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1

Genetic background affects susceptibility to tumoral stem cell reprogramming  

PubMed Central

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

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

2

Association between susceptibility to photodynamic oxidation and the genetic background of Staphylococcus aureus.  

PubMed

Multidrug resistant strains of Staphylococcus aureus are a major cause of skin and soft tissue infections requiring the development of novel and alternative therapeutic options. Photodynamic oxidation is the cornerstone of antimicrobial photodynamic therapy (aPDT) involving the combined use of light and a photosensitizer, which, in the presence of oxygen, originates cytotoxic species capable of oxidizing biological molecules and leads to inactivation of target cells. We have previously shown that susceptibility to aPDT differs significantly across S. aureus isolates and could be associated with several genetic elements. However, the effect of the photodynamic process regarding the S. aureus genetic background has never been reported. We have compared the genetic backgrounds of the strains (SCCmec types, spa types and main clonal complexes) with respect to their susceptibility to protoporphyrin IX-mediated photodynamic inactivation. SCCmec typing revealed no differences in response to photoinactivation. However, detection of spa types and clonal complexes clustered the studied population of MRSA strains according to their response to photodynamic oxidation. Clonal complex 1 (CC1) accounted for elevated resistance and CC30 (ST36) for susceptibility to photoinactivation. Moreover, spa typing identified isolates resistant (t032) and susceptible to photodynamic oxidation (t051, t015). The very tight association between clonal lineages and response to photodynamic inactivation indicates the important role of genetic background for aPDT efficacy. These results make a case for the development of a diagnostic tool with the predictive value of aPDT efficacy according to an identified genetic background of S. aureus isolates. PMID:24158686

Rapacka-Zdonczyk, A; Larsen, A Rhod; Empel, J; Patel, A; Grinholc, M

2014-04-01

3

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

PubMed Central

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

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

4

Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.  

PubMed

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 mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to 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 harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with 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 ROS generation and susceptibility to cardiac stress. PMID:23924350

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

2013-10-15

5

Methicillin-susceptible Staphylococcus aureus CC398: first description in prosthetic joint infection and genetic background comparison with nasal carriage isolates.  

PubMed

Few reports described infections with CC398 methicillin-susceptible Staphylococcus aureus (MSSA). We compared the genetic background of CC398 MSSA strains from nasal carriage and knee arthroplasty infection. DNA microarray analysis shows acquisition of particular adhesin, iron capture system and immune defense evasion mechanisms. These characteristics could explain pathogenesis in this type of infection. PMID:24767465

Aubin, Guillaume G; Lepelletier, Didier; Reynaud, Alain; Lavigne, Jean-Philippe; Corvec, Stéphane

2014-06-01

6

Murine Adipose Tissue-Derived Stromal Cell Apoptosis and Susceptibility to Oxidative Stress In Vitro Are Regulated by Genetic Background  

PubMed Central

Adipose tissue-derived stromal cells (ADSCs) are of interest for regenerative medicine as they are isolated easily and can differentiate into multiple cell lineages. Studies of their in vitro proliferation, survival, and differentiation are common; however, genetic effects on these phenotypes remain unknown. To test if these phenotypes are genetically regulated, ADSCs were isolated from three genetically diverse inbred mouse strains- C57BL/6J (B6), BALB/cByJ (BALB), and DBA/2J (D2)- in which genetic regulation of hematopoietic stem function is well known. ADSCs from all three strains differentiated into osteogenic and chondrogenic lineages in vitro. ADSCs from BALB grew least well in vitro, probably due to apoptotic cell death after several days in culture. BALB ADSCs were also the most susceptible to the free radical inducers menadione and H2O2. ADSCs from the three possible F1 hybrids were employed to further define genetic regulation of ADSC phenotypes. D2, but not B6, alleles stimulated ADSC expansion in BALB cells. In contrast, B6, but not D2, alleles rescued BALB H2O2 resistance. We conclude that low oxidative stress resistance does not limit BALB ADSC growth in vitro, as these phenotypes are genetically regulated independently. In addition, ADSCs from these strains are an appropriate model system to investigate genetic regulation of ADSC apoptosis and stress resistance in future studies. Such investigations are essential to optimize cell expansion and differentiation and thus, potential for regenerative medicine. PMID:23593442

Pazdro, Robert; Harrison, David E.

2013-01-01

7

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

PubMed

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

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

2013-05-01

8

Genetic Architecture of Intrinsic Antibiotic Susceptibility  

Microsoft Academic Search

Background: Antibiotic exposure rapidly selects for more resistant bacterial strains, and both a drug's chemical structure and a bacterium's cellular network affect the types of mutations acquired. Methodology\\/Principal Findings: To better characterize the genetic determinants of antibiotic susceptibility, we exposed a transposon-mutagenized library of Escherichia coli to each of 17 antibiotics that encompass a wide range of drug classes and

Hany S. Girgis; Alison K. Hottes; Saeed Tavazoie

2009-01-01

9

Genetic susceptibility to childhood infections  

Microsoft Academic Search

There has been increasing recognition in recent years that genetic factors play a role in determining both susceptibility and outcome of many infectious diseases. In the case of tuberculosis, one-third of the world's population is infected by Mycobacterium tuberculosis but clinical disease develops in only a small proportion of cases. Familial occurrence of cases, twin studies and differences in racial

Mike Levin

2000-01-01

10

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

PubMed Central

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

2014-01-01

11

Genetically and medically susceptible workers.  

PubMed

The likelihood of an individual becoming ill from a hazardous material or condition is strongly influenced by both their genetic makeup and their underlying state of health. Although the past decade has seen great advances in understanding human variation in health and genetic polymorphisms and in the diagnosis and treatment of disease, much less progress has been made in effectively using this information to protect worker health. Scientific evidence for increased susceptibility often is weak and rarely satisfies legal thresholds for sufficient risk to warrant exclusion from a particular job. When public safety is a major concern, many legally mandated exclusions are not well justified. Medical opinions about fitness to work should be based upon a systematic and credible analysis of the condition, its relationship to ability and risk for a particular job, and knowledge of possible accommodations. Conclusions should reflect the limitations of scientific knowledge and guidance from antidiscrimination legislation. PMID:10378978

Mohr, S; Gochfeld, M; Pransky, G

1999-01-01

12

Genetic Architecture of Intrinsic Antibiotic Susceptibility  

PubMed Central

Background Antibiotic exposure rapidly selects for more resistant bacterial strains, and both a drug's chemical structure and a bacterium's cellular network affect the types of mutations acquired. Methodology/Principal Findings To better characterize the genetic determinants of antibiotic susceptibility, we exposed a transposon-mutagenized library of Escherichia coli to each of 17 antibiotics that encompass a wide range of drug classes and mechanisms of action. Propagating the library for multiple generations with drug concentrations that moderately inhibited the growth of the isogenic parental strain caused the abundance of strains with even minor fitness advantages or disadvantages to change measurably and reproducibly. Using a microarray-based genetic footprinting strategy, we then determined the quantitative contribution of each gene to E. coli's intrinsