, both parents also were enrolled to form family trios. As of November 2005, GoKinD included 3075 participants who comprise 671 case singletons, 623 control singletons, 272 case trios, and 323 control trios. Interested investigators may request the DNA collection and corresponding clinical data for GoKinD participants using the instructions and application form that are available at http://www.gokind.org/access. Participating scientists will have access to three data sets, each with distinct advantages. The set of 1294 singletons has adequate power to detect a wide range of genetic effects, even those of modest size. The set of case trios, which has adequate power to detect effects of moderate size, is not susceptible to false-positive results because of population substructure. The set of control trios is critical for excluding certain false-positive results that can occur in case trios and may be particularly useful for testing gene-environment interactions. Integration of the evidence from these three components into a single, unified analysis presents a challenge. This overview of the GoKinD study examines in detail the power of each study component and discusses analytic challenges that investigators will face in using this resource. PMID:16775037

  6. Genetic Susceptibility to Norovirus GII.3 and GII.4 Infections in Chinese Pediatric Diarrheal Children

    PubMed Central

    Liu, Pengbo; Wang, Xiaoqin; Lee, Joong-Chul; Teunis, Peter; Hu, Senke; Paradise, Helen Tang; Moe, Christine

    2015-01-01

    Background Noroviruses (NoVs) are a leading cause of viral diarrhea in young children. Secretor status has been confirmed to be linked with Norwalk virus (NoV GI.1) infection but there is limited information about whether secretor genotypes are associated with pediatric NoV epidemic strains in vivo. Methods In this study, fecal specimens and serum samples were collected from 124 hospitalized children with acute diarrhea in Xi'an, China. TaqMan real-time RT-PCR was used to detect NoV in fecal samples and NoV positive samples were further verified using conventional RT-PCR and sequenced. DNA was extracted from sera and TaqMan single nucleotide polymorphism genotyping assay was applied to determine FUT2 A385T polymorphism. Results Only NoV GII.3 and GII.4 genotypes were found in NoV positive samples and NoV were detected in 25% (15/60), 40.5% (17/42), and 9.1% (2/22) of children with homozygous secretor genotype (Se385Se385), heterozygous secretor genotype (Se385se385), and homozygous weak secretor genotype (se385se385), respectively. Children with secretor genotypes (Se385Se385 and Se385se385) were significantly (P < 0.05) more susceptible to combined NoV GII.3 and GII.4 infections than children with weak secretor genotype (se385se385). Conclusions These findings indicate that secretor positive is significantly associated with GII.3 and GII.4 infections in Chinese pediatric diarrheal children and weak secretor is not a complete protection of children from GII.3 and GII.4 infections. PMID:25037042

  7. Genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region.

    PubMed

    Stewart, Paula; Campbell, Lauren; Skogtvedt, Susan; Griffin, Karen A; Arnemo, Jon M; Tryland, Morten; Girling, Simon; Miller, Michael W; Tranulis, Michael A; Goldmann, Wilfred

    2012-01-01

    Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrP(C)) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C) protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter. PMID:23236380

  8. Genetic Predictions of Prion Disease Susceptibility in Carnivore Species Based on Variability of the Prion Gene Coding Region

    PubMed Central

    Stewart, Paula; Campbell, Lauren; Skogtvedt, Susan; Griffin, Karen A.; Arnemo, Jon M.; Tryland, Morten; Girling, Simon; Miller, Michael W.; Tranulis, Michael A.; Goldmann, Wilfred

    2012-01-01

    Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrPC) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrPC protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter. PMID:23236380

  9. GENETIC POLYMORPHISMS AFFECTING SUSCEPTIBILITY TO MERCURY NEUROTOXICITY IN CHILDREN: SUMMARY FINDINGS FROM THE CASA PIA CHILDREN's AMALGAM CLINICAL TRIAL

    PubMed Central

    Woods, James S.; Heyer, Nicholas J.; Russo, Joan E.; Martin, Michael D.; Farin, Federico M.

    2014-01-01

    Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic predisposition. We examined the possibility that common genetic variants that are known to affect neurologic functions or Hg handling in adults would modify the adverse neurobehavioral effects of Hg exposure in children. Three hundred thirty subjects who participated as children in the recently completed Casa Pia Clinical Trial of Dental Amalgams in Children were genotyped for 27 variants of 13 genes that are reported to affect neurologic functions and/or Hg disposition in adults. Urinary Hg concentrations, reflecting Hg exposure from any source, served as the Hg exposure index. Regression modeling strategies were employed to evaluate potential associations between allelic status for individual genes or combinations of genes, Hg exposure, and neurobehavioral test outcomes assessed at baseline and for 7 subsequent years during the clinical trial. Among boys, significant modification of Hg effects on neurobehavioral outcomes over a broad range of neurologic domains was observed with variant genotypes for 4 of 13 genes evaluated. Modification of Hg effects on a more limited number of neurobehavioral outcomes was also observed for variants of another 8 genes. Cluster analyses suggested some genes interacting in common processes to affect Hg neurotoxicity. In contrast, significant modification of Hg effects on neurobehavioral functions among girls with the same genotypes was substantially more limited. These observations suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children, particularly boys, with genetic variants that are relatively common to the general human population. These findings advance public health goals to identify factors underlying susceptibility to Hg toxicity and may contribute to strategies for preventing adverse health risks associated with Hg exposure. PMID:25109824

  10. Genetic background of Escherichia coli isolates from peritoneal dialysis patients with peritonitis and uninfected control subjects.

    PubMed

    Li, Y F; Su, N; Chen, S Y; Hu, W X; Li, F F; Jiang, Z P; Yu, X Q

    2016-01-01

    Escherichia coli is the most common cause of Gram-negative peritonitis resulting in peritoneal function deterioration as well as poor clinical outcome in continuous ambulatory peritoneal dialysis (PD) patients. In this study, we analyzed the phylogenetic background and genetic profile of the E. coli isolates and sought to determine the characteristics of specific bacteria associated with peritonitis. E. coli isolates from 56 episodes of peritonitis in 46 PD patient cases and rectal isolates from 57 matched PD control patient cases were compared for both phylogenetic groups and the presence of virulence factors (VFs). There were no significant differences in terms of demographic data between the peritonitis and control groups. Peritonitis isolates exhibited a significantly greater prevalence of 8 VFs. In multivariate logistic regression analysis, kpsMT II (group 2 capsule synthesis) was the strongest VF predictor of peritonitis (OR = 8.02; 95%CI = 3.18-20.25; P < 0.001), followed by traT (serum-resistance-associated outer membrane protein) (OR = 3.83; 95%CI = 1.33-11.03; P = 0.013). The pathogenic groups of E. coli contained a higher concentration of individual VFs compared to the commensal groups. The prevalence of pathogenic E. coli was much higher in peritoneal isolates than rectal isolates (64.3 vs 31.6%, P = 0.001). Our results indicate that the E. coli peritonitis and rectal isolates are different in PD patients. The specific VFs associated with peritonitis isolates may directly contribute to the pathogenesis of peritonitis. PMID:27051010

  11. Genetic background, and not ontogenetic effects, affects avian seasonal timing of reproduction.

    PubMed

    Gienapp, P; van Noordwijk, A J; Visser, M E

    2013-10-01

    Avian seasonal timing is a life-history trait with important fitness consequences and which is currently under directional selection due to climate change. To predict micro-evolution in this trait, it is crucial to properly estimate its heritability. Heritabilities are often estimated from pedigreed wild populations. As these are observational data, it leaves the possibility that the resemblance between related individuals is not due to shared genes but to ontogenetic effects; when the environment for the offspring provided by early laying pairs differs from that by late pairs and the laying dates of these offspring when they reproduce themselves is affected by this environment, this may lead to inflated heritability estimates. Using simulation studies, we first tested whether and how much such an early environmental effect can inflate heritability estimates from animal models, and we showed that pedigree structure determines by how much early environmental effects inflate heritability estimates. We then used data from a wild population of great tits (Parus major) to compare laying dates of females born early in the season in first broods and from sisters born much later, in second broods. These birds are raised under very different environmental conditions but have the same genetic background. The laying dates of first and second brood offspring do not differ when they reproduce themselves, clearly showing that ontogenetic effects are very small and hence, family resemblance in timing is due to genes. This finding is essential for the interpretation of the heritabilities reported from wild populations and for predicting micro-evolution in response to climate change. PMID:23837446

  12. Association of genetic polymorphisms on BTNL2 with susceptibility to and prognosis of dilated cardiomyopathy in a Chinese population

    PubMed Central

    Cheng, Liang; Zhao, Rong; Jin, ZhenXiao; Ren, Kai; Deng, Chao; Yu, Shiqiang

    2015-01-01

    Background: Dilated cardiomyopathy (DCM) is one type of primary myocardial disease, partly caused by immunity dysfunctions. BTNL2 (butyrophilin-like 2) has already been confirmed to be involved in the etiology of autoimmune disorders and GWAS (genome wide association study) has also identified mutants of a SNP (single nucleotide polymorphism) near BTNL2 could modulate risk of coronary heart disease (also cardiomyopathy). The current study, therefore, was aimed to investigate whether polymorphisms within or around BTNL2 would be correlated with susceptibility to and prognosis of DCM. Material and methods: Peripheral blood samples were gathered from 82 DCM patients and 75 healthy controls. Nine tag-SNPs within or near BTNL2 were obtained from HapMap Database and previously published studies. Eligible haplotypes were gained on the basis of SHesis software. Genotyping of SNPs was implemented with aid of Sequenom MassArray iPLEX platform and subsequently analyzed via MALDI-TOF mass spectrometry. The odd ratios and their 95% confidence interval (95% CI) were utilized to evaluate the correlations between SNPs/haplotypes and DCM risks. Finally, Cox proportional hazard models and Kaplan-Meier curves were performed to assess association of SNPs/haplotypes with prognosis of DCM patients. The statistical analyses were conducted with SPSS 19.0 software. Results: Under the allelic model, rs3763313 (A > C), rs9268494 (C > A), rs9268492 (C > G) and rs9268402 (A > G) were remarkably associated with susceptibility to grade IV of DCM classified by NYHA (New York heart association) (OR = 0.43, 95% CI: 0.22-0.84; P = 0.018; OR = 0.49, 95% CI: 0.27-0.91; P = 0.024; OR = 0.50, 95% CI: 0.27-0.94; P = 0.035; OR = 0.53, 95% CI: 0.28-0.97; P = 0.048). Haplotype C-C-A-T (rs9268492, rs9268494, rs3763313 and rs3763317 synthesized) was also regarded as a protective factor for DCM patients compared with carriers of other haplotypes (OR = 0.50, 95% CI: 0.26-0.97, P = 0.038). Moreover, the univariate survival analysis and multivariate Cox regression analysis both indicated noticeable correlations between rs9268402 and haplotype C-C-A-T and prognosis of DCM patients (NYHA IV), respectively (Long-Rank P = 0.029, HR: 0.241, 95% CI: 0.089-0.650, P = 0.005; Long-Rank P = 0.036; HR = 0.126, 95% CI: 0.035-0.457, P = 0.002). Nonetheless, rs3763313 was found only associated with prognosis of DCM patients (NYHA IV) expressed in the Kaplan-Meier curve (P = 0.009). Conclusion: The genetic mutations within or around BTNL2 (rs3763313, rs9268494, rs9268492 and rs9268402) could alter susceptibility to grade IV of DCM in a Chinese population, and the 2 SNPs (rs3763313 and rs9268402) therein added with haplotype C-C-A-T might separately predict the prognosis of DCM patients. However, additional studies regarding diverse ethnicities need to be furthered to validate our results. PMID:26617759

  13. [Association of XRCC1 genetic polymorphism with susceptibility to non-Hodgkin's lymphoma].

    PubMed

    Li, Su-Xia; Zhu, Hong-Li; Guo, Bo; Yang, Yang; Wang, Hong-Yan; Sun, Jing-Fen; Cao, Yong-Bin

    2014-08-01

    The purpose of this study was to explore the association between X-ray repair cross-complementing group 1 (XRCC1)gene polymorphism and non-Hodgkin's lymphoma risk. A total of 282 non-Hodgkin's lymphoma (NHL) patients and 231 normal controls were used to investigate the effect of three XRCC1 gene polymorphisms (rs25487, rs25489, rs1799782) on susceptibility to non-Hodgkin's lymphoma. Genotyping was performed by using SNaPshot method. All statistical analyses were done with R software. Genotype and allele frequencies of XRCC1 were compared between the patients and controls by using the chi-square test. Crude and adjusted odd ratios and 95% confidence intervals were calculated by using logistic regression on the basis of genetic different models. For four kinds of NHL, subgroup analyses were also conducted. Combined genotype analyses of the three XRCC1 polymorphisms were also done by using logistic regression. The results showed that the variant genotype frequency was not significantly different between the controls and NHL or NHL subtype cases. Combined genotype analyses of XRCC1 399-280-194 results showed that the combined genotype was not associated with risk of NHL overall, but the VT-WT-WT combined genotype was associated with the decreased risk of T-NHL (OR: 0.21; 95%CI (0.06-0.8); P = 0.022), and the WT-VT-WT combined genotype was associated with the increased risk of FL(OR:15.23; 95%CI (1.69-137.39); P = 0.015). It is concluded that any studied polymorphism (rs25487, rs25489, rs1799782) alone was not shown to be rela-ted with the risk of NHL or each histologic subtype of NHL. The combined genotype with mutation of three SNP of XRCC1 was not related to the risk of NHL. However, further large-scale studies would be needed to confirm the association of decreased or increased risk for T-NHL and FL with the risk 3 combined SNP mutants of XRCC1 polymorphism. PMID:25130814

  14. Genetic and Functional Profiling of Crohn's Disease: Autophagy Mechanism and Susceptibility to Infectious Diseases

    PubMed Central

    Bianco, Anna Monica; Girardelli, Martina; Tommasini, Alberto; Martelossi, Stefano

    2013-01-01

    Crohn's disease is a complex disease in which genome, microbiome, and environment interact to produce the immunological background of the disease. Disease in childhood is more extensive and characterized by a rapid progression, leading to severe repercussions in the course of the disorder. Several genetic variations have been associated with an increased risk of developing the disease and most of these are also implicated in other autoimmune disorders. The gut has many tiers of defense against incursion by luminal microbes, including the epithelial barrier and the innate and adaptive immune responses. Moreover, recent evidence shows that bacterial and viral infections, as well as inflammasome genes and genes involved in the autophagy process, are implicated in Crohn's disease pathogenesis. The aim of this review is to establish how much the diagnostic system can improve, thus increasing the success of Crohn's disease diagnosis. The major expectation for the near future is to be able to anticipate the possible consequences of the disease already in childhood, thus preventing associated complications, and to choose the best treatment for each patient. PMID:23738324

  15. The Conditional Nature of Genetic Interactions: The Consequences of Wild-Type Backgrounds on Mutational Interactions in a Genome-Wide Modifier Screen

    PubMed Central

    Chari, Sudarshan; Dworkin, Ian

    2013-01-01

    The phenotypic outcome of a mutation cannot be simply mapped onto the underlying DNA variant. Instead, the phenotype is a function of the allele, the genetic background in which it occurs and the environment where the mutational effects are expressed. While the influence of genetic background on the expressivity of individual mutations is recognized, its consequences on the interactions between genes, or the genetic network they form, is largely unknown. The description of genetic networks is essential for much of biology; yet if, and how, the topologies of such networks are influenced by background is unknown. Furthermore, a comprehensive examination of the background dependent nature of genetic interactions may lead to identification of novel modifiers of biological processes. Previous work in Drosophila melanogaster demonstrated that wild-type genetic background influences the effects of an allele of scalloped (sd), with respect to both its principal consequence on wing development and its interactions with a mutation in optomotor blind. In this study we address whether the background dependence of mutational interactions is a general property of genetic systems by performing a genome wide dominant modifier screen of the sdE3 allele in two wild-type genetic backgrounds using molecularly defined deletions. We demonstrate that ∼74% of all modifiers of the sdE3 phenotype are background-dependent due in part to differential sensitivity to genetic perturbation. These background dependent interactions include some with qualitative differences in the phenotypic outcome, as well as instances of sign epistasis. This suggests that genetic interactions are often contingent on genetic background, with flexibility in genetic networks due to segregating variation in populations. Such background dependent effects can substantially alter conclusions about how genes influence biological processes, the potential for genetic screens in alternative wild-type backgrounds identifying new loci that contribute to trait expression, and the inferences of the topology of genetic networks. PMID:23935530

  16. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

    PubMed

    Mahajan, Anubha; Go, Min Jin; Zhang, Weihua; Below, Jennifer E; Gaulton, Kyle J; Ferreira, Teresa; Horikoshi, Momoko; Johnson, Andrew D; Ng, Maggie C Y; Prokopenko, Inga; Saleheen, Danish; Wang, Xu; Zeggini, Eleftheria; Abecasis, Goncalo R; Adair, Linda S; Almgren, Peter; Atalay, Mustafa; Aung, Tin; Baldassarre, Damiano; Balkau, Beverley; Bao, Yuqian; Barnett, Anthony H; Barroso, Ines; Basit, Abdul; Been, Latonya F; Beilby, John; Bell, Graeme I; Benediktsson, Rafn; Bergman, Richard N; Boehm, Bernhard O; Boerwinkle, Eric; Bonnycastle, Lori L; Burtt, Noël; Cai, Qiuyin; Campbell, Harry; Carey, Jason; Cauchi, Stephane; Caulfield, Mark; Chan, Juliana C N; Chang, Li-Ching; Chang, Tien-Jyun; Chang, Yi-Cheng; Charpentier, Guillaume; Chen, Chien-Hsiun; Chen, Han; Chen, Yuan-Tsong; Chia, Kee-Seng; Chidambaram, Manickam; Chines, Peter S; Cho, Nam H; Cho, Young Min; Chuang, Lee-Ming; Collins, Francis S; Cornelis, Marylin C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Danesh, John; Das, Debashish; de Faire, Ulf; Dedoussis, George; Deloukas, Panos; Dimas, Antigone S; Dina, Christian; Doney, Alex S; Donnelly, Peter J; Dorkhan, Mozhgan; van Duijn, Cornelia; Dupuis, Josée; Edkins, Sarah; Elliott, Paul; Emilsson, Valur; Erbel, Raimund; Eriksson, Johan G; Escobedo, Jorge; Esko, Tonu; Eury, Elodie; Florez, Jose C; Fontanillas, Pierre; Forouhi, Nita G; Forsen, Tom; Fox, Caroline; Fraser, Ross M; Frayling, Timothy M; Froguel, Philippe; Frossard, Philippe; Gao, Yutang; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Grallert, Harald; Grant, George B; Grrop, Leif C; Groves, Chrisropher J; Grundberg, Elin; Guiducci, Candace; Hamsten, Anders; Han, Bok-Ghee; Hara, Kazuo; Hassanali, Neelam; Hattersley, Andrew T; Hayward, Caroline; Hedman, Asa K; Herder, Christian; Hofman, Albert; Holmen, Oddgeir L; Hovingh, Kees; Hreidarsson, Astradur B; Hu, Cheng; Hu, Frank B; Hui, Jennie; Humphries, Steve E; Hunt, Sarah E; Hunter, David J; Hveem, Kristian; Hydrie, Zafar I; Ikegami, Hiroshi; Illig, Thomas; Ingelsson, Erik; Islam, Muhammed; Isomaa, Bo; Jackson, Anne U; Jafar, Tazeen; James, Alan; Jia, Weiping; Jöckel, Karl-Heinz; Jonsson, Anna; Jowett, Jeremy B M; Kadowaki, Takashi; Kang, Hyun Min; Kanoni, Stavroula; Kao, Wen Hong L; Kathiresan, Sekar; Kato, Norihiro; Katulanda, Prasad; Keinanen-Kiukaanniemi, Kirkka M; Kelly, Ann M; Khan, Hassan; Khaw, Kay-Tee; Khor, Chiea-Chuen; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Korpi-Hyövälti, Eeva; Kowlessur, Sudhir; Kraft, Peter; Kravic, Jasmina; Kristensen, Malene M; Krithika, S; Kumar, Ashish; Kumate, Jesus; Kuusisto, Johanna; Kwak, Soo Heon; Laakso, Markku; Lagou, Vasiliki; Lakka, Timo A; Langenberg, Claudia; Langford, Cordelia; Lawrence, Robert; Leander, Karin; Lee, Jen-Mai; Lee, Nanette R; Li, Man; Li, Xinzhong; Li, Yun; Liang, Junbin; Liju, Samuel; Lim, Wei-Yen; Lind, Lars; Lindgren, Cecilia M; Lindholm, Eero; Liu, Ching-Ti; Liu, Jian Jun; Lobbens, Stéphane; Long, Jirong; Loos, Ruth J F; Lu, Wei; Luan, Jian'an; Lyssenko, Valeriya; Ma, Ronald C W; Maeda, Shiro; Mägi, Reedik; Männisto, Satu; Matthews, David R; Meigs, James B; Melander, Olle; Metspalu, Andres; Meyer, Julia; Mirza, Ghazala; Mihailov, Evelin; Moebus, Susanne; Mohan, Viswanathan; Mohlke, Karen L; Morris, Andrew D; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Musk, Bill; Nakamura, Jiro; Nakashima, Eitaro; Navarro, Pau; Ng, Peng-Keat; Nica, Alexandra C; Nilsson, Peter M; Njølstad, Inger; Nöthen, Markus M; Ohnaka, Keizo; Ong, Twee Hee; Owen, Katharine R; Palmer, Colin N A; Pankow, James S; Park, Kyong Soo; Parkin, Melissa; Pechlivanis, Sonali; Pedersen, Nancy L; Peltonen, Leena; Perry, John R B; Peters, Annette; Pinidiyapathirage, Janini M; Platou, Carl G; Potter, Simon; Price, Jackie F; Qi, Lu; Radha, Venkatesan; Rallidis, Loukianos; Rasheed, Asif; Rathman, Wolfgang; Rauramaa, Rainer; Raychaudhuri, Soumya; Rayner, N William; Rees, Simon D; Rehnberg, Emil; Ripatti, Samuli; Robertson, Neil; Roden, Michael; Rossin, Elizabeth J; Rudan, Igor; Rybin, Denis; Saaristo, Timo E; Salomaa, Veikko; Saltevo, Juha; Samuel, Maria; Sanghera, Dharambir K; Saramies, Jouko; Scott, James; Scott, Laura J; Scott, Robert A; Segrè, Ayellet V; Sehmi, Joban; Sennblad, Bengt; Shah, Nabi; Shah, Sonia; Shera, A Samad; Shu, Xiao Ou; Shuldiner, Alan R; Sigurđsson, Gunnar; Sijbrands, Eric; Silveira, Angela; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S; So, Wing Yee; Stančáková, Alena; Stefansson, Kari; Steinbach, Gerald; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Strawbridge, Rona J; Stringham, Heather M; Sun, Qi; Suo, Chen; Syvänen, Ann-Christine; Takayanagi, Ryoichi; Takeuchi, Fumihiko; Tay, Wan Ting; Teslovich, Tanya M; Thorand, Barbara; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Trakalo, Joseph; Tremoli, Elena; Trip, Mieke D; Tsai, Fuu Jen; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uitterlinden, Andre G; Valladares-Salgado, Adan; Vedantam, Sailaja; Veglia, Fabrizio; Voight, Benjamin F; Wang, Congrong; Wareham, Nicholas J; Wennauer, Roman; Wickremasinghe, Ananda R; Wilsgaard, Tom; Wilson, James F; Wiltshire, Steven; Winckler, Wendy; Wong, Tien Yin; Wood, Andrew R; Wu, Jer-Yuarn; Wu, Ying; Yamamoto, Ken; Yamauchi, Toshimasa; Yang, Mingyu; Yengo, Loic; Yokota, Mitsuhiro; Young, Robin; Zabaneh, Delilah; Zhang, Fan; Zhang, Rong; Zheng, Wei; Zimmet, Paul Z; Altshuler, David; Bowden, Donald W; Cho, Yoon Shin; Cox, Nancy J; Cruz, Miguel; Hanis, Craig L; Kooner, Jaspal; Lee, Jong-Young; Seielstad, Mark; Teo, Yik Ying; Boehnke, Michael; Parra, Esteban J; Chambers, Jonh C; Tai, E Shyong; McCarthy, Mark I; Morris, Andrew P

    2014-03-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. PMID:24509480

  17. Study of Associated Genetic Variants in Indian Subjects Reveals the Basis of Ethnicity Related Differences in Susceptibility to Venous Thromboembolism

    PubMed Central

    Kumari, Babita; Srivastava, Swati; Chatterjee, Tathagat; Vardhan, Rig; Tyagi, Tarun; Gupta, Neha; Sahu, Anita; Chandra, Khem; Ashraf, Mohammad Zahid

    2014-01-01

    The genetic variants linked with the susceptibility of individuals to VTE are well known; however, the studies explaining the ethnicity based difference in susceptibility to VTE are limited. Present study assesses mutations in six candidate genes contributing to the etiology of VTE in Indian subjects. The study comprised 93 VTE patients and 102 healthy controls. A PCR-RFLP based analysis was performed for nine mutations in the following genes associated with VTE: favtor V Leiden (FVL), prothrombin, tissue factor pathway inhibitor (TFPI), fibrinogen-beta, plasminogen activator inhibitor 1 (PAI-1), and methylene tetrahydrofolatereductase (MTHFR). All the subjects were found to be monomorphic for FVL 1691G/A, prothrombin 20210G/A and TFPI ?536C/T mutations. The mutation in the MTHFR gene (677C/T) was observed only in patients. Contrarily, higher frequency of mutation in the PAI-1 ?844G/A and the fibrinogen-? ?455G/A was observed in controls in comparison to the patients. This study suggests that the PAI-1 ?844G/A and fibrinogen-? ?455G/A could be protective variants against VTE in Indians. While MTHFR 677C/T mutation was found to be associated, in contrast to other populations, the established genetic variants FVL 1691G/A, prothrombin 20210G/A, and TFPI ?536C/T may not be associated with VTE in Indians thus revealing the basis of ethnicity related differences in susceptibility of Indians to VTE. PMID:25349733

  18. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

    PubMed Central

    2014-01-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS) including 26,488 cases and 83,964 controls of European, East Asian, South Asian, and Mexican and Mexican American ancestry. We observed significant excess in directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven novel T2D susceptibility loci. Furthermore, we observed considerable improvements in fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterisation of complex trait loci, and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. PMID:24509480

  19. Response to Dietary Phosphate Deficiency is Affected by Genetic Background in Growing Pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Concern over the environmental impact of phosphate (P) excretion from pig production has led to reduced dietary P supplementation. To examine how genetics influence P utilization, 94 gilts sired by 2 genetic lines (PIC337 and PIC280) were fed either a P adequate diet (PA) or a 20% P deficient diet ...

  20. Genetic differential susceptibility in literacy-delayed children: a randomized controlled trial on emergent literacy in kindergarten.

    PubMed

    Plak, Rachel D; Kegel, Cornelia A T; Bus, Adriana G

    2015-02-01

    In this randomized controlled trial, 508 5-year-old kindergarten children participated, of whom 257 were delayed in literacy skills because they belonged to the lowest quartile of a national standard literacy test. We tested the hypothesis that some children are more susceptible to school-entry educational interventions than their peers due to their genetic makeup, and thus whether the dopamine receptor D4 gene moderated intervention effects. Children were randomly assigned to a control condition or one of two interventions involving computer programs tailored to the literacy needs of delayed pupils: Living Letters for alphabetic knowledge and Living Books for text comprehension. Effects of Living Books met the criteria of differential susceptibility. For carriers of the dopamine receptor D4 gene seven-repeat allele (about one-third of the delayed group), the Living Books program was an important addition to the common core curriculum in kindergarten (effect size d = 0.56), whereas the program did not affect the other children (d = -0.09). The same seven-repeat carriers benefited more from Living Letters than did the noncarriers, as reflected in effect sizes of 0.63 and 0.34, respectively, although such differences did not fulfill the statistical criteria for differential susceptibility. The implications of differential susceptibility for education and regarding the crucial question "what works for whom?" are discussed. PMID:25640831

  1. Genetic-Background Modulation of Core and Variable Autistic-Like Symptoms in Fmr1 Knock-Out Mice

    PubMed Central

    Pietropaolo, Susanna; Guilleminot, Aurélie; Martin, Benoît; D'Amato, Francesca R.; Crusio, Wim E.

    2011-01-01

    Background No animal models of autism spectrum disorders (ASD) with good construct validity are currently available; using genetic models of pathologies characterized by ASD-like deficits, but with known causes, may be therefore a promising strategy. The Fmr1-KO mouse is an example of this approach, modeling Fragile X syndrome, a well-known genetic disorder presenting ASD symptoms. The Fmr1-KO is available on different genetic backgrounds (FVB versus C57BL/6), which may explain some of the conflicting results that have been obtained with these mutants up till now. Methods Fmr1 KO and their wild-type littermates on both the FVB and C57BL/6 genetic backgrounds were examined on a battery of tests modeling the clinical symptoms of ASD, including the triad of core symptoms (alterations in social interaction and communication, presence of repetitive behaviors), as well as the secondary symptoms (disturbances in sensori-motor reactivity and in circadian patterns of activity, epileptic events). Results Fmr1-KO mice displayed autistic-like core symptoms of altered social interaction and occurrence of repetitive behaviors with additional hyperactivity. The genetic background modulated the effects of the Fmr1 deletion and it appears that the C57BL/6 background may be more suitable for further research on core autistic-like symptoms. Conclusions The Fmr1-mouse line does not recapitulate all of the main core and secondary ASD symptoms, but still can be useful to elucidate the neurobiological mechanisms underlying specific ASD-like endophenotypes. PMID:21364941

  2. Functional evaluation of TERT-CLPTM1L genetic variants associated with susceptibility of papillary thyroid carcinoma.

    PubMed

    Ge, Minghua; Shi, Meng; An, Changming; Yang, Wenjun; Nie, Xilin; Zhang, Jian; Lv, Zheng; Li, Jinliang; Zhou, Liqing; Du, Zhongli; Yang, Ming

    2016-01-01

    TERT is the catalytic subunit of telomerase which plays an essential part in cellular immortality by maintaining telomere integrity. TERT is commonly over-expressed in human malignancies, indicating its key role in cell transformation. The chromosome 5p15.33 TERT-CLPTM1L region has been associated with susceptibility of multiple cancers via a genome-wide association approach. However, the involvement of this locus in papillary thyroid carcinoma (PTC) etiology is still largely unknown. We analyzed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) of the TERT-CLPTM1L region in a two stage case-control design. After genotyping 2300 PTC patients and frequency-matched 2300 unaffected controls, we found that TERT rs2736100 genetic variant is significantly associated with elevated PTC risk. Ex vivo reporter gene assays indicated that the PTC susceptibility rs2736100 polymorphism locating in a potential TERT intronic enhancer has a genotype-specific effect on TERT expression. Correlations between rs2736100 genotypes and tissue-specific TERT expression supported the regulatory function of this genetic variant in vivo. Our data demonstrated that the functional TERT rs2736100 SNP as a novel genetic component of PTC etiology. This study, together with recent studies in other cancers, unequivocally establishes an essential role of TERT in cancers. PMID:27185198

  3. Gene-environment interactions in determining differences in genetic susceptibility to cancer in subsites of the head and neck.

    PubMed

    Maurya, Shailendra S; Katiyar, Tridiv; Dhawan, Ankur; Singh, Sudhir; Jain, Swatantra K; Pant, Mohan C; Parmar, Devendra

    2015-04-01

    Genetic differences in susceptibility to cancer in subsites of the head and neck were investigated in a case-control study involving 750 cases of cancers of the oral cavity, larynx, or pharynx, and an equal number of healthy controls. The prevalence of variant genotypes of cytochrome P450 (CYP) 1A1, 1B1, 2E1, or glutathione-S-transferase M1 (null) in cases suggests that polymorphisms in drug metabolizing enzymes (DMEs) modify cancer risk within subsites of the head and neck. Tobacco or alcohol use was found to increase the risk in cases of laryngeal, pharyngeal, or oral cavity cancers. Interaction between genetic variation in DMEs and tobacco smoke (or smoking) exposures conferred significant risk for laryngeal cancer. Likewise, strong associations of the polymorphic genotypes of DMEs with cases of pharyngeal and oral cavity cancer who were tobacco chewers or alcohol users demonstrate that gene-environment interactions may explain differences in genetic susceptibility for cancers of the oral cavity, larynx, and pharynx. PMID:25399842

  4. Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans.

    PubMed

    Céspedes-Garro, Carolina; Jiménez-Arce, Gerardo; Naranjo, María-Eugenia G; Barrantes, Ramiro; Llerena, Adrián

    2014-12-01

    CYP2D6 differences have already been demonstrated within Latin American populations by the CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics (RIBEF, as per the acronym in Spanish). However, within the population of Costa Rica, no research has been conducted until now, even though this population has a trihybrid component ancestry that represents an interesting condition. Thus, the present study was aimed to determine the frequency of Ultra-rapid Metabolizers (UMs) and Poor Metabolizers (PMs) in a Costa Rican population, as well as to determine whether there are differences in the CYP2D6-predicted phenotype frequencies among three Costa Rican groups with different ethnic backgrounds. Additionally, these frequencies of PMs and UMs obtained were compared with Ibero-American populations published data. Finally, we also aimed to describe allele frequencies among different Costa Rican ethnic groups. This research has been undertaken within the framework of the RIBEF CEIBA Consortium studies on Latin American populations. A total of 385 individuals were included in the study: 139 mestizos, 197 Amerindians, and 49 Afro-Caribbeans. CYP2D6 genotypes were determined by XL-PCR and Real-Time PCR. The CYP2D6 variant alleles *2, *3, *4, *5, *6, *10, "17, *29, *35 and *41 were also determined. For the entire Costa Rican population, the frequency of PMs and UMs was 6% and 6.5%, respectively. The percentage of UMs in the mestizo population was higher than in the Amerindian population. CYP2D6 UMs vary from 3.6% to 10.1% and PMs from 1.4% to 10.2% among three Costa Rican groups. The highest frequencies of UMs (10.1%) and PMs (10.2%) were found in the mestizo and Amerindian populations, respectively. In conclusion, the frequencies of UMs and PMs for CYP2D6 varied widely across the mestizo, Amerindian and Afro-Caribbean Costa Rican populations. Future research in this population should be oriented to identify new CYP2D6 variants through sequencing methods, as well as to determine CYP2D6 phenotype, in order to establish the phenotype-genotype relation. Finally, further studies involving genetic markers of ancestry are needed in the Costa Rican population. PMID:25720195

  5. [Genetic consequences of an increased radiation background at mouse-like rodents].

    PubMed

    Pomerantseva, M D; Ramaĭia, L K; Rubanovich, A V; Shevchenko, V A

    2006-01-01

    The frequency of genetic disturbances in germ-line and in somatic cells was studied in animals caught in radionuclide-cotaminated areas within the 30-km Chernobyl NPP zone as well as in model experiments in laboratory mice exposed to chronic external gamma-radiation or to the internal action of incorporated radionuclides (131I, 137Cs, 238Pu). The results of genetic and of cytologic analysis of germ-line and somatic cells in the caught or exposed house mice and in laboratory mice after incorporation of radionuclides are presented. An estimation of relative genetic efficiency of the most harmful radionuclides was made. PMID:16869159

  6. Genetic variation for susceptibility to storm-induced stem breakage in Solidago altissima: The role of stem height and morphology

    NASA Astrophysics Data System (ADS)

    Wise, Michael J.; Abrahamson, Warren G.

    2010-07-01

    While storms can have obvious ecological impacts on plants, plants' potential to respond evolutionarily to selection for increased resistance to storm damage has received little study. We took advantage of a thunderstorm with strong wind and hail to examine genetic variation for resistance to stem breakage in the herbaceous perennial Solidago altissima. The storm broke the apex of nearly 10% of 1883 marked ramets in a common-garden plot containing 26 genets of S. altissima. Plant genets varied 20-fold in resistance to breakage. Stem height was strongly correlated with resistance to breakage, with taller stems being significantly more susceptible. A stem's growth form (erect versus nodding) had no detectable effect on its resistance to breakage. Therefore, we rejected the hypothesis that a function of the nodding, or "candy-cane," morphology is protection of the apex from storm damage. The significant genetic variation in S. altissima for stem breakage suggests that this plant has the capacity to respond to selection imposed by storms - particularly through changes in mean stem height. Tradeoffs between breakage resistance and competition for light and pollinators may act to maintain a large amount of genetic variation in stem height.

  7. Testing the Role of Genetic Background in Parallel Evolution Using the Comparative Experimental Evolution of Antibiotic Resistance

    PubMed Central

    Vogwill, Tom; Kojadinovic, Mila; Furió, Victoria; MacLean, R. Craig

    2014-01-01

    Parallel evolution is the independent evolution of the same phenotype or genotype in response to the same selection pressure. There are examples of parallel molecular evolution across divergent genetic backgrounds, suggesting that genetic background may not play an important role in determining the outcome of adaptation. Here, we measure the influence of genetic background on phenotypic and molecular adaptation by combining experimental evolution with comparative analysis. We selected for resistance to the antibiotic rifampicin in eight strains of bacteria from the genus Pseudomonas using a short term selection experiment. Adaptation occurred by 47 mutations at conserved sites in rpoB, the target of rifampicin, and due to the high diversity of possible mutations the probability of within-strain parallel evolution was low. The probability of between-strain parallel evolution was only marginally lower, because different strains substituted similar rpoB mutations. In contrast, we found that more than 30% of the phenotypic variation in the growth rate of evolved clones was attributable to among-strain differences. Parallel molecular evolution across strains resulted in divergent phenotypic evolution because rpoB mutations had different effects on growth rate in different strains. This study shows that genetic divergence between strains constrains parallel phenotypic evolution, but had little detectable impact on the molecular basis of adaptation in this system. PMID:25228081

  8. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.

    PubMed Central

    McGlynn, K A; Rosvold, E A; Lustbader, E D; Hu, Y; Clapper, M L; Zhou, T; Wild, C P; Xia, X L; Baffoe-Bonnie, A; Ofori-Adjei, D

    1995-01-01

    Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype. PMID:7892276

  9. Elucidation of Genetic Backgrounds Necessary for Chlorophyll a Biosynthesis Toward Artificial Creation of Oxygenic Photosynthesis

    NASA Astrophysics Data System (ADS)

    Tsukatani, Yusuke; Masuda, Shinji

    2015-09-01

    We succeeded to create the genetically modified purple photosynthetic bacterium capable of synthesizing chlorophyll a. The results indicate that not only chlorophyll synthase, but also an enzyme for galactolipid synthesis and reaction center proteins are required for accumulating chlorophyll a.

  10. DBA/2J Genetic Background Exacerbates Spontaneous Lethal Seizures but Lessens Amyloid Deposition in a Mouse Model of Alzheimer’s Disease

    PubMed Central

    Jackson, Harriet M.; Onos, Kristen D.; Pepper, Keating W.; Graham, Leah C.; Akeson, Ellen C.; Byers, Candice; Reinholdt, Laura G.; Frankel, Wayne N.; Howell, Gareth R.

    2015-01-01

    Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APPswe and PSEN1de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1de9 has not been tested. Our study shows that DBA/2J.APPswePSEN1de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APPswePSEN1de9 mice—70% of DBA/2J.APPswePSEN1de9 mice die between 2-3 months of age. Of the DBA/2J.APPswePSEN1de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APPswePSEN1de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity. PMID:25933409

  11. KRAS2 as a genetic marker for lung tumor susceptibility in inbred mice.

    PubMed

    Ryan, J; Barker, P E; Nesbitt, M N; Ruddle, F H

    1987-12-01

    An Eco-RI restriction fragment length polymorphism occurring in a DNA fragment containing the first exon of the murine KRAS2 gene was shown to correlate with the inherited susceptibility of inbred strains of mice to urethan (CAS: 51-79-6)-induced pulmonary adenomas. Eco-RI digestion of murine DNA yielded four KRAS2-specific fragments. Polymorphic variation occurred in the smallest molecular-weight fragment with alleles of either 0.70 or 0.55 kb in size. Genotyping of 14 inbred strains of mice revealed a correlation between KRAS2 Eco-RI polymorphic variation and the differential susceptibility among inbred strains to development of pulmonary adenomas. Strains with a high incidence of pulmonary adenomas, either spontaneously occurring or in response to carcinogen induction, had the 0.55-kb KRAS2 allele whereas adenoma-resistant strains had the 0.70-kb allele. Analysis of a series of recombinant inbred strains (AXB, BXA) that developed from reciprocal crosses between a highly susceptible strain (A/J) and a highly resistant strain (C57BL/6J) revealed a statistically significant threefold difference in lung tumor susceptibility on the basis of KRAS2 genotype. Further analysis of individual F2 mice of a C57BL/6 female X A/J male cross also demonstrated a threefold difference in tumor susceptibility on the basis of KRAS2 allelic variation. PMID:2891865

  12. Murine Cep290 phenotypes are modified by genetic backgrounds and provide an impetus for investigating disease modifier alleles

    PubMed Central

    Ramsbottom, Simon; Miles, Colin; Sayer, John

    2015-01-01

    The study of primary cilia is of broad interest both in terms of disease pathogenesis and the fundamental biological role of these structures. Murine models of ciliopathies provide valuable tools for the study of these diseases. However, it is important to consider the precise phenotype of murine models and how dependant it is upon genetic background. Here we compare and contrast murine models of Cep290, a frequent genetic cause of Joubert syndrome in order to refine our concept of genotype-phenotype correlations. PMID:26594343

  13. A trans-acting Variant within the Transcription Factor RIM101 Interacts with Genetic Background to Determine its Regulatory Capacity

    PubMed Central

    Read, Timothy; Richmond, Phillip A.; Dowell, Robin D.

    2016-01-01

    Most genetic variants associated with disease occur within regulatory regions of the genome, underscoring the importance of defining the mechanisms underlying differences in regulation of gene expression between individuals. We discovered a pair of co-regulated, divergently oriented transcripts, AQY2 and ncFRE6, that are expressed in one strain of Saccharomyces cerevisiae, ∑1278b, but not in another, S288c. By combining classical genetics techniques with high-throughput sequencing, we identified a trans-acting single nucleotide polymorphism within the transcription factor RIM101 that causes the background-dependent expression of both transcripts. Subsequent RNA-seq experiments revealed that RIM101 regulates many more targets in S288c than in ∑1278b and that deletion of RIM101 in both backgrounds abrogates the majority of differential expression between the strains. Strikingly, only three transcripts undergo a significant change in expression after swapping RIM101 alleles between backgrounds, implying that the differences in the RIM101 allele lead to a remarkably focused transcriptional response. However, hundreds of RIM101-dependent targets undergo a subtle but consistent shift in expression in the S288c RIM101-swapped strain, but not its ∑1278b counterpart. We conclude that ∑1278b may harbor a variant(s) that buffers against widespread transcriptional dysregulation upon introduction of a non-native RIM101 allele, emphasizing the importance of accounting for genetic background when assessing the impact of a regulatory variant. PMID:26751950

  14. A trans-acting Variant within the Transcription Factor RIM101 Interacts with Genetic Background to Determine its Regulatory Capacity.

    PubMed

    Read, Timothy; Richmond, Phillip A; Dowell, Robin D

    2016-01-01

    Most genetic variants associated with disease occur within regulatory regions of the genome, underscoring the importance of defining the mechanisms underlying differences in regulation of gene expression between individuals. We discovered a pair of co-regulated, divergently oriented transcripts, AQY2 and ncFRE6, that are expressed in one strain of Saccharomyces cerevisiae, ∑1278b, but not in another, S288c. By combining classical genetics techniques with high-throughput sequencing, we identified a trans-acting single nucleotide polymorphism within the transcription factor RIM101 that causes the background-dependent expression of both transcripts. Subsequent RNA-seq experiments revealed that RIM101 regulates many more targets in S288c than in ∑1278b and that deletion of RIM101 in both backgrounds abrogates the majority of differential expression between the strains. Strikingly, only three transcripts undergo a significant change in expression after swapping RIM101 alleles between backgrounds, implying that the differences in the RIM101 allele lead to a remarkably focused transcriptional response. However, hundreds of RIM101-dependent targets undergo a subtle but consistent shift in expression in the S288c RIM101-swapped strain, but not its ∑1278b counterpart. We conclude that ∑1278b may harbor a variant(s) that buffers against widespread transcriptional dysregulation upon introduction of a non-native RIM101 allele, emphasizing the importance of accounting for genetic background when assessing the impact of a regulatory variant. PMID:26751950

  15. Genetic variants of CDH13 determine the susceptibility to chronic obstructive pulmonary disease in a Chinese population

    PubMed Central

    Yuan, Yi-ming; Zhang, Jin-long; Xu, Si-cheng; Ye, Ren-song; Xu, Dan; Zhang, You; Zhang, Yan-Jie; Chen, Yu-long; Liu, Yu-lan; Su, Zhi-guang

    2016-01-01

    Aim: Adiponectin has been implicated in the development of chronic obstructive pulmonary disease (COPD). The CDH13 gene encodes T-cadherin that is an adiponectin receptor, and genetic variants of CDH13 determine blood adiponectin levels. The aim of this study was to investigate the effects of CDH13 variants on COPD susceptibility in a Chinese population. Methods: Ten single-nucleotide polymorphisms (SNP) in CDH13 were screened using the SNaPshot method in 279 COPD patients and 367 control subjects. Association of genotypes or haplotypes constructed from these loci with COPD was analyzed in different genetic models. Results: Among the 10 SNPs tested, rs4783244 and rs12922394 exhibited significant differences in allele or genotype frequencies between COPD patients and control subjects, whereas 8 other SNPs did not. The minor allele T was associated with decreased risk of COPD in the recessive model at rs4783244 (OR=0.42, P=0.023) and in the dominant model at rs12922394 (OR=0.70, P=0.022). The genotype TT at either rs4783244 or rs12922394 was associated with a significantly low level of plasma adiponectin when compared to genotypes GG and CC (P<0.05). Haplotypes GC in block 1 (rs4783244-rs12922394) as well as GTAC and ATGT in block 3 (rs4783266-rs11640522-rs11646849-rs11860282) significantly increased the risk of COPD, whereas haplotypes TT in block 1, TG in block 2 (rs11646011- rs11640875) and ATGC in block 3 were protective against COPD. Conclusion: CDH13 genetic variants determine Chinese individuals' susceptibility to COPD and thus are efficient genetic biomarkers for early detection of COPD. PMID:26806298

  16. Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau

    PubMed Central

    Leng, Shuguang; Picchi, Maria A.; Liu, Yushi; Thomas, Cynthia L.; Willis, Derall G.; Bernauer, Amanda M.; Carr, Teara G.; Mabel, Padilla T.; Han, Younghun; Amos, Christopher I.; Lin, Yong; Stidley, Christine A.; Gilliland, Frank D.; Jacobson, Marty R.; Belinsky, Steven A.

    2013-01-01

    Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2×10−5) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners. PMID:23354305

  17. Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau.

    PubMed

    Leng, Shuguang; Picchi, Maria A; Liu, Yushi; Thomas, Cynthia L; Willis, Derall G; Bernauer, Amanda M; Carr, Teara G; Mabel, Padilla T; Han, Younghun; Amos, Christopher I; Lin, Yong; Stidley, Christine A; Gilliland, Frank D; Jacobson, Marty R; Belinsky, Steven A

    2013-05-01

    Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 × 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners. PMID:23354305

  18. A mutation in negative regulator of basal resistance WRKY17 of Arabidopsis increases susceptibility to Agrobacterium-mediated genetic transformation

    PubMed Central

    Lacroix, Benoît; Citovsky, Vitaly

    2013-01-01

    Agrobacterium is a phytopathogenic bacterium that induces crown gall disease in many plant species by transferring and integrating a segment of its own DNA (T-DNA) into its host genome. Whereas Agrobacterium usually does not trigger an extensive defense response in its host plants, it induces the expression of several defense-related genes and activates plant stress reactions. In the complex interplay between Agrobacterium and its host plant, Agrobacterium has evolved to take advantage of these plant defense pathways for its own purpose of advancement of the infection process. For example, Agrobacterium utilizes the host stress response transcriptional regulator VIP1 to facilitate nuclear import and proteasomal uncoating of its T-DNA during genetic transformation of the host cell. In Arabidopsis, the VIP1 gene expression is repressed by WRKY17, a negative regulator of basal resistance to Pseudomonas. Thus, we examined whether WRKY17 is also involved in plant susceptibility to genetic transformation by Agrobacterium. Using reverse genetics, we showed that a wrky17 mutant displays higher expression of the VIP1 gene in roots, but not in shoots. In a root infection assay, the wrky17 mutant plants were hyper-susceptible to Agrobacterium compared to wild type plants. WRKY17, therefore, may act as a positive regulator of Arabidopsis resistance to Agrobacterium. This notion is important for understanding the complex regulation of Agrobacterium-mediated genetic transformation; thus, although this paper reports a relatively small set of data that we do not plan to pursue further in our lab, we believe it might be useful for the broad community of plant pathologists and plant biotechnologists. PMID:24358874

  19. Genetic susceptibility to lung cancerlight at the end of the tunnel?

    PubMed Central

    Christiani, David C.

    2013-01-01

    Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. Early work focused on the presence of relatively prevalent but low-penetrance alterations in candidate genes leading to increased risk of lung cancer. Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients. PMID:23349013

  20. Analysis of a p53 Mutation Associated with Cancer Susceptibility for Biochemistry and Genetic Laboratory Courses

    ERIC Educational Resources Information Center

    Soto-Cruz, Isabel; Legorreta-Herrera, Martha

    2009-01-01

    We have devised and implemented a module for an upper division undergraduate laboratory based on the amplification and analysis of a p53 polymorphism associated with cancer susceptibility. First, students collected a drop of peripheral blood cells using a sterile sting and then used FTA cards to extract the genomic DNA. The p53 region is then PCR…

  1. Analysis of a p53 Mutation Associated with Cancer Susceptibility for Biochemistry and Genetic Laboratory Courses

    ERIC Educational Resources Information Center

    Soto-Cruz, Isabel; Legorreta-Herrera, Martha

    2009-01-01

    We have devised and implemented a module for an upper division undergraduate laboratory based on the amplification and analysis of a p53 polymorphism associated with cancer susceptibility. First, students collected a drop of peripheral blood cells using a sterile sting and then used FTA cards to extract the genomic DNA. The p53 region is then PCR

  2. Genetic variability among the brown rust resistant and susceptible genotypes of sugarcane by RAPD technique

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brown leaf rust in sugarcane is caused by Puccinia melanocephala (Syd. & P. Syd.), which is major cause of cultivar withdrawal. We attempted to analyze the RAPD diversity of two discrete phenotypic classes i.e. rust resistant (R) and rust susceptible (S) of six commercially available sugarcane elite...

  3. Genetic characterization of Vga ABC proteins conferring reduced susceptibility to pleuromutilins in Staphylococcus aureus.

    PubMed

    Gentry, Daniel R; McCloskey, Lynn; Gwynn, Michael N; Rittenhouse, Stephen F; Scangarella, Nicole; Shawar, Ribhi; Holmes, David J

    2008-12-01

    Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates. PMID:18838584

  4. Blood chimerism confounds genetic relative susceptibility testing for classical scrapie in sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scrapie is a transmissible spongiform encephalopathy of sheep targeted for eradication in the U.S. Susceptibility of sheep to classical scrapie is linked with certain polymorphisms in the prion protein gene (PRNP), such as disease resistance associated with homozygosity for arginine at codon 171 (R1...

  5. Genetic analysis and antimicrobial susceptibility of Francisella noatunensis subsp. orientalis (sun. F. asiatica) isolates from fish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Francisella noatunensis subsp. orientalis (syn. F. asiatica) (Fno) is an emergent fish pathogen that causes acute to chronic disease in a wide variety of freshwater, brackish and marine fish. Due to the emergent nature of this bacterium, established protocols to measure antimicrobial susceptibility ...

  6. A two-phase case–control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22

    PubMed Central

    Abulí, A; Fernández-Rozadilla, C; Giráldez, M D; Muñoz, J; Gonzalo, V; Bessa, X; Bujanda, L; Reñé, J M; Lanas, A; García, A M; Saló, J; Argüello, L; Vilella, À; Carreño, R; Jover, R; Xicola, R M; Llor, X; Carvajal-Carmona, L; Tomlinson, I P M; Kerr, D J; Houlston, R S; Piqué, J M; Carracedo, A; Castells, A; Andreu, M; Ruiz-Ponte, C; Castellví-Bel, S

    2011-01-01

    Background: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22–31, 3q21–24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22–31, and EPHB1 and MRAS in 3q21–q24. Methods: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22–31 and 3q21–q24. Results: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. Conclusions: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts. PMID:21811255

  7. Strain, Sex, and Open-Field Behavior: Factors Underlying the Genetic Susceptibility to Helplessness

    PubMed Central

    Padilla, Eimeira; Barrett, Douglas W.; Shumake, Jason D.; Gonzalez-Lima, F.

    2009-01-01

    Learned helplessness represents a failure to escape after exposure to inescapable stress and may model human psychiatric disorders related to stress. Previous work has demonstrated individual differences in susceptibility to learned helplessness. In this study, we assessed different factors associated with this susceptibility, including strain, sex, and open-field behavior. Testing of three rat strains (Holtzman, Long-Evans, and Sprague-Dawley) revealed that Holtzman rats were the most susceptible to helplessness. Holtzman rats not only had the longest escape latencies following inescapable shock, but also showed spontaneous escape deficits in the absence of prior shock when tested with a fixed-ratio 2 (FR2) running response. Moreover, when tested with fixed-ratio 1 (FR1) running—an easy response normally unaffected by helplessness training in rats—inescapable shock significantly increased the escape latencies of Holtzman rats. Within the Holtzman strain, we confirmed recent findings that females showed superior escape performance and therefore appeared more resistant to helplessness than males. However, regression and covariance analyses suggest that this sex difference may be explained by more baseline ambulatory activity among females. In addition, some indices of novelty reactivity (greater exploration of novel vs. familiar open-field) predicted subsequent helpless behavior. In conclusion, Holtzman rats, and especially male Holtzman rats, have a strong predisposition to become immobile when stressed which interferes with their ability to learn active escape responses. The Holtzman strain therefore appears to be a commercially available model for studying susceptibility to helplessness in males, and novelty-seeking may be a marker of this susceptibility. PMID:19428642

  8. The CRHR1 gene contributes to genetic susceptibility of aggressive behavior towards others in Chinese southwest Han population.

    PubMed

    Chen, Bifeng; Gu, Tao; Ma, Bo; Zheng, Guoqing; Ke, Bingxiong; Zhang, Xiufeng; Zhang, Lirui; Wang, Yuanyuan; Hu, Liping; Chen, Yang; Qiu, Jianbo; Nie, Shengjie

    2014-04-01

    Accumulating evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis might play a major role in genetic susceptibility of aggressive behavior. The aim of the present study is to investigate the association between corticotrophin-releasing hormone receptor 1 (CRHR1) gene and aggressive behavior in Chinese southwest Han population. Participants consist of 282 healthy controls and 177 violent criminals (including robbery and intentional injury, which represent for aggressive behavior towards property and aggressive behavior towards others). Three tag single nucleotide polymorphisms (SNPs) of CRHR1 gene including rs4458044, rs242924, and rs1768996 were genotyped using improved multiplex ligase detection reaction (iMLDR) methods. Single-locus analysis revealed that none of the studied SNPs was significantly associated with the risk of aggressive behavior; however, haplotype analysis showed that a haplotype GGA significantly increased the susceptibility of aggressive behavior towards others with an odds ratios equal to 3.32 (p = 0.003). The present results, for the first time, indicate that the CRHR1 gene polymorphism is significantly associated with aggressive behavior in Chinese southwest Han population. Subjects with GGA haplotype have an increased susceptibility to aggressive behavior towards others. PMID:24243082

  9. Relationship between genetic polymorphisms of DNA ligase 1 and non-small cell lung cancer susceptibility and radiosensitivity.

    PubMed

    Tian, H; He, X; Yin, L; Guo, W J; Xia, Y Y; Jiang, Z X

    2015-01-01

    The aim of this study was to examine the relationship between genetic polymorphisms in DNA ligase 1 (LIG1) and non-small cell lung cancer (NSCLC) susceptibility and radiosensitivity in a Chinese population. This was a case-control study that included 352 NSCLC patients and 448 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was conducted to detect HaeIII polymorphisms in exon 6 of the LIG1 gene in this popula-tion. This information was used to observe the effects of radiation in pa-tients with different genotypes in order to determine the genotypes as-sociated with radiosensitivity. The CC genotype and C allele frequency were significantly higher in the NSCLC group than in the control group (P = 0.012 and P = 0.023, respectively). The relative risk of experienc-ing NSCLC was 2.55 [95% confidence interval (CI), 1.12-3.98] for CC homozygous patients and 0.87 (95%CI, 0.46-1.88) for AA homozygous patients. Analysis of LIG1 genetic polymorphisms and radiosensitiv-ity of NSCLC patients showed that AA homozygous patients were sig-nificantly more radiosensitive than the control group (AA vs AC, P = 0.014; AA vs CC, P < 0.001; AC vs CC, P = 0.023). Therefore, the LIG1 CC genotype was associated with susceptibility to NSCLC, and the AA genotype demonstrated increased radiosensitivity compared to the AC and CC genotypes. PMID:26125914

  10. Legal and ethical issues in genetic testing and counseling for susceptibility to breast, ovarian and colon cancer.

    PubMed Central

    Dickens, B M; Pei, N; Taylor, K M

    1996-01-01

    The prediction of susceptibility to heritable breast, ovarian and colon cancer raises important legal and ethical concerns. Health care professionals have a duty to disclose sufficient information to enable patients to make informed decisions. They must also safeguard the confidentiality of patient data. These duties may come into conflict if a positive finding in one patient implies that family members are also at risk. A legal distinction is made between a breach of confidentiality and the legitimate sharing of information in a patient's interest or to prevent harm to a third party. Physicians also have a fiduciary duty to warn. Other issues concern the legal liability assumed by genetic counsellors, whose disclosures may influence decisions about childbearing, for example, and the risk of socioeconomic discrimination faced by people with a known genetic susceptibility. Traditional ethical orientations and principals may be applied to these and other questions, but feminist ethics will likely have particular importance in the development of an ethical stance toward testing and counseling for heritable breast and ovarian cancer. PMID:8634959

  11. Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes.

    PubMed

    Thier, Ricarda; Brüning, Thomas; Roos, Peter H; Rihs, Hans-Peter; Golka, Klaus; Ko, Yon; Bolt, Hermann M

    2003-06-01

    Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1*0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology. PMID:12872524

  12. Elucidation of Genetic Backgrounds Necessary for Chlorophyll a Biosynthesis Toward Artificial Creation of Oxygenic Photosynthesis.

    PubMed

    Tsukatani, Yusuke; Masuda, Shinji

    2015-09-01

    We succeeded to create the genetically modified purple photosynthetic bacterium capable of synthesizing chlorophyll a. The results indicate that not only chlorophyll synthase, but also an enzyme for galactolipid synthesis and reaction center proteins are required for accumulating chlorophyll a. PMID:26021277

  13. Inheritance of grain polyphenol oxidase (PPO) activity in multiple wheat (Triticum aestivum L.) genetic backgrounds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Grain polyphenol oxidase (PPO) activity can cause discoloration of wheat (Triticum aestivum L.) food products. Five crosses (PI 117635/Antelope; Fielder/NW03681; Fielder/Antelope; NW07OR1070/Antelope; NW07OR1066/OR2050272H) were selected to study the genetic inheritance of PPO activity. STS marker...

  14. Influence of genetic background on anthocyanin and copigment composition and behavior during thermoalkaline processing of maize

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Visual color is a primary factor for foods purchase; identifying factors that influence in-situ color quality of pigmented maize during processing is important. We used 24 genetically distinct pigmented maize hybrids (red/blue, blue, red, and purple) to investigate the effect of pigment and copigme...

  15. Mitochondrial genetic background in Ghanaian patients with primary open-angle glaucoma

    PubMed Central

    Hauser, Michael A.; Mohamed, Gamal; Liu, Yutao; Gibson, Jason; Gonzalez, Ana M.; Akafo, Stephen; Allingham, R. Rand

    2012-01-01

    Purpose Prevalence rates for primary open-angle glaucoma (POAG) are significantly higher in Africans than in European or Asians. It has been reported recently that mitochondrial DNA (mtDNA) lineages of African origin, excluding L2, conferred susceptibility to POAG in Saudi Arabia. This prompted us to test the role of mtDNA haplogroups in the incidence of POAG in the Ghanaian population who has a high frequency of L2 lineages. Methods DNA was extracted from two independent cohorts of clinically diagnosed POAG patients (n=373) and healthy controls (n=451). All patients and controls were from Accra and Tema (the southern region of Ghana). The hypervariable region-I (HVS-I) and coding regions comprising mtDNA haplogroup diagnostic polymorphisms were polymerase chain reaction (PCR) amplified and sequenced in all patients and controls and the haplotypes obtained were assorted into haplogroups and their frequencies compared between cohorts. Results No statistically significant differences were found in mtDNA haplogroup frequencies between POAG patients and matched controls in this cohort for the various mtDNA haplogroups tested. Conclusions In this Ghanaian cohort, mtDNA haplogroups do not seem to confer susceptibility to POAG. PMID:22876121

  16. Genetic susceptibility to male infertility: news from genome-wide association studies.

    PubMed

    Aston, K I

    2014-05-01

    A thorough understanding of the genetic basis of male infertility has eluded researchers in spite of significant efforts to identify novel genetic causes of the disease, particularly over the past decade. Approximately half of male factor infertility cases have no known cause; however, it is likely that the majority of idiopathic male factor infertility cases have some unidentified genetic basis. Well-established genetic causes of male infertility are limited to Y chromosome microdeletions and Klinefelter's syndrome, together accounting for 10-20% of cases of severe spermatogenic failure. In addition to these, several genetic polymorphisms have been demonstrated to be significantly associated with male infertility. The discovery of new genetic associations with male infertility has been hampered by two primary factors. First, most studies are underpowered because of insufficient sample size and ethnic and phenotypic heterogeneity. Second, most studies evaluate a single gene, an approach that is very inefficient in the context of male infertility, considering that many hundreds of genes are involved in the process of testicular development and spermatogenesis. Significant recent advances in microarray and next-generation sequencing technologies have enabled the application of whole-genome approaches to the study of male infertility. We recently performed a pilot genome-wide association study (GWAS) for severe spermatogenic failure, and several additional male infertility GWAS have since been published. More recently, genomic microarray tools have been applied to the association of copy number variants with male infertility. These studies are beginning to shed additional light on the genetic architecture of male infertility, and whole-genome studies have proven effective in identifying novel genetic causes of the disease. This review will discuss some of the recent findings of these whole-genome studies as well as future directions for this research that will likely be the most productive moving forward. PMID:24574159

  17. Multiple gene loci affecting genetic background-controlled disease resistance conferred by R gene Xa3/Xa26 in rice.

    PubMed

    Zhou, Yan; Cao, Yinglong; Huang, Yi; Xie, Weibo; Xu, Caiguo; Li, Xianghua; Wang, Shiping

    2009-12-01

    The function of bacterial-blight resistance gene Xa3/Xa26 in rice is influenced by genetic background; the Oryza sativa L. ssp. japonica background can increase Xa3/Xa26 expression, resulting in an enhanced resistance. To identify whether Xa3/Xa26 transcript level is the only factor contributing to genetic background-controlled resistance, we screened an F(2) population that was developed from a cross between Oryza sativa L. ssp. indica and japonica rice lines and was segregating for Xa3/Xa26, and compared the expression profiles of a pair of indica and japonica rice lines that both carried Xa3/Xa26. Eight quantitative trait loci (QTLs), in addition to Xa3/Xa26, were identified as contributing to the bacterial resistance of this population. Four of the eight QTLs were contributed to the japonica line. The resistance of this population was also affected by epistatic effects. Some F(2) individuals showed significantly increased Xa3/Xa26 transcripts, but the increased transcripts did not completely correlate with the reduced disease in this population. The analysis of the expression profile of Xa3/Xa26-mediated resistance using a microarray containing approximate 7,990 rice genes identified 44 differentially expressed genes. Thirty-five genes were rapidly activated in the japonica background, but not in the indica background, during disease resistance. These results suggest that multiple factors, including the one resulting in increased Xa3/Xa26 expression, may contribute to the enhanced resistance in the japonica background. These factors can cause a variation in gene expression profile that differs from that in the indica background during disease resistance. PMID:19826775

  18. Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis

    PubMed Central

    Kiryluk, Krzysztof; Li, Yifu; Sanna-Cherchi, Simone; Rohanizadegan, Mersedeh; Suzuki, Hitoshi; Eitner, Frank; Snyder, Holly J.; Choi, Murim; Hou, Ping; Scolari, Francesco; Izzi, Claudia; Gigante, Maddalena; Gesualdo, Loreto; Savoldi, Silvana; Amoroso, Antonio; Cusi, Daniele; Zamboli, Pasquale; Julian, Bruce A.; Novak, Jan; Wyatt, Robert J.; Mucha, Krzysztof; Perola, Markus; Kristiansson, Kati; Viktorin, Alexander; Magnusson, Patrik K.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari; Boland, Anne; Metzger, Marie; Thibaudin, Lise; Wanner, Christoph; Jager, Kitty J.; Goto, Shin; Maixnerova, Dita; Karnib, Hussein H.; Nagy, Judit; Panzer, Ulf; Xie, Jingyuan; Chen, Nan; Tesar, Vladimir; Narita, Ichiei; Berthoux, Francois; Floege, Jürgen; Stengel, Benedicte; Zhang, Hong; Lifton, Richard P.; Gharavi, Ali G.

    2012-01-01

    IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10−32–3×10−10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10−4). A seven–SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10−128). This model paralleled the known East–West gradient in disease risk. Moreover, the prediction of a South–North axis was confirmed by registry data showing that the prevalence of IgAN–attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN. PMID:22737082

  19. Vitamin D level and vitamin D receptor genetic variations contribute to HCV infection susceptibility and chronicity in a Chinese population.

    PubMed

    Wu, Mengping; Yue, Ming; Huang, Peng; Zhang, Yun; Xie, Chaonan; Yu, Rongbin; Li, Jun; Wang, Jie

    2016-07-01

    Vitamin D and vitamin D receptor (VDR) are involved in multiple immune-mediated disorders including chronic hepatitis C virus (HCV) infection. The aim of this study was to determine the association between plasma vitamin D level, VDR genetic polymorphisms and risk of HCV infection susceptibility and chronicity. Seven single nucleotide polymorphisms (SNPs) in VDR gene were genotyped and plasma 25-hydroxyvitamin D [25(OH)D] levels were measured in a Han Chinese population of 898 HCV persistent infection cases, 558 spontaneous clearance subjects and 1136 uninfected controls with high risk of HCV infection. In this case-control study, the average plasma 25(OH)D level in persistent infection patients was significantly lower than that in spontaneous clearance cases (P=0.039) and controls (P=0.005). Logistic analyses indicated that rs7975232-C, rs2239185-T and rs11574129-T alleles were significantly associated with a decreased risk of HCV infection susceptibility (all PBonferroni<0.05, in additive/dominant models; Ptrend=9.000×10(-4), combined effects in a locus-dosage manner). The protective effects of three favorable alleles were more evident among males, females and subjects aged ≤50years (all P<0.05). Haplotype analyses suggested that compared with the most frequent haplotype Ars7975232Trs731236Crs11574129, CTT was correlated with a reduced risk of HCV infection susceptibility (P=2.200×10(-3)). These findings implied that low vitamin D levels might be associated with an increased risk for HCV infection and chronicity, and favorable VDR variants (rs7975232-C, rs2239185-T and rs11574129-T) might contribute to a decreased susceptibility to HCV infection in a high-risk Chinese population. PMID:27063396

  20. Plant Genetic Background Increasing the Efficiency and Durability of Major Resistance Genes to Root-knot Nematodes Can Be Resolved into a Few Resistance QTLs

    PubMed Central

    Barbary, Arnaud; Djian-Caporalino, Caroline; Marteu, Nathalie; Fazari, Ariane; Caromel, Bernard; Castagnone-Sereno, Philippe; Palloix, Alain

    2016-01-01

    With the banning of most chemical nematicides, the control of root-knot nematodes (RKNs) in vegetable crops is now based essentially on the deployment of single, major resistance genes (R-genes). However, these genes are rare and their efficacy is threatened by the capacity of RKNs to adapt. In pepper, several dominant R-genes are effective against RKNs, and their efficacy and durability have been shown to be greater in a partially resistant genetic background. However, the genetic determinants of this partial resistance were unknown. Here, a quantitative trait loci (QTL) analysis was performed on the F2:3 population from the cross between Yolo Wonder, an accession considered partially resistant or resistant, depending on the RKN species, and Doux Long des Landes, a susceptible cultivar. A genetic linkage map was constructed from 130 F2 individuals, and the 130 F3 families were tested for resistance to the three main RKN species, Meloidogyne incognita, M. arenaria, and M. javanica. For the first time in the pepper-RKN pathosystem, four major QTLs were identified and mapped to two clusters. The cluster on chromosome P1 includes three tightly linked QTLs with specific effects against individual RKN species. The fourth QTL, providing specific resistance to M. javanica, mapped to pepper chromosome P9, which is known to carry multiple NBS–LRR repeats, together with major R-genes for resistance to nematodes and other pathogens. The newly discovered cluster on chromosome P1 has a broad spectrum of action with major additive effects on resistance. These data highlight the role of host QTLs involved in plant-RKN interactions and provide innovative potential for the breeding of new pepper cultivars or rootstocks combining quantitative resistance and major R-genes, to increase both the efficacy and durability of RKN control by resistance genes.

  1. Refinement of the background genetic map of Xq26-q27 and gene localisation for Boerjeson-Forssman-Lehmann syndrome

    SciTech Connect

    Gedeon, A.K.; Kozman, H.M.; Mulley, J.C.

    1996-07-12

    A detailed map of genetic markers was constructed around the gene for the X-linked mental retardation syndrome of Borjeson-Forssman-Lehmann (BFLS). A multipoint linkage map of framework markers across Xq26-27, based on CEPH families, was integrated with the physical map, based on a YAC contig, to confirm marker order. The remaining genetic markers, which could not be ordered by linkage, were added to create the comprehensive genetic background map, in the order determined by physical mapping, to determine genetic distances between adjacent markers. This background genetic map is applicable to the refinement of the regional localization for any disease gene mapping to this region. The BFLS gene was localized using this background map in an extended version of the family described by Turner et al. The regional localization for BFLS extends between recombination events at DXS425 and DXS105, an interval of 24.6 cM on the background genetic map. The phenotypic findings commonly seen in the feet of affected males and obligate carrier females may represent a useful clinical indicator of carrier status in potential female carriers in the family. Recombination between DXS425 and DXS105 in a female with such characteristic feet suggests that the distal limit of the regional localization for the BFLS gene might reasonably be reduced to DXS294 for the purpose of selecting candidate genes, reducing the interval for the BFLS gene to 15.5 cM. Positional candidate genes from the interval between DXS425 and DXS105 include the SOX3 gene, mapped between DXS51(52A) and DXS98(4D-8). SOX3 may have a role in regulating the development of the nervous system. The HMG-box region of this single exon gene was examined by PCR for a deletion and then sequenced. No deviation from normal was observed, excluding mutations in the conserved HMG-box region as the cause of BFLS in this family. 27 refs., 1 fig., 2 tabs.

  2. Genetic association between TRAIL-R1 Thr209Arg and cancer susceptibility

    PubMed Central

    Geng, Peiliang; Li, Jianjun; Wang, Ning; Liao, Yunmei; Ou, Juanjuan; Sa, Rina; Xie, Ganfeng; Liu, Chen; Li, Hongtao; Xiang, Lisha; Liang, Houjie

    2015-01-01

    We aimed to determine the indecisive association between tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) Thr209Arg polymorphism and inherited susceptibility to cancer. A meta-analysis combining data on 9,517 individuals was performed to assess the association between TRAIL-R1 Thr209Arg and cancer incidence. The summary ORs with 95% CI calculated with the fixed effects model suggested that Thr209Arg was not significantly associated with cancer susceptibility (homozygous model: OR 0.98, 95% CI 0.88–1.09; heterozygous model: OR 0.95, 95% CI 0.87–1.04; allele frequency model: OR 0.99, 95% CI 0.94–1.05; dominant model: OR 0.98, 95% CI 0.91–1.05; recessive model: OR 1.01, 95% CI 0.92–1.10). Stratified analysis by ethnicity and cancer type yielded similar null associations. These statistical data suggest that Thr209Arg in exon 4 of the TRAIL-R1 gene may not represent a modifier of susceptibility to cancer. PMID:26315998

  3. Antimicrobial susceptibility patterns, emm type distribution and genetic diversity of Streptococcus pyogenes recovered in Brazil.

    PubMed

    Arêas, Glauber P; Schuab, Rôde B B; Neves, Felipe P G; Barros, Rosana R

    2014-11-01

    Streptococcus pyogenes is responsible for a variety of infectious diseases and immunological complications. In this study, 91 isolates of S. pyogenes recovered from oropharynx secretions were submitted to antimicrobial susceptibility testing, emm typing and pulsed-field gel electrophoresis (PFGE) analysis. All isolates were susceptible to ceftriaxone, levofloxacin, penicillin G and vancomycin. Resistance to erythromycin and clindamycin was 15.4%, which is higher than previous reports from this area, while 20.9% of the isolates were not susceptible to tetracycline. The macrolide resistance phenotypes were cMLSB (10) and iMLSB (4). The ermB gene was predominant, followed by the ermA gene. Thirty-two emm types and subtypes were found, but five (emm1, emm4, emm12, emm22, emm81) were detected in 48% of the isolates. Three new emm subtypes were identified (emm1.74, emm58.14, emm76.7). There was a strong association between emm type and PFGE clustering. A variety of PFGE profiles as well as emm types were found among tetracycline and erythromycin-resistant isolates, demonstrating that antimicrobial resistant strains do not result from the expansion of one or a few clones. This study provides epidemiological data that contribute to the development of suitable strategies for the prevention and treatment of such infections in a poorly studied area. PMID:25410998

  4. Correlation between XRCC1 Arg399Gln genetic polymorphisms and susceptibility to bladder cancer: a meta-analysis

    PubMed Central

    Liu, Nannan; Fei, Xiawei; Shen, Yi; Shi, Weifeng; Ma, Jinhong

    2016-01-01

    The relationship between XRCC1 polymorphisms and bladder cancer has been widely studied. Here, our meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in XRCC1 and susceptibility to bladder cancer. In order to derive a more precise estimation of the association, 27 clinical case-control studies (which met all the inclusion criteria) were included in this meta-analysis. A total of 8,539 cancer cases and 10,750 controls were involved in this meta-analysis. Overall, no significant association was detected in allelic model (A allele vs T allele odds ratio [OR] =0.87, 95% confidence interval [CI], 0.71–1.06), homozygote comparison (AA vs GG OR =1.12, 95% CI, 0.68–1.85), heterozygote comparison (AT vs TT OR =1.01, 95% CI, 0.81–1.26), dominant model (AA + AG vs GG OR =0.93, 95% CI, 0.85–1.02), and recessive model (AA vs AG + GG OR =1.01, 95% CI, 0.88–1.15), but a moderately significant association was found for AG vs GG (OR =0.241, 95% CI =0.17–0.35). Subgroup analysis based on ethnicity. Ethnicity analysis suggested that genetic polymorphisms in XRCC1 were not correlated with increased bladder cancer risk among Asians (all P>0.05). Therefore, we concluded that XRCC1 genetic polymorphism may not contribute to bladder cancer susceptibility in the present meta-analysis, and further well-designed studies with a large sample size are warranted to validate our conclusion. PMID:26869802

  5. Sardinians genetic background explained by runs of homozygosity and genomic regions under positive selection.

    PubMed

    Di Gaetano, Cornelia; Fiorito, Giovanni; Ortu, Maria Francesca; Rosa, Fabio; Guarrera, Simonetta; Pardini, Barbara; Cusi, Daniele; Frau, Francesca; Barlassina, Cristina; Troffa, Chiara; Argiolas, Giuseppe; Zaninello, Roberta; Fresu, Giovanni; Glorioso, Nicola; Piazza, Alberto; Matullo, Giuseppe

    2014-01-01

    The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods--fixation index, inflation factor, principal component analysis and ancestry estimation--we were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs>0.5 Mb (F(RoH%0.5)) when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces. PMID:24651212

  6. Sardinians Genetic Background Explained by Runs of Homozygosity and Genomic Regions under Positive Selection

    PubMed Central

    Di Gaetano, Cornelia; Fiorito, Giovanni; Ortu, Maria Francesca; Rosa, Fabio; Guarrera, Simonetta; Pardini, Barbara; Cusi, Daniele; Frau, Francesca; Barlassina, Cristina; Troffa, Chiara; Argiolas, Giuseppe; Zaninello, Roberta; Fresu, Giovanni; Glorioso, Nicola; Piazza, Alberto; Matullo, Giuseppe

    2014-01-01

    The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods - fixation index, inflation factor, principal component analysis and ancestry estimation - we were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs>0.5 Mb (FRoH%0.5) when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces. PMID:24651212

  7. Genomic selection for recovery of original genetic background from hybrids of endangered and common breeds

    PubMed Central

    Amador, Carmen; Hayes, Ben J; Daetwyler, Hans D

    2014-01-01

    Critically endangered breeds and populations are often crossed with more common breeds or subspecies. This results in genetic admixture that can be undesirable when it challenges the genetic integrity of wild and domestic populations, causing a loss in special characteristics or unique genetic material and ultimately extinction. Here, we present two genomic selection strategies, using genome-wide DNA markers, to recover the genomic content of the original endangered population from admixtures. Each strategy relies on the estimation of the proportion of nonintrogressed genome in individuals based on a different method: either genomic prediction or identification of breed-specific haplotypes. Then, breeding programs that remove introgressed genomic information can be designed. To test these strategies, we used empirical 50K SNP array data from two pure sheep breeds, Merino (used as target breed), Poll Dorset and an existing admixed population of both breeds. Sheep populations with varying degrees of introgression and admixture were simulated starting from these real genotypes. Both strategies were capable of identifying segment origin, and both removed up to the 100% of the Poll Dorset segments. While the selection process led to substantial inbreeding, we controlled it by imposing a minimum number of individuals contributing to the next generation. PMID:24567744

  8. Joint effects of genetic hitchhiking and background selection on neutral variation.

    PubMed Central

    Kim, Y; Stephan, W

    2000-01-01

    Due to relatively high rates of strongly selected deleterious mutations, directional selection on favorable alleles (causing hitchhiking effects on linked neutral polymorphisms) is expected to occur while a deleterious mutation-selection balance is present in a population. We analyze this interaction of directional selection and background selection and study their combined effects on neutral variation, using a three-locus model in which each locus is subjected to either deleterious, favorable, or neutral mutations. Average heterozygosity is measured by simulations (1) at the stationary state under the assumption of recurrent hitchhiking events and (2) as a transient level after a single hitchhiking event. The simulation results are compared to theoretical predictions. It is shown that known analytical solutions describing the hitchhiking effect without background selection can be modified such that they accurately predict the joint effects of hitchhiking and background on linked, neutral variation. Generalization of these results to a more appropriate multilocus model (such that background selection can occur at multiple sites) suggests that, in regions of very low recombination rates, stationary levels of nucleotide diversity are primarily determined by hitchhiking, whereas in regions of high recombination, background selection is the dominant force. The implications of these results on the identification and estimation of the relevant parameters of the model are discussed. PMID:10880499

  9. Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep☆

    PubMed Central

    Banks, Gareth; Heise, Ines; Starbuck, Becky; Osborne, Tamzin; Wisby, Laura; Potter, Paul; Jackson, Ian J.; Foster, Russell G.; Peirson, Stuart N.; Nolan, Patrick M.

    2015-01-01

    The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep. PMID:25179226

  10. Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep.

    PubMed

    Banks, Gareth; Heise, Ines; Starbuck, Becky; Osborne, Tamzin; Wisby, Laura; Potter, Paul; Jackson, Ian J; Foster, Russell G; Peirson, Stuart N; Nolan, Patrick M

    2015-01-01

    The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep. PMID:25179226

  11. Genetic background influences embryonic lethality and the occurrence of neural tube defects in Men1 null mice: relevance to genetic modifiers.

    PubMed

    Lemos, Manuel C; Harding, Brian; Reed, Anita A C; Jeyabalan, Jeshmi; Walls, Gerard V; Bowl, Michael R; Sharpe, James; Wedden, Sarah; Moss, Julie E; Ross, Allyson; Davidson, Duncan; Thakker, Rajesh V

    2009-10-01

    Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) gene cause parathyroid, pancreatic and pituitary tumours in man. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP) and the same MEN1 mutations, in different families, can cause either FIHP or MEN1. This suggests a role for genetic background and modifier genes in altering the expression of a mutation. We investigated the effects of genetic background on the phenotype of embryonic lethality that occurs in a mouse model for MEN1. Men1(+/-) mice were backcrossed to generate C57BL/6 and 129S6/SvEv incipient congenic strains, and used to obtain homozygous Men1(-/-) mice. No viable Men1(-/-) mice were obtained. The analysis of 411 live embryos obtained at 9.5-16.5 days post-coitum (dpc) revealed that significant deviations from the expected Mendelian 1:2:1 genotype ratio were first observed at 12.5 and 14.5 dpc in the 129S6/SvEv and C57BL/6 strains respectively (P<0.05). Moreover, live Men1(-/-) embryos were absent by 13.5 and 15.5 dpc in the 129S6/SvEv and C57BL/6 strains respectively thereby indicating an earlier lethality by 2 days in the 129S6/SvEv strain (P<0.01). Men1(-/-) embryos had macroscopic haemorrhages, and histology and optical projection tomography revealed them to have internal haemorrhages, myocardial hypotrophy, pericardial effusion, hepatic abnormalities and neural tube defects. The neural tube defects occurred exclusively in 129S6/SvEv embryos (21 vs 0%, P<0.01). Thus, our findings demonstrate the importance of genetic background in influencing the phenotypes of embryonic lethality and neural tube defects in Men1(-/-) mice, and implicate a role for genetic modifiers. PMID:19587266

  12. XRCC1 and XPD genetic polymorphisms and susceptibility to age-related cataract: A meta-analysis

    PubMed Central

    Chi, Xin-Xin; Liu, You-Yu; Shi, Su-Ning; Cong, Zhuang; Liang, Yu-Qing

    2015-01-01

    Objective This meta-analysis aimed to determine the relationships between XRCC1 Arg399Gln (rs25487 G>A) and XPD Lys751Gln (rs1052559 A>C) polymorphisms and susceptibility to age-related cataract. Methods Medline (1966–2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980–2013), CINAHL (1982–2013), Web of Science (1945–2013) and the Chinese Biomedical Database (CBM; 1982–2013) were searched without language restrictions. Various combinations of the keywords and MeSH terms were used to screen for potentially relevant studies, specifically “genetic polymorphisms” or “SNPs” or “variation” or “single nucleotide polymorphism” or “polymorphism” or “mutation” or “variant”; “X-ray repair cross complementing protein 1” or “Xeroderma Pigmentosum Group D Protein” or “X-ray repair cross complementing protein 1” or “Xeroderma Pigmentosum Group D Protein” or “XPD” or “Xeroderma Pigmentosum Complementation Group D Protein” or “ERCC2” or “XRCC1” or “XRCC1 DNA repair protein”; and “Cataract” or “ Membranous Cataract” or “ Pseudoaphakia.” Meta-analyses were conducted using Stata 12.0 software. Crude odds ratios (ORs) and their corresponding 95% confidence intervals (95% CI) were calculated. Results Six independent case-control studies were included in the meta-analysis. Our results indicated that the association between the genetic polymorphisms of XRCC1 Arg399Gln G>A and XPD Lys751Gln A>C and increased susceptibility to age-related cataracts was statistically significant (XRCC1 Arg399Gln: OR=1.30, 95% CI=1.17–1.44, p<0.001; XPD Lys751Gln: OR=1.25, 95% CI=1.12–1.40, p<0.001, respectively). Ethnicity-stratified analysis indicated that the XRCC1 Arg399Gln G>A polymorphism was correlated with the development and progression of age-related cataract in China, India, and Turkey in the allele model and the dominant model. For the XPD Lys751Gln A>C variant, the association with the pathogenesis of age-related cataract in China and Turkey in the allele model and the dominant model was investigated. Conclusions The association of XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms with age-related cataract susceptibility observed in our meta-analyses supports the view that XRCC1 and XPD may play important roles in susceptibility to age-related cataract. PMID:25873778

  13. Genetic Susceptibility to Type 2 Diabetes and Obesity: Follow-Up of Findings from Genome-Wide Association Studies

    PubMed Central

    Basile, Kevin J.; Johnson, Matthew E.; Xia, Qianghua; Grant, Struan F. A.

    2014-01-01

    Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context. PMID:24719615

  14. Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations?

    PubMed

    Li, Xiao; Zhang, Wen; Tang, Jinsong; Tan, Liwen; Luo, Xiong-jian; Chen, Xiaogang; Yao, Yong-Gang

    2015-01-01

    Schizophrenia is one of the most prevalent psychiatric disorders with complex genetic etiology. Accumulating evidence suggests that energy metabolism and oxidative stress play important roles in the pathophysiology of schizophrenia. Dysfunction of mitochondrial respiratory chain and altered expression of complex I subunits were frequently reported in schizophrenia. To investigate whether nuclear-encoded core subunit genes of mitochondrial complex I are associated with schizophrenia, we performed a genetic association study in Han Chinese. In total, 46 tag single nucleotide polymorphisms (SNPs) from 7 nuclear-encoded core genes of mitochondrial complex I were genotyped in 918 schizophrenia patients and 1042 healthy controls. We also analyzed these SNPs in a large sample mainly composed of Europeans through using the available GWAS datasets from the Psychiatric Genomics Consortium (PGC). No significant associations were detected between these SNPs and schizophrenia in Han Chinese and the PGC data set. However, we observed nominal significant associations of 2 SNPs in the NDUFS1 gene and 4 SNPs in the NDUFS2 gene with early onset schizophrenia (EOS), but none of these associations survived the Bonferroni correction. Taken together, our results suggested that common SNPs in the nuclear-encoded core subunit genes of mitochondrial complex I may not confer genetic susceptibility to schizophrenia. PMID:26053550

  15. Utilization of frozen-thawed epididymal ram semen to preserve genetic diversity in Scrapie susceptible sheep breeds.

    PubMed

    Ehling, C; Rath, D; Struckmann, C; Frenzel, A; Schindler, L; Niemann, H

    2006-12-01

    The European Union has introduced transmissible spongiform encephalopathy (TSE) resistance breeding programmes for several sheep breeds to cope with the genetic susceptibility to Scrapie infections. Due to the different allele frequencies among breeds, strong selection for ARR alleles is associated with a loss of genetic diversity in small populations and in larger populations with unfavourable ARR allele frequencies. To ensure maintenance of genetic diversity, an adhoc cryopreservation programme was initiated employing epididymal sperm from 109 rams representing 16 different breeds within one breeding season. Epididymal semen was chosen for this adhoc programme because time consuming training of rams for ejaculated semen collection via an artificial vagina was not possible. Prior to freezing, average sperm motility was 79.7% and acrosome integrity was 93.7%. After freezing, these levels were decreased to 60.5 and 72.8%, respectively. An insemination trial using frozen-thawed epididymal semen resulted in a lambing rate of 87.5%. Results show that this semen preservation method is robust and efficient and associated with high fertility. It may also be useful for other animal species. PMID:16905182

  16. Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium.

    PubMed

    Campa, Daniele; Rizzato, Cosmeri; Capurso, Gabriele; Giese, Nathalia; Funel, Niccola; Greenhalf, William; Soucek, Pavel; Gazouli, Maria; Pezzilli, Raffaele; Pasquali, Claudio; Talar-Wojnarowska, Renata; Cantore, Maurizio; Andriulli, Angelo; Scarpa, Aldo; Jamroziak, Krzysztof; Delle Fave, Gianfranco; Costello, Eithne; Khaw, Kay-Tee; Heller, Anette; Key, Tim J; Theodoropoulos, George; Malecka-Panas, Ewa; Mambrini, Andrea; Bambi, Franco; Landi, Stefano; Pedrazzoli, Sergio; Bassi, Claudio; Pacetti, Paola; Piepoli, Ada; Tavano, Francesca; di Sebastiano, Pierluigi; Vodickova, Ludmila; Basso, Daniela; Plebani, Mario; Fogar, Paola; Büchler, Markus W; Bugert, Peter; Vodicka, Pavel; Boggi, Ugo; Neoptolemos, John P; Werner, Jens; Canzian, Federico

    2013-02-01

    Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going. PMID:23206934

  17. Molecular Assay for Detection of Genetic Markers Associated with Decreased Susceptibility to Cephalosporins in Neisseria gonorrhoeae

    PubMed Central

    Peterson, S. W.; Martin, I.; Demczuk, W.; Bharat, A.; Hoang, L.; Wylie, J.; Allen, V.; Lefebvre, B.; Tyrrell, G.; Horsman, G.; Haldane, D.; Garceau, R.; Wong, T.

    2015-01-01

    The incidence of antimicrobial-resistant Neisseria gonorrhoeae continues to rise in Canada; however, antimicrobial resistance data are lacking for approximately 70% of gonorrhea infections that are diagnosed directly from clinical specimens by nucleic acid amplification tests (NAATs). We developed a molecular assay for surveillance use to detect mutations in genes associated with decreased susceptibility to cephalosporins that can be applied to both culture isolates and clinical samples. Real-time PCR assays were developed to detect single nucleotide polymorphisms (SNPs) in ponA, mtrR, penA, porB, and one N. gonorrhoeae-specific marker (porA). We tested the real-time PCR assay with 252 gonococcal isolates, 50 nongonococcal isolates, 24 N. gonorrhoeae-negative NAAT specimens, and 34 N. gonorrhoeae-positive NAAT specimens. Twenty-four of the N. gonorrhoeae-positive NAAT specimens had matched culture isolates. Assay results were confirmed by comparison with whole-genome sequencing data. For 252 N. gonorrhoeae strains, the agreement between the DNA sequence and real-time PCR was 100% for porA, ponA, and penA, 99.6% for mtrR, and 95.2% for porB. The presence of ≥2 SNPs correlated with decreased susceptibility to ceftriaxone (sensitivities of >98%) and cefixime (sensitivities of >96%). Of 24 NAAT specimens with matched cultures, the agreement between the DNA sequence and real-time PCR was 100% for porB, 95.8% for ponA and mtrR, and 91.7% for penA. We demonstrated the utility of a real-time PCR assay for sensitive detection of known markers for the decreased susceptibility to cephalosporins in N. gonorrhoeae. Preliminary results with clinical NAAT specimens were also promising, as they correlated well with bacterial culture results. PMID:25878350

  18. Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ovine lentiviruses cause incurable, progressive, lymphoproliferative diseases that affect millions of sheep worldwide. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been recently associated with lentivirus infections in U.S. sheep. Sheep with the two most common TMEM1...

  19. Influence of Genetic Background on Anthocyanin and Copigment Composition and Behavior during Thermoalkaline Processing of Maize.

    PubMed

    Collison, Amy; Yang, Liyi; Dykes, Linda; Murray, Seth; Awika, Joseph M

    2015-06-10

    Visual color is a primary quality factor for foods purchase; identifying factors that influence in situ color quality of pigmented maize during processing is important. Twenty-four genetically distinct pigmented maize hybrids (red/blue, blue, red, and purple) were used to investigate the effect of pigment and copigment composition on color stability during nixtamalization and tortilla chip processing. The red/blue and blue samples generally contained higher proportions of acylated anthocyanins (mainly cyanidin-3-(6″-malonylglucoside)) than the red and purple color classes. Phenolic amides were the major extractable copigments in all samples (450-764 μg/g), with red samples containing the most putrescines and blue samples containing the most spermidines. Even though samples with higher proportions of acylated anthocyanins retained more pigments during processing, this did not relate to final product color quality. In general, the red/blue samples retained their color quality the best and thus are good candidates for genetic improvement for direct processing into alkalized products. PMID:26010030

  20. Large variations in ocular dimensions in a multiethnic population with similar genetic background

    PubMed Central

    Niu, Zhiqiang; Li, Jun; Zhong, Hua; Yuan, Zhonghua; Zhou, Hua; Zhang, Yang; Yuan, Yuansheng; Chen, Qin; Pan, Chen-Wei

    2016-01-01

    We aimed to describe the ethnic variations in ocular dimensions among three ethnic groups with similar genetic ancestry from mainland of China. We included 2119 ethnic Bai, 2202 ethnic Yi and 2183 ethnic Han adults aged 50 years or older in the study. Ocular dimensions including axial length (AL), anterior chamber depth (ACD), vitreous chamber depth (VCD) and lens thickness (LT) were measured using A-scan ultrasonography. Bai Chinese had longer ALs (P < 0.001), deeper ACDs (P < 0.001) but shallower VCDs (P < 0.001) compared with the other two ethnic groups. There were no ethnic variations in LTs. Diabetes was associated with shallower ACDs and this association was stronger in Bai Chinese compared with Yi or Han Chinese (P for interaction = 0.02). Thicker lenses were associated with younger age (P = 0.04), male gender (P < 0.001), smoking history (P = 0.01), alcohol intake (P = 0.03), the presence of cataract (P < 0.001), and the presence of diabetes (P < 0.001). There were significant differences in ocular dimensions among different ethnic groups with small differences in genetics but large variations in cultures and lifestyles. PMID:26947903

  1. Silver-Russell Syndrome - Part I: Clinical Characteristics and Genetic Background.

    PubMed

    Marczak-Hałupka, Anna; Kalina, Maria A; Tańska, Anna; Chrzanowska, Krystyna H

    2015-01-01

    Silver-Russell syndrome (SRS) is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alternations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry. About 40-60% of cases are caused by hypomethylation of 11p.15.5 Imprinting Centre Region 1 (ICR1) on the paternal chromosome, and maternal uniparental disomy for chromosome 7 (UPD(7)mat) is found in 5-10% of cases. There are suggested correlations between genotype and the phenotype. Psychomotor development may be delayed, usually mildly, with school difficulties and speech delay more common in patients with UPD(7)mat. Children with 11p15 hypomethylation are shorter and lighter at birth in comparison to children with UPD(7)mat, however further deceleration tends to be more apparent in the latter group. The onset of puberty tends to occur early, with acceleration of bone age, resulting in less apparent growth spurt. Failure to thrive and feeding problems are characteristic for the infant period, and further development of a child may be conditioned by additional congenital defects. PMID:26615046

  2. Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus.

    PubMed

    Gharahkhani, Puya; Tung, Joyce; Hinds, David; Mishra, Aniket; Vaughan, Thomas L; Whiteman, David C; MacGregor, Stuart

    2016-02-15

    Esophageal adenocarcinoma (EA) is a rapidly fatal cancer with rising incidence in the developed world. Most EAs arise in a metaplastic epithelium, Barrett's esophagus (BE), which is associated with greatly increased risk of EA. One of the key risk factors for both BE and EA is chronic gastroesophageal reflux disease (GERD). This study used the linkage disequilibrium (LD) score regression and genomic profile risk scoring approaches to investigate the contribution of multiple common single-nucleotide polymorphisms (SNPs) to the risk of GERD, and the extent of genetic overlap between GERD and BE or EA. Using LD score regression, we estimated an overall phenotypic variance of 7% (95% CI 3-11%) for GERD explained by all the genotyped SNPs. A genetic correlation of 77% (s.e. = 24%, P = 0.0012) between GERD and BE and 88% between GERD and EA (s.e. = 25%, P = 0.0004) was estimated using the LD score regression approach. Results from the genomic profile risk scoring approach, as a robustness check, were broadly similar to those from the LD score regression. This study provides the first evidence for a polygenic basis for GERD and supports for a polygenic overlap between GERD and BE, and GERD and EA. PMID:26704365

  3. Large variations in ocular dimensions in a multiethnic population with similar genetic background.

    PubMed

    Niu, Zhiqiang; Li, Jun; Zhong, Hua; Yuan, Zhonghua; Zhou, Hua; Zhang, Yang; Yuan, Yuansheng; Chen, Qin; Pan, Chen-Wei

    2016-01-01

    We aimed to describe the ethnic variations in ocular dimensions among three ethnic groups with similar genetic ancestry from mainland of China. We included 2119 ethnic Bai, 2202 ethnic Yi and 2183 ethnic Han adults aged 50 years or older in the study. Ocular dimensions including axial length (AL), anterior chamber depth (ACD), vitreous chamber depth (VCD) and lens thickness (LT) were measured using A-scan ultrasonography. Bai Chinese had longer ALs (P < 0.001), deeper ACDs (P < 0.001) but shallower VCDs (P < 0.001) compared with the other two ethnic groups. There were no ethnic variations in LTs. Diabetes was associated with shallower ACDs and this association was stronger in Bai Chinese compared with Yi or Han Chinese (P for interaction = 0.02). Thicker lenses were associated with younger age (P = 0.04), male gender (P < 0.001), smoking history (P = 0.01), alcohol intake (P = 0.03), the presence of cataract (P < 0.001), and the presence of diabetes (P < 0.001). There were significant differences in ocular dimensions among different ethnic groups with small differences in genetics but large variations in cultures and lifestyles. PMID:26947903

  4. Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus

    PubMed Central

    Gharahkhani, Puya; Tung, Joyce; Hinds, David; Mishra, Aniket; Vaughan, Thomas L.; Whiteman, David C.; MacGregor, Stuart

    2016-01-01

    Esophageal adenocarcinoma (EA) is a rapidly fatal cancer with rising incidence in the developed world. Most EAs arise in a metaplastic epithelium, Barrett's esophagus (BE), which is associated with greatly increased risk of EA. One of the key risk factors for both BE and EA is chronic gastroesophageal reflux disease (GERD). This study used the linkage disequilibrium (LD) score regression and genomic profile risk scoring approaches to investigate the contribution of multiple common single-nucleotide polymorphisms (SNPs) to the risk of GERD, and the extent of genetic overlap between GERD and BE or EA. Using LD score regression, we estimated an overall phenotypic variance of 7% (95% CI 3–11%) for GERD explained by all the genotyped SNPs. A genetic correlation of 77% (s.e. = 24%, P = 0.0012) between GERD and BE and 88% between GERD and EA (s.e. = 25%, P = 0.0004) was estimated using the LD score regression approach. Results from the genomic profile risk scoring approach, as a robustness check, were broadly similar to those from the LD score regression. This study provides the first evidence for a polygenic basis for GERD and supports for a polygenic overlap between GERD and BE, and GERD and EA. PMID:26704365

  5. Prenatal exposure of mice to the human liver carcinogen aflatoxin B1 reveals a critical window of susceptibility to genetic change.

    PubMed

    Chawanthayatham, Supawadee; Thiantanawat, Apinya; Egner, Patricia A; Groopman, John D; Wogan, Gerald N; Croy, Robert G; Essigmann, John M

    2015-03-15

    It has become axiomatic that critical windows of susceptibility to genotoxins exist and that genetic damage in utero may be a trigger for later life cancers. Data supporting this critical window hypothesis are remarkably few. This study provides a quantitative bridge between DNA damage by the liver carcinogen aflatoxin B1 (AFB1 ) during prenatal development and the risk of later life genetic disease. AFB1 was given to pregnant C57BL/6J mice, carrying F1 gestation day 14 (GD14) embryos of the B6C3F1 genotype. Ultra-high performance liquid chromatography and mass spectrometry (UPLC-MS) using aflatoxin-(15) N5 -guanine adduct standards afforded measurement of the AFB1 -N(7) -Gua and AFB1 -FAPY adducts 6-hr post dosing in liver DNA of mothers and embryos. A parallel cohort gave birth and the livers of the F1 were analyzed for mutations in the gpt gene at 3 and 10 weeks of age. The data revealed mutational spectra dominated by G:C to T:A mutations in both the mother and offspring that are characteristic of AFB1 and distinct from background. It was shown that adducts in GD14 embryos were 20-fold more potent inducers of mutagenesis than adducts in parallel-dosed adults. This sensitivity enhancement correlated with Ki67 staining of the liver, reflecting the proliferative potential of the tissue. Taken together, these data provide insight into the relative genetic risks of prenatal and adult exposures to AFB1 . Early life exposure, especially during the embryonic period, is strikingly more mutagenic than treatment later in life. Moreover the data provide a baseline against which risk prevention strategies can be evaluated. PMID:25070670

  6. Differential susceptibility of transgenic mice expressing human surfactant protein B genetic variants to Pseudomonas aeruginosa induced pneumonia.

    PubMed

    Ge, Lin; Liu, Xinyu; Chen, Rimei; Xu, Yongan; Zuo, Yi Y; Cooney, Robert N; Wang, Guirong

    2016-01-01

    Surfactant protein B (SP-B) is essential for lung function. Previous studies have indicated that a SP-B 1580C/T polymorphism (SNP rs1130866) was associated with lung diseases including pneumonia. The SNP causes an altered N-linked glycosylation modification at Asn129 of proSP-B, e.g. the C allele with this glycosylation site but not in the T allele. This study aimed to generate humanized SP-B transgenic mice carrying either SP-B C or T allele without a mouse SP-B background and then examine functional susceptibility to bacterial pneumonia in vivo. A total of 18 transgenic mouse founders were generated by the DNA microinjection method. These founders were back-crossed with SP-B KO mice to eliminate mouse SP-B background. Four founder lines expressing similar SP-B levels to human lung were chosen for further investigation. After intratracheal infection with 50 μl of Pseudomonas aeruginosa solution (1 × 10(6) CFU/mouse) or saline in SP-B-C, SP-B-T mice the mice were sacrificed 24 h post-infection and tissues were harvested. Analysis of surfactant activity revealed differential susceptibility between SP-B-C and SP-B-T mice to bacterial infection, e.g. higher minimum surface tension in infected SP-B-C versus infected SP-B-T mice. These results demonstrate for the first time that human SP-B C allele is more susceptible to bacterial pneumonia than SP-B T allele in vivo. PMID:26620227

  7. The Moral Reasoning of Genetic Dilemmas Amongst Jewish Israeli Undergraduate Students with Different Religious Affiliations and Scientific Backgrounds.

    PubMed

    Siani, Merav; Ben-Zvi Assaraf, Orit

    2016-06-01

    The main objective of this study was to shed light on the moral reasoning of undergraduate Israeli students towards genetic dilemmas, and on how these are affected by their religious affiliation, by the field they study and by their gender. An open ended questionnaire was distributed among 449 undergraduate students in institutions of higher education in Israel, and their answers were analyzed according to the framework described by Sadler and Zeidler (Science Education, 88(1), 4-27, 2004). They were divided into two major categories: those whose reasoning was based on the consideration of moral consequences (MC), and those who supported their opinion by citing non-consequentialist moral principles (MP). Students' elaborations to questions dealing with values towards genetic testing showed a correlation between the students' religious affiliation and their reasoning, with religious students' elaborations tending to be more principle based than those of secular ones. Overall, the students' elaborations indicate that their main concern is the possibility that their personal genetic information will be exposed, and that their body's personal rights will be violated. We conclude the paper by offering several practical recommendations based on our findings for genetic counseling that is specifically tailored to fit different patients according to their background. PMID:26642964

  8. Genetic Association Between NFKBIA -881A>G Polymorphism and Cancer Susceptibility.

    PubMed

    Geng, Peiliang; Ou, Juanjuan; Li, Jianjun; Liao, Yunmei; Wang, Ning; Sa, Rina; Xiang, Lisha; Liang, Houjie

    2015-08-01

    Several epidemiological studies have focused on the role of nuclear factor-kappa-B inhibitor-alpha (NFKBIA) -881 A>G polymorphism in cancer susceptibility. However, the published data have led to contentious results. This study was designed to examine the association between -881 A>G polymorphism and cancer risk.Comprehensive search of PubMed, Web of science and Embase, identified a total of 5 case-control studies. To assess the association, comparison among all subjects plus subgroup analysis by ethnicity was performed and odds ratio (OR) along with 95% confidence interval (CI) was calculated with the fixed-effect model or the random-effects model dependent on the heterogeneity.The pooling data consisting of 1965 cancer cases and 2717 cancer-free controls demonstrated no significant association with overall cancer risk. However, the subgroup of Asian populations showed statistical evidence for an increase in risk of cancer (GG vs. AA, OR, 2.14; 95% CI, 1.03-4.46; GG?+?GA vs. AA, OR, 1.22; 95% CI, 1.01-1.47; GG vs. GA?+?AA, OR, 2.09; 95% CI, 1.01-4.34).This investigation on the association of -881 A>G polymorphism and cancer susceptibility reveals that -881 A>G polymorphism may act as a candidate for cancer development in Asian populations. PMID:26252270

  9. Genetic diversity and antifungal susceptibility testing of Trichosporon asahii isolated of Intensive Care Units patients

    PubMed Central

    de Oliveira Silva, Rosana Bellan; Fusco-Almeida, Ana Marisa; Matsumoto, Marcelo Teruyuki; Baeza, Lilian Cristiane; Benaducci, Tatiane; Mendes-Giannini, Maria José Soares

    2008-01-01

    Trichosporon asahii is an opportunistic pathogen, associated with a high mortality rate in immunocompromised patients. In this study, ten isolates, recovered from oral cavity and urine of patients in Intensive Care Units (ICU) over six months, were identified by classical and molecular methods, typed by RAPD and tested in vitro for susceptibility to fluconazole, itraconazole, 5-flucytosine and amphotericin B. A total agreement between the identification of Trichosporon sp by PCR based on sequences of the Internal Transcribed Spacer Regions (ITS) and on the sequences of small-subunit (SSU) ribosomal DNA (rDNA) was found. Randomly amplified of polymorphic DNA (RAPD), with primers P6 and M13, was used to determine the genomic profiles. The dendogram analysis indicated that almost all strains showed similarity >0.9 among them and all strains were multidrug-resistant. This study brings new results on the identification and genotyping of T. asahii isolated from Brazilian ICU patients and information about their antifungal drugs susceptibility. PMID:24031270

  10. Evaluation of Genetic Susceptibility to Childhood Allergy and Asthma in an African American Urban Population

    EPA Science Inventory

    Background: Asthma and allergy represent complex phenotypes, which disproportionately burden ethnic minorities in the United States. Strong evidence for genomic factors predisposing subjects to asthma/allergy is available. However, methods to utilize this information to identify ...

  11. Genetic Variations in ABCG2 Gene Predict Breast Carcinoma Susceptibility and Clinical Outcomes after Treatment with Anthracycline-Based Chemotherapy

    PubMed Central

    Wu, Huizhe; Liu, Yong; Kang, Hui; Xiao, Qinghuan; Yao, Weifan; Zhao, Haishan; Wang, Enhua; Wei, Minjie

    2015-01-01

    The genetic variants of the ATP-binding cassette, subfamily G, member 2 (ABCG2) are known to be involved in developing cancer risk and interindividual differences in chemotherapeutic response. The polymorphisms in ABCG2 gene were genotyped by using PCR-RFLP assays. We found that ABCG2 G34A GA/AA genotype, C421A AA genotype, and haplotypes 34A-421C and 34G-421A were significantly associated with increased risk for developing breast carcinoma. Furthermore, ABCG2 C421A AA homozygote had a significant enhanced therapeutic response in patients with neoadjuvant anthracycline-based chemotherapy. Moreover, ABCG2 G34A AA genotype carriers displayed a longer OS in ER positive patients or PR positive patients after postoperative anthracycline-based chemotherapy. These results suggested that the ABCG2 polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis for breast carcinoma patients. PMID:26634205

  12. [Permanent neonatal diabetes with known genetic background: oral drugs in treatment of childhood diabetes].

    PubMed

    Gach, Agnieszka; Gadzicka, Anna; Młynarski, Wojciech

    2008-01-01

    Diabetes, which is diagnosed before 6 months of age, is patogenetically different than type 1 diabetes. This kind of diabetes also known as a neonatal diabetes is genetically determined with monogenic mode of inheritance. Most of these patients are carriers of heterozygous mutation in the KCNJ11 or ABCC8 gene. These mutations may activate the Kir6.2/SUR1 potassium channel in the beta cells and disturb insulin secretion, which in consequence leads to diabetes. This patological phenomenon is reversible if sulfonylureas are used as a first line therapy. In the current paper a systematic review of clinical aspects of sulfonylurea treatment in neonatal diabetes has been performed. This gives the further evidence that knowlegde of the patogenesis of neonatal diabetes may be easily transferred to bedside and clinical practice. PMID:18577347

  13. [Clinical and genetic background of familial myelodysplasia and acute myeloid leukemia].

    PubMed

    Király, Péter Attila; Kállay, Krisztián; Marosvári, Dóra; Benyó, Gábor; Szőke, Anita; Csomor, Judit; Bödör, Csaba

    2016-02-21

    Myelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia. PMID:26876264

  14. Genetic background and risk of postpartum haemorrhage: results from an Italian cohort of 3219 women.

    PubMed

    Biguzzi, E; Franchi, F; Acaia, B; Ossola, W; Nava, U; Paraboschi, E M; Asselta, R; Peyvandi, F

    2014-11-01

    Postpartum haemorrhage (PPH) is a leading cause of maternal mortality, particularly in the developing countries, and of severe maternal morbidity worldwide. To investigate the impact of genetic influences on postpartum haemorrhage, in association with maternal and intrapartum risk factors, using a candidate gene approach. All women (n = 6694) who underwent a vaginal delivery at the Obstetric Unit of a large University hospital in Milan (Italy) between July 2007 and September 2009 were enrolled. The first consecutive 3219 women entered the genetic study. Postpartum haemorrhage was defined as ≥500 mL blood loss. Eight functional polymorphisms in seven candidate genes were chosen because of their potential role in predisposing to or protecting from haemorrhagic conditions: tissue factor (F3), factor V (F5), tissue factor pathway inhibitor (TFPI), platelet glycoprotein Ia/IIa (ITGA2), prothrombin (F2), platelet glycoproteins Ibα (GP1BA) and angiotensin-converting enzyme (ACE). After correction for the already known PPH risk factors, only the promoter polymorphism of the tissue factor gene (F3 -603A>G) showed a significant association with PPH, the G allele exerting a protective effect (P = 0.00053; OR = 0.79, 95% CI = 0.69-0.90). The protective effect against PPH of the TF -603A>G polymorphism is biologically plausible since the G allele is associated with an increased protein expression and Tissue Factor is strongly represented in the placenta at term, particularly in decidual cells of maternal origin. PMID:25333208

  15. Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus

    PubMed Central

    Wilson, Gareth A.; Rakyan, Vardhman K.; Teschendorff, Andrew E.; Akan, Pelin; Stupka, Elia; Down, Thomas A.; Prokopenko, Inga; Morison, Ian M.; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M.; Hattersley, Andrew T.; McCarthy, Mark I.; Beck, Stephan; Hitman, Graham A.

    2010-01-01

    Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10−4, permutation p = 1.0×10−3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10−7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

  16. [Sporadic upper urinary tract urothelial cell carcinomas: identification of interaction between toxic carcinogens and individuals genetic susceptibility].

    PubMed

    Colin, P; Koenig, P; Ballereau, C; Ph, V; Berthon, N; Villers, A; Biserte, J; Rouprt, M

    2010-01-01

    Upper urinary tract urothelial cell carcinomas (UUT UCC) are rare sporadic tumors. Recent epidemiologic and molecular data have shown a singular susceptibility of UUT UCCs for specific risk factors. The main exogenic factors involved in UUT UCCs carcinogenesis remain tobacco and occupational exposure (aromatic amines, polycyclic hydrocarbures and chlored solvents). Enzymatic variants of detoxification system may be responsible of carcinogenesis with these toxics. Tumors induced by phenacetine consumption are decreasing since it was banned in the 1970s. Also, acid aristolochic exposure (Balkan nephropathy, Chinese Herb nephropathy) has been demonstrated to specifically induce UUT UCCs. Familial genic polymorphism of detoxification system would explain geographic distribution in endemic areas. In Taiwan, chronic arsenic exposition would constitute the main risk factor of UUT UCC. However, theses mechanisms of carcinogenesis remain unclear. The knowledge of UUT UCC development mechanisms implying toxic detoxification systems is still incomplete. To date, there is a growing body of evidence supporting that the interaction between individual genetic susceptibilities and environmental toxic exposure is a key to explain carcinogenesis in the majority of sporadic UUT UCC occurrence. PMID:20123521

  17. Genetic susceptibility, colony size, and water temperature drive white-pox disease on the coral Acropora palmata.

    PubMed

    Muller, Erinn M; van Woesik, Robert

    2014-01-01

    Outbreaks of coral diseases are one of the greatest threats to reef corals in the Caribbean, yet the mechanisms that lead to coral diseases are still largely unknown. Here we examined the spatial-temporal dynamics of white-pox disease on Acropora palmata coral colonies of known genotypes. We took a Bayesian approach, using Integrated Nested Laplace Approximation algorithms, to examine which covariates influenced the presence of white-pox disease over seven years. We showed that colony size, genetic susceptibility of the coral host, and high-water temperatures were the primary tested variables that were positively associated with the presence of white-pox disease on A. palmata colonies. Our study also showed that neither distance from previously diseased individuals, nor colony location, influenced the dynamics of white-pox disease. These results suggest that white-pox disease was most likely a consequence of anomalously high water temperatures that selectively compromised the oldest colonies and the most susceptible coral genotypes. PMID:25372835

  18. Genetic Variation in the Extended Major Histocompatibility Complex and Susceptibility to Childhood Acute Lymphoblastic Leukemia: A Review of the Evidence

    PubMed Central

    Urayama, Kevin Y.; Thompson, Pamela D.; Taylor, Malcolm; Trachtenberg, Elizabeth A.; Chokkalingam, Anand P.

    2013-01-01

    The enduring suspicion that infections and immunologic response may play a role in the etiology of childhood leukemia, particularly acute lymphoblastic leukemia (ALL), is now supported, albeit still indirectly, by numerous epidemiological studies. The cumulative evidence includes, for example, descriptive observations of a peculiar peak incidence at age 2–5 years for ALL in economically developed countries, clustering of cases in situations of population mixing associated with unusual patterns of personal contacts, associations with various proxy measures for immune modulatory exposures early in life, and genetic susceptibility conferred by variation in genes involved in the immune system. In this review, our focus is the extended major histocompatibility complex (MHC), an approximately 7.6 Mb region that is well-known for its high-density of expressed genes, extensive polymorphisms exhibiting complex linkage disequilibrium patterns, and its disproportionately large number of immune-related genes, including human leukocyte antigen (HLA). First discovered through the role they play in transplant rejection, the classical HLA class I (HLA-A, -B, and -C) and class II (HLA-DR, HLA-DQ, and HLA-DP) molecules reside at the epicenter of the immune response pathways and are now the targets of many disease susceptibility studies, including those for childhood leukemia. The genes encoding the HLA molecules are only a minority of the over 250 expressed genes in the xMHC, and a growing number of studies are beginning to evaluate other loci through targeted investigations or utilizing a mapping approach with a comprehensive screen of the entire region. Here, we review the current epidemiologic evidence available to date regarding genetic variation contained within this highly unique region of the genome and its relationship with childhood ALL risk. PMID:24377085

  19. Pathway Analysis of GWAS Provides New Insights into Genetic Susceptibility to 3 Inflammatory Diseases

    PubMed Central

    Hoggart, Clive; Hartikainen, Anna-Liisa; Jarvelin, Marjo-Riitta; Balding, David; Coin, Lachlan; Levin, Michael

    2009-01-01

    Although the introduction of genome-wide association studies (GWAS) have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD), rheumatoid arthritis (RA) and type 1 diabetes (T1D) with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC). The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10?310?20) with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes) for T1D, 350 SNPs (189 genes) for RA and 493 SNPs (277 genes) for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC) and RA (85% AUC), and weakly predictive of CD (60% AUC). The predictive ability of the T1D model (without any parameter refitting) had good predictive ability (79% AUC) in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways. PMID:19956648

  20. Dissecting the genetic heterogeneity of myopia susceptibility in an Ashkenazi Jewish population using ordered subset analysis

    PubMed Central

    Simpson, Claire L.; Wojciechowski, Robert; Ibay, Grace; Stambolian, Dwight

    2011-01-01

    Purpose Despite many years of research, most of the genetic factors contributing to myopia development remain unknown. Genetic studies have pointed to a strong inherited component, but although many candidate regions have been implicated, few genes have been positively identified. Methods We have previously reported 2 genomewide linkage scans in a population of 63 highly aggregated Ashkenazi Jewish families that identified a locus on chromosome 22. Here we used ordered subset analysis (OSA), conditioned on non-parametric linkage to chromosome 22 to detect other chromosomal regions which had evidence of linkage to myopia in subsets of the families, but not the overall sample. Results Strong evidence of linkage to a 19-cM linkage interval with a peak OSA nonparametric allele-sharing logarithm-of-odds (LOD) score of 3.14 on 20p12-q11.1 (ΔLOD=2.39, empirical p=0.029) was identified in a subset of 20 families that also exhibited strong evidence of linkage to chromosome 22. One other locus also presented with suggestive LOD scores >2.0 on chromosome 11p14-q14 and one locus on chromosome 6q22-q24 had an OSA LOD score=1.76 (ΔLOD=1.65, empirical p=0.02). Conclusions The chromosome 6 and 20 loci are entirely novel and appear linked in a subset of families whose myopia is known to be linked to chromosome 22. The chromosome 11 locus overlaps with the known Myopia-7 (MYP7, OMIM 609256) locus. Using ordered subset analysis allows us to find additional loci linked to myopia in subsets of families, and underlines the complex genetic heterogeneity of myopia even in highly aggregated families and genetically isolated populations such as the Ashkenazi Jews. PMID:21738393

  1. Differences in the Genetic Susceptibility to Age-Related Macular Degeneration Clinical Subtypes

    PubMed Central

    Shen, Ling; Hoffmann, Thomas J.; Melles, Ronald B.; Sakoda, Lori C.; Kvale, Mark N.; Banda, Yambazi; Schaefer, Catherine; Risch, Neil; Jorgenson, Eric

    2015-01-01

    Purpose We compared across age-related macular degeneration (AMD) subtypes the effect of AMD risk variants, their predictive power, and heritability. Methods The prevalence of AMD was estimated among active non-Hispanic white Kaiser Permanente Northern California members who were at least 65 years of age as of June 2013. The genetic analysis included 5,170 overall AMD cases ascertained from electronic health records (EHR), including 1,239 choroidal neovascularization (CNV) cases and 1,060 nonexudative AMD cases without CNV, and 23,130 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Imputation was based on the 1000 Genomes Project reference panel. Results The narrow-sense heritability due to common autosomal single nucleotide polymorphisms (SNPs) was 0.37 for overall AMD, 0.19 for AMD unspecified, 0.20 for nonexudative AMD, and 0.60 for CNV. For the 19 previously reported AMD risk loci, the area under the receiver operating characteristic (ROC) curve was 0.675 for overall AMD, 0.640 for AMD unspecified, 0.678 for nonexudative AMD, and 0.766 for CNV. The individual effects on the risk of AMD for 18 of the 19 SNPs were in a consistent direction with those previously reported, including a protective effect of the APOE ε4 allele. Conversely, the risk of AMD was significantly increased in carriers of the ε2 allele. Conclusions These findings provide an independent confirmation of many of the previously identified AMD risk loci, and support a potentially greater role of genetic factors in the development of CNV. The replication of established associations validates the use of EHR in genetic studies of ophthalmologic traits. PMID:26176866

  2. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    PubMed

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  3. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes

    PubMed Central

    Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P.; Keane, Thomas

    2016-01-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  4. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis

    SciTech Connect

    Mulcahy, B.; Waldron-Lynch, F.; Adams, C.; O`Gara, F.

    1996-09-01

    The major histocompatibility complex class H1 tumor necrosis factor-tymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3 % not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 {open_quotes}shared epitope{close_quotes} (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, BS, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR. 50 refs., 1 fig., 1 tab.

  5. Longevity effect of IGF-1R+/− mutation depends on genetic background-specific receptor activation

    PubMed Central

    Xu, Jie; Gontier, Géraldine; Chaker, Zayna; Lacube, Philippe; Dupont, Joëlle; Holzenberger, Martin

    2014-01-01

    Growth hormone (GH) and insulin-like growth factor (IGF) signaling regulates lifespan in mice. The modulating effects of genetic background gained much attention because it was shown that life-prolonging effects in Snell dwarf and GH receptor knockout vary between mouse strains. We previously reported that heterozygous IGF-1R inactivation (IGF-1R+/−) extends lifespan in female mice on 129/SvPas background, but it remained unclear whether this mutation produces a similar effect in other genetic backgrounds and which molecules possibly modify this effect. Here, we measured the life-prolonging effect of IGF-1R+/− mutation in C57BL/6J background and investigated the role of insulin/IGF signaling molecules in strain-dependent differences. We found significant lifespan extension in female IGF-1R+/− mutants on C57BL/6J background, but the effect was smaller than in 129/SvPas, suggesting strain-specific penetrance of longevity phenotypes. Comparing GH/IGF pathways between wild-type 129/SvPas and C57BL/6J mice, we found that circulating IGF-I and activation of IGF-1R, IRS-1, and IRS-2 were markedly elevated in 129/SvPas, while activation of IGF pathways was constitutively low in spontaneously long-lived C57BL/6J mice. Importantly, we demonstrated that loss of one IGF-1R allele diminished the level of activated IGF-1R and IRS more profoundly and triggered stronger endocrine feedback in 129/SvPas background than in C57BL/6J. We also revealed that acute oxidative stress entails robust IGF-1R pathway activation, which could account for the fact that IGF-1R+/− stress resistance phenotypes are fully penetrant in both backgrounds. Together, these results provide a possible explanation why IGF-1R+/− was less efficient in extending lifespan in C57BL/6J compared with 129/SvPas. PMID:23898955

  6. The conserved genetic background for pluteus arm development in brittle stars and sea urchin.

    PubMed

    Morino, Yoshiaki; Koga, Hiroyuki; Wada, Hiroshi

    2016-03-01

    Echinoderm pluteus larvae are considered a classical example of convergent evolution that occurred in sea urchins and brittle stars. Several genes are known to be involved in the development of pluteus arms in sea urchins, including fgfA, pax2/5/8, pea3, otp, wnt5, and tet. To determine whether the convergent evolution of larval arms also involves these genes in brittle stars, their expression patterns were determined in brittle star. We found that all genes showed similar expression in the arms of ophiopluteus to that seen in echinopluteus, suggesting that convergent evolution of pluteus arms occurred by recruitment of a similar set of genes. This may be explained by our observation that some of these genes are also expressed in the spine rudiment of direct-type development sea urchins. We propose an evolutionary scenario wherein the pluteus arms of both echinopluteus and ophiopluteus were acquired by independent co-options of the genetic module responsible for the projection of the adult skeleton. PMID:26773338

  7. Evaluation of polymorphisms in pbp4 gene and genetic diversity in penicillin-resistant, ampicillin-susceptible Enterococcus faecalis from hospitals in different states in Brazil.

    PubMed

    Infante, Victor Hugo Pacagnelli; Conceição, Natália; de Oliveira, Adriana Gonçalves; da Costa Darini, Ana Lúcia

    2016-04-01

    The aim of the present study was to verify whether penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) occurred in Brazil prior to the beginning of the 21st century, and to verify whether ampicillin susceptibility can predict susceptibility to other β-lactams in E. faecalis with this inconsistent phenotype. The presence of polymorphisms in the pbp4 gene and genetic diversity among the isolates were investigated. Of 21 PRASEF analyzed, 5 (23.8%) and 4 (19.0%) were imipenem and piperacillin resistant simultaneously by disk diffusion and broth dilution respectively, contradicting the current internationally accepted standards of susceptibility testing. Sequencing of pbp4 gene revealed an amino acid substitution (Asp-573→Glu) in all PRASEF isolates but not in the penicillin-susceptible, ampicillin-susceptible E. faecalis. Most PRASEF (90.5%) had related pulsed-field gel electrophoresis profiles, but were different from other PRASEF described to date. Results demonstrate that penicillin-resistant, ampicillin-susceptible phenotype was already a reality in the 1990s in E. faecalis isolates in different Brazilian states, and some of these isolates were also imipenem- and piperacillin-resistant; therefore, internationally accepted susceptibility criteria cannot be applied to these isolates. According to pbp4 gene sequencing, this study suggests that a specific amino acid substitution in pbp4 gene found in all PRASEF analyzed is associated with penicillin resistance. PMID:26903013

  8. Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility.

    PubMed

    Skakkebaek, Niels E; Rajpert-De Meyts, Ewa; Buck Louis, Germaine M; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H; Sapra, Katherine J; Ziebe, Søren; Priskorn, Lærke; Juul, Anders

    2016-01-01

    It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography. PMID:26582516

  9. Genetic susceptibility to early onset pauciarticular juvenile chronic arthritis: a study of HLA and complement markers in 158 British patients.

    PubMed Central

    Hall, P J; Burman, S J; Laurent, M R; Briggs, D C; Venning, H E; Leak, A M; Bedford, P A; Ansell, B M

    1986-01-01

    To investigate the genetics of susceptibility to early onset pauciarticular juvenile chronic arthritis (JCA), 158 unrelated ethnic British patients with a mean disease onset of 3.2 years, together with controls, were tested for HLA-A, B, C, and DR antigens. Additionally, 117 patients were also investigated for complement Bf and C4 markers. New observations included an increased frequency of the C4B 2 allotype (p corrected (pc) less than 0.02) and C4A 4,B 2 phenotype (p less than 0.0005). Findings suggested a unique increase of the haplotype HLA-DRw8, Bf*S, C4A*4, C4B*2, HLA-B39, possibly predisposing to more severe disease. Strong positive associations were confirmed with HLA antigens A2 (pc = 2.5 X 10(-8)), DRw8 (pc = 3.5 X 10(-14)), DR5 (pc less than 0.02), DRw52 (pc = 2.8 X 10(-6)) and DR5, w8 phenotype (pc = 3.9 X 10(-6)), and negative associations with DR7 (pc = 5.8 X 10(-7)), DR4 (pc less than 0.002), and DRw53 (pc = 0.004). Antinuclear antibody (ANA) seropositivity correlated with DR5 (p less than 0.02), and in children with chronic iridocyclitis (CIR) Bw62 incidence was raised (p less than 0.03) and B44 reduced (p less than 0.03). HLA-A2 was found in 88% of ANA+, CIR+ patients (p less than 0.01). A significant excess of DR5, w8 heterozygotes was present (relative risk = 41.1) and a lack of corresponding homozygotes. Results are inconsistent with a recessive, dominant, or intermediate mode of inheritance of susceptibility, and favour the existence of at least two DR linked 'disease' genes. Moreover, there may be an interaction in heterozygotes of combinatorial factors associated with DR5 and DRw8 in enhancing susceptibility. Possible immunogenetic mechanisms underlying the observed associations with three antigen classes are discussed. Evidence here suggests a role for the HLA-DQ locus in determining susceptibility to this disease. PMID:3488035

  10. Genetic Variation in the IL7RA/IL7 Pathway Increases Multiple Sclerosis Susceptibility

    PubMed Central

    Zuvich, Rebecca L.; McCauley, Jacob L.; Oksenberg, Jorge R.; Sawcer, Stephen J.; De Jager, Philip L.; Aubin, Cristin; Cross, Anne H.; Piccio, Laura; Aggarwal, Neelum T.; Evans, Denis; Hafler, David A.; Compston, Alastair; Hauser, Stephen L.; Pericak-Vance, Margaret A.; Haines, Jonathan L.

    2010-01-01

    Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large datasets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. 2007; International Multiple Sclerosis Genetics Consortium 2007; Lundmark 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case-control dataset, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case-control dataset (4,831 samples) with joint p-values as high as 8.2910-6 and 3.4810-7, respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p-values reaching 3.4710-4 and BCL2 with p-values reaching 4.3210-4. The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease. PMID:20112030

  11. TM6SF2 E167K Variant, a Novel Genetic Susceptibility Variant, Contributing to Nonalcoholic Fatty Liver Disease

    PubMed Central

    Chen, Li-Zhen; Xia, Harry Hua-Xiang; Xin, Yong-Ning; Lin, Zhong-Hua; Xuan, Shi-Ying

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver dysfunction worldwide, and its prevalence is highly associated with genetic susceptibility. The transmembrane 6 superfamily member 2 (TM6SF2) E167K variant represents a general genetic determinant of hepatic triglyceride content and lobular inflammation, and its presence appears to be directly involved in the pathogenesis and development of NAFLD. Although this variant appears to be a novel powerful modifier in the development of NAFLD, whether it is associated with an increased risk of NAFLD-related liver fibrosis and hepatocellular carcinoma (HCC) remains to be determined. The aim of this review is to describe the functions of the TM6SF2 E167K variant and its association with NAFLD, with particular emphasis on the underlying mechanisms of its role in the development and progression of NAFLD. Additionally, the links between the TM6SF2 E167K variant and NAFLD-related liver fibrosis and HCC will be discussed. PMID:26807382

  12. The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract

    PubMed Central

    Delahaye-Sourdeix, Manon; Oliver, Javier; Timofeeva, Maria N.; Gaborieau, Valérie; Johansson, Mattias; Chabrier, Amélie; Wozniak, Magdalena B.; Brenner, Darren R.; Vallée, Maxime P.; Anantharaman, Devasena; Lagiou, Pagona; Holcátová, Ivana; Richiardi, Lorenzo; Kjaerheim, Kristina; Agudo, Antonio; Castellsagué, Xavier; Macfarlane, Tatiana V.; Barzan, Luigi; Canova, Cristina; Thakker, Nalin S.; Conway, David I.; Znaor, Ariana; Healy, Claire M.; Ahrens, Wolfgang; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Fabianova, Eleonora; Mates, Ioan Nicolae; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Curado, Maria Paula; Koifman, Sergio; Menezes, Ana; Wünsch-Filho, Victor; Eluf-Neto, José; Boffetta, Paolo; Garrote, Leticia Fernández; Serraino, Diego; Lener, Marcin; Jaworowska, Ewa; Lubiński, Jan; Boccia, Stefania; Rajkumar, Thangarajan; Samant, Tanuja A.; Mahimkar, Manoj B.; Matsuo, Keitaro; Franceschi, Silvia; Byrnes, Graham; Brennan, Paul; McKay, James D.

    2015-01-01

    Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04–1.15, p = 6x10−4). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10−3) and LUSC (p = 9x10−4) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10−48 and p = 3x10−29 in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors. PMID:25793373

  13. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

    PubMed Central

    Bustamante, Jacinta; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent

    2014-01-01

    Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity. PMID:25453225

  14. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity.

    PubMed

    Bustamante, Jacinta; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent

    2014-12-01

    Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity. PMID:25453225

  15. Interleukin-18 gene 105A/C genetic polymorphism is associated with the susceptibility of Kawasaki disease.

    PubMed

    Chen, Shih-Yin; Wan, Lei; Huang, Yu-Chuen; Sheu, Jim Jinn-Chyuan; Lan, Yu-Ching; Lai, Chih-Ho; Lin, Cheng-Wen; Chang, Jeng Sheng; Tsai, Yuhsin; Liu, Shih-Ping; Lin, Ying-Ju; Tsai, Fuu-Jen

    2009-01-01

    Interleukin-18 (IL-18)-656T/G, -607A/C, and -137C/G promoter polymorphisms had been reported associated with Kawasaki disease (KD). An IL-18 genetic A/C polymorphism at coding position 105 (rs549908) has been linked with asthma, rheumatoid, and systemic lupus erythematosus. We tested a hypothesis that the IL-18 105A/C genetic polymorphism confers KD susceptibility. Study participants were Taiwanese KD patients and a healthy control group. Our data indicated that the frequency of C allele was significantly higher in the patient group (13.9%) than in the control group (2.7%; P<0.0001, odds ratio [OR]=5.93; 95% confidence interval [CI]=2.57-13.73). Therefore, persons with the C allele may have higher risk of developing KD. In addition, compared with the haplotype frequencies between case and control groups, the KD patients with TACC haplotype appeared to be a significant "at-risk" haplotype compared with other haplotypes (OR: 4.62, 95% CI: 1.71-12.43; P=0.001). KD patient with the TAGA haplotype appeared to be a significant "protective" haplotype compared with other haplotypes (OR: 0.51, 95% CI:0.29-0.89; P=0.017). Our results suggest that 105A/C polymorphism and the haplotypes in IL-18 gene are associated with the risk of KD in Taiwanese population. PMID:19288449

  16. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

    PubMed Central

    Bowes, John; Budu-Aggrey, Ashley; Huffmeier, Ulrike; Uebe, Steffen; Steel, Kathryn; Hebert, Harry L.; Wallace, Chris; Massey, Jonathan; Bruce, Ian N.; Bluett, James; Feletar, Marie; Morgan, Ann W.; Marzo-Ortega, Helena; Donohoe, Gary; Morris, Derek W.; Helliwell, Philip; Ryan, Anthony W.; Kane, David; Warren, Richard B.; Korendowych, Eleanor; Alenius, Gerd-Marie; Giardina, Emiliano; Packham, Jonathan; McManus, Ross; FitzGerald, Oliver; McHugh, Neil; Brown, Matthew A.; Ho, Pauline; Behrens, Frank; Burkhardt, Harald; Reis, Andre; Barton, Anne

    2015-01-01

    Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8+ memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA. PMID:25651891

  17. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis.

    PubMed

    Bowes, John; Budu-Aggrey, Ashley; Huffmeier, Ulrike; Uebe, Steffen; Steel, Kathryn; Hebert, Harry L; Wallace, Chris; Massey, Jonathan; Bruce, Ian N; Bluett, James; Feletar, Marie; Morgan, Ann W; Marzo-Ortega, Helena; Donohoe, Gary; Morris, Derek W; Helliwell, Philip; Ryan, Anthony W; Kane, David; Warren, Richard B; Korendowych, Eleanor; Alenius, Gerd-Marie; Giardina, Emiliano; Packham, Jonathan; McManus, Ross; FitzGerald, Oliver; McHugh, Neil; Brown, Matthew A; Ho, Pauline; Behrens, Frank; Burkhardt, Harald; Reis, Andre; Barton, Anne

    2015-01-01

    Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA. PMID:25651891

  18. The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract.

    PubMed

    Delahaye-Sourdeix, Manon; Oliver, Javier; Timofeeva, Maria N; Gaborieau, Valérie; Johansson, Mattias; Chabrier, Amélie; Wozniak, Magdalena B; Brenner, Darren R; Vallée, Maxime P; Anantharaman, Devasena; Lagiou, Pagona; Holcátová, Ivana; Richiardi, Lorenzo; Kjaerheim, Kristina; Agudo, Antonio; Castellsagué, Xavier; Macfarlane, Tatiana V; Barzan, Luigi; Canova, Cristina; Thakker, Nalin S; Conway, David I; Znaor, Ariana; Healy, Claire M; Ahrens, Wolfgang; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Fabianova, Eleonora; Mates, Ioan Nicolae; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Curado, Maria Paula; Koifman, Sergio; Menezes, Ana; Wünsch-Filho, Victor; Eluf-Neto, José; Boffetta, Paolo; Garrote, Leticia Fernández; Serraino, Diego; Lener, Marcin; Jaworowska, Ewa; Lubiński, Jan; Boccia, Stefania; Rajkumar, Thangarajan; Samant, Tanuja A; Mahimkar, Manoj B; Matsuo, Keitaro; Franceschi, Silvia; Byrnes, Graham; Brennan, Paul; McKay, James D

    2015-01-01

    Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors. PMID:25793373

  19. Fc Gamma Receptor IIA (CD32A) R131 Polymorphism as a Marker of Genetic Susceptibility to Sepsis.

    PubMed

    Beppler, Jaqueline; Koehler-Santos, Patrícia; Pasqualim, Gabriela; Matte, Ursula; Alho, Clarice Sampaio; Dias, Fernando Suparregui; Kowalski, Thayne Woycinck; Velasco, Irineu Tadeu; Monteiro, Renato C; Pinheiro da Silva, Fabiano

    2016-04-01

    Sepsis is a devastating disease that can affect humans at any time between neonates and the elderly and is associated with mortality rates that range from 30 to 80 %. Despite intensive efforts, its treatment has remained the same over the last few decades. Fc receptors regulate multiple immune responses and have been investigated in diverse complex diseases. FcγRIIA (CD32A) is an immunoreceptor, tyrosine-based activation motif-bearing receptor that binds immunoglobulin G and C-reactive protein, important opsonins in host defense. We conducted a study of 702 patients (184 healthy individuals, 171 non-infected critically ill patients, and 347 sepsis patients) to investigate if genetic polymorphisms in the CD32A coding region affect the risk of septic shock. All individuals were genotyped for a variant at position 131 of the FcγRIIA gene. We found that allele G, associated with the R131 genotype, was significantly more frequent in septic patients than in the other groups (p = 0.05). Our data indicate that FcγRIIA genotyping can be used as a marker of genetic susceptibility to sepsis. PMID:26490967

  20. GENETIC BACKGROUND AFFECTS THE BIOMECHANICAL BEHAVIOUR OF THE POSTPARTUM MOUSE CERVIX

    PubMed Central

    Buhimschi, Catalin S.; Sora, Nicoleta; Zhao, Guomao; Buhimschi, Irina A.

    2016-01-01

    OBJECTIVE We hypothesized that the genetic makeup impacts on functional behavior of the uterine cervix. Therefore, we compared the biomechanical properties of uterine cervix in postpartum 2 strains of mice that differ in their underlying regenerative collagen remodeling characteristics: MRL/MpJ+/+ (MRL: high regenerative repair) and C57BL/6 (C57: low regenerative high fibrotic repair). METHODS Cervical tensile proprieties were assessed on day (d) 3, 15, and 60 postpartum in MRL (n=14) and C57 (n=13) mice (4-5 animals at each time point). Stress-strain curves were generated using Shimadzu EZ-test instrumentation. Cervical tissue was stretched by 0.42 mm/min. until rupture. Parameters of viscoelasticity including slope (a measure of stiffness - force needed to produce similar extension), yield point (YP; moment when tissue changes its proprieties from elastic to plastic), and break point (BP; measure of tissue strength) were recorded and analyzed blindly between strains. Data were normalized to the weight of the tissue and analyzed by 2-way ANOVA. Histological evaluation and collagen birefringence of the uterine cervix (MRL: n=4; C57: n=4) was performed 5d post-delivery. RESULTS At 3 and 15 d postpartum cervices of MRL mice were significantly more compliant than those of C57 (P<0.001). MRL mice displayed a significant increase in stiffness from d3 to d 60 [slope, median ± SEM: d3: 3.1 ± 0.5 vs. d15: 20.3 ± 4.9 vs. d60: 33.1 ± 3.5 N/mm/gram, P<0.001]. In contrast, the stiffness of C57 cervices reached maximum on d15 [slope d3: 14.1 ± 4.3 vs. d15: 40.0 ± 6.5 N/mm/gram, p=0.02] and rested at a similar level on d60. [d60: 26.1 ± 7.0 N/mm/gram, d60 vs. d15: P=0.937]. More force was required to reach YP in C57 on d3 (C57: 72.5 ± 14.7 vs. MRL: 19.9 ± 1.6 N/gram, P<0.001) but not on either d15 (C57: 156.1 ± 27.5 vs. MRL: 109.2 ± 26.0 N/gram, P=0.120) or on d60 (C57: 143.4 ± 26.5 vs. MRL: 164.5 ± 18.7 N/gram, P=0.412). There was a significant decrease in BP in both strains on both d15 and d60 compared with d3 postpartum (P=0.856 for strain, P=0.008 for d). MRL mice displayed significantly less cervical collagen birefringence compared to C57 control (P<0.001) but increased proteoglycan staining and increased water content. CONCLUSION We provide evidence that genetic makeup may impact on cervical tissue remodeling and function. There are significant differences in postpartum cervical stiffness and compliance which vary with the regenerative collagen remodeling phenotype. PMID:19200937

  1. The role of genetic breast cancer susceptibility variants as prognostic factors.

    PubMed

    Fasching, Peter A; Pharoah, Paul D P; Cox, Angela; Nevanlinna, Heli; Bojesen, Stig E; Karn, Thomas; Broeks, Annegien; van Leeuwen, Flora E; van't Veer, Laura J; Udo, Renate; Dunning, Alison M; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Shah, Mitul; Nordestgaard, Børge G; Flyger, Henrik; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Garcia-Closas, Montserrat; Sherman, Mark; Lissowska, Jolanta; Seynaeve, Caroline; Huijts, Petra E A; Tollenaar, Rob A E M; Ziogas, Argyrios; Ekici, Arif B; Rauh, Claudia; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Andrulis, Irene L; Ozcelik, Hilmi; Mulligan, Anna-Marie; Glendon, Gord; Hall, Per; Czene, Kamila; Liu, Jianjun; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Nickels, Stefan; Dörk, Thilo; Schiekel, Maria; Bremer, Michael; Park-Simon, Tjoung-Won; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Hooning, Maartje J; Martens, John W M; Jager, Agnes; Kriege, Mieke; Lindblom, Annika; Margolin, Sara; Couch, Fergus J; Stevens, Kristen N; Olson, Janet E; Kosel, Matthew; Cross, Simon S; Balasubramanian, Sabapathy P; Reed, Malcolm W R; Miron, Alexander; John, Esther M; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Chenevix-Trench, Georgia; Lambrechts, Diether; Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik; Benitez, Javier; Milne, Roger L; Zamora, M Pilar; Pérez, José Ignacio Arias; Bonanni, Bernardo; Peissel, Bernard; Loris, Bernard; Peterlongo, Paolo; Rajaraman, Preetha; Schonfeld, Sara J; Anton-Culver, Hoda; Devilee, Peter; Beckmann, Matthias W; Slamon, Dennis J; Phillips, Kelly-Anne; Figueroa, Jonine D; Humphreys, Manjeet K; Easton, Douglas F; Schmidt, Marjanka K

    2012-09-01

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. PMID:22532573

  2. The role of genetic breast cancer susceptibility variants as prognostic factors

    PubMed Central

    Fasching, Peter A.; Pharoah, Paul D.P.; Cox, Angela; Nevanlinna, Heli; Bojesen, Stig E.; Karn, Thomas; Broeks, Annegien; van Leeuwen, Flora E.; van 't Veer, Laura J.; Udo, Renate; Dunning, Alison M.; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Shah, Mitul; Nordestgaard, Børge G.; Flyger, Henrik; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Garcia-Closas, Montserrat; Sherman, Mark; Lissowska, Jolanta; Seynaeve, Caroline; Huijts, Petra E.A.; Tollenaar, Rob A.E.M.; Ziogas, Argyrios; Ekici, Arif B.; Rauh, Claudia; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna-Marie; Glendon, Gord; Hall, Per; Czene, Kamila; Liu, Jianjun; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Nickels, Stefan; Dörk, Thilo; Schiekel, Maria; Bremer, Michael; Park-Simon, Tjoung-Won; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Hooning, Maartje J.; Martens, John W.M.; Jager, Agnes; Kriege, Mieke; Lindblom, Annika; Margolin, Sara; Couch, Fergus J.; Stevens, Kristen N.; Olson, Janet E.; Kosel, Matthew; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W.R.; Miron, Alexander; John, Esther M.; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Chenevix-Trench, Georgia; Lambrechts, Diether; Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik; Benitez, Javier; Milne, Roger L.; Zamora, M. Pilar; Pérez, José Ignacio Arias; Bonanni, Bernardo; Peissel, Bernard; Loris, Bernard; Peterlongo, Paolo; Rajaraman, Preetha; Schonfeld, Sara J.; Anton-Culver, Hoda; Devilee, Peter; Beckmann, Matthias W.; Slamon, Dennis J.; Phillips, Kelly-Anne; Figueroa, Jonine D.; Humphreys, Manjeet K.; Easton, Douglas F.; Schmidt, Marjanka K.

    2012-01-01

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09–1.35, P=0.0002 and HR=1.29; 95% CI: 1.12–1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. PMID:22532573

  3. Comparative Genomics Reveals Multiple Genetic Backgrounds of Human Pathogenicity in the Trypanosoma brucei Complex

    PubMed Central

    Sistrom, Mark; Evans, Benjamin; Bjornson, Robert; Gibson, Wendy; Balmer, Oliver; Mäser, Pascal; Aksoy, Serap; Caccone, Adalgisa

    2014-01-01

    The Trypanosoma brucei complex contains a number of subspecies with exceptionally variable life histories, including zoonotic subspecies, which are causative agents of human African trypanosomiasis (HAT) in sub-Saharan Africa. Paradoxically, genomic variation between taxa is extremely low. We analyzed the whole-genome sequences of 39 isolates across the T. brucei complex from diverse hosts and regions, identifying 608,501 single nucleotide polymorphisms that represent 2.33% of the nuclear genome. We show that human pathogenicity occurs across a wide range of parasite genotypes, and taxonomic designation does not reflect genetic variation across the group, as previous studies have suggested based on a small number of genes. This genome-wide study allowed the identification of significant host and geographic location associations. Strong purifying selection was detected in genomic regions associated with cytoskeleton structure, and regulatory genes associated with antigenic variation, suggesting conservation of these regions in African trypanosomes. In agreement with expectations drawn from meiotic reciprocal recombination, differences in average linkage disequilibrium between chromosomes in T. brucei correlate positively with chromosome size. In addition to insights into the life history of a diverse group of eukaryotic parasites, the documentation of genomic variation across the T. brucei complex and its association with specific hosts and geographic localities will aid in the development of comprehensive monitoring tools crucial to the proposed elimination of HAT by 2020, and on a shorter term, for monitoring the feared merger between the two human infective parasites, T. brucei rhodesiense and T. b. gambiense, in northern Uganda. PMID:25287146

  4. Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

    PubMed Central

    Elvers, Ingegerd; Turner-Maier, Jason; Swofford, Ross; Koltookian, Michele; Johnson, Jeremy; Stewart, Chip; Zhang, Cheng-Zhong; Schumacher, Steven E.; Beroukhim, Rameen; Rosenberg, Mara; Thomas, Rachael; Mauceli, Evan; Getz, Gad; Palma, Federica Di; Modiano, Jaime F.; Breen, Matthew; Lindblad-Toh, Kerstin; Alföldi, Jessica

    2015-01-01

    Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B- and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options. PMID:26377837

  5. Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background.

    PubMed

    Elvers, Ingegerd; Turner-Maier, Jason; Swofford, Ross; Koltookian, Michele; Johnson, Jeremy; Stewart, Chip; Zhang, Cheng-Zhong; Schumacher, Steven E; Beroukhim, Rameen; Rosenberg, Mara; Thomas, Rachael; Mauceli, Evan; Getz, Gad; Palma, Federica Di; Modiano, Jaime F; Breen, Matthew; Lindblad-Toh, Kerstin; Alföldi, Jessica

    2015-11-01

    Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B- and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options. PMID:26377837

  6. Comparative genomics reveals multiple genetic backgrounds of human pathogenicity in the Trypanosoma brucei complex.

    PubMed

    Sistrom, Mark; Evans, Benjamin; Bjornson, Robert; Gibson, Wendy; Balmer, Oliver; Mäser, Pascal; Aksoy, Serap; Caccone, Adalgisa

    2014-10-01

    The Trypanosoma brucei complex contains a number of subspecies with exceptionally variable life histories, including zoonotic subspecies, which are causative agents of human African trypanosomiasis (HAT) in sub-Saharan Africa. Paradoxically, genomic variation between taxa is extremely low. We analyzed the whole-genome sequences of 39 isolates across the T. brucei complex from diverse hosts and regions, identifying 608,501 single nucleotide polymorphisms that represent 2.33% of the nuclear genome. We show that human pathogenicity occurs across a wide range of parasite genotypes, and taxonomic designation does not reflect genetic variation across the group, as previous studies have suggested based on a small number of genes. This genome-wide study allowed the identification of significant host and geographic location associations. Strong purifying selection was detected in genomic regions associated with cytoskeleton structure, and regulatory genes associated with antigenic variation, suggesting conservation of these regions in African trypanosomes. In agreement with expectations drawn from meiotic reciprocal recombination, differences in average linkage disequilibrium between chromosomes in T. brucei correlate positively with chromosome size. In addition to insights into the life history of a diverse group of eukaryotic parasites, the documentation of genomic variation across the T. brucei complex and its association with specific hosts and geographic localities will aid in the development of comprehensive monitoring tools crucial to the proposed elimination of HAT by 2020, and on a shorter term, for monitoring the feared merger between the two human infective parasites, T. brucei rhodesiense and T. b. gambiense, in northern Uganda. PMID:25287146

  7. Epistasis between antibiotic resistance mutations and genetic background shape the fitness effect of resistance across species of Pseudomonas

    PubMed Central

    Kojadinovic, M.; MacLean, R. C.

    2016-01-01

    Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase (rpoB) across eight strains that span the diversity of the genus Pseudomonas. We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas. Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds. PMID:27170722

  8. Epistasis between antibiotic resistance mutations and genetic background shape the fitness effect of resistance across species of Pseudomonas.

    PubMed

    Vogwill, T; Kojadinovic, M; MacLean, R C

    2016-05-11

    Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase (rpoB) across eight strains that span the diversity of the genus Pseudomonas We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds. PMID:27170722

  9. BRCA1/2 genetic background-based therapeutic tailoring of human ovarian cancer: hope or reality?

    PubMed Central

    Tagliaferri, Pierosandro; Ventura, Monica; Baudi, Francesco; Cucinotto, Iole; Arbitrio, Mariamena; Di Martino, Maria Teresa; Tassone, Pierfrancesco

    2009-01-01

    Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients. PMID:19825178

  10. Genetic Susceptibility Testing and Readiness to Control Weight: Results from a Randomized Controlled Trial

    PubMed Central

    Meisel, Susanne F; Beeken, Rebecca J; van Jaarsveld, Cornelia H M; Wardle, Jane

    2015-01-01

    Objective To test the hypothesis that adding obesity gene feedback (FTO) to simple weight control advice at a life stage with raised risk of weight gain (university) increases readiness to control weight. Methods Individually randomized controlled trial comparing the effect of: (i) simple weight control advice plus FTO feedback (FA) and (ii) simple weight control advice only (AO) on readiness to engage with weight control. Differences in stage of change by genotype and differential weight control behaviors were secondary outcomes. Results Of 1,016 participants randomized, only 279 completed follow-up, yielding 90% power to detect a small effect for readiness to control weight. As predicted, FA participants were more likely to be in the contemplation stage than AO participants (P = 0.023). Participants receiving higher-risk genetic results were at a higher stage of change than controls (P = 0.003), with a trend toward a higher stage of change than those getting lower-risk results (P = 0.051). Lower-risk results did not decrease weight control intentions compared with controls (P = 0.55). There were no group differences in adherence to recommended weight control behaviors (P = 0.87). Conclusions Adding FTO feedback to weight control advice enhanced readiness to control weight, without evidence for genetic determinism, but had no more effect on behavior than weight control advice alone. PMID:25522302

  11. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

    PubMed Central

    Chattopadhyay, Koushik

    2011-01-01

    Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals. PMID:22345983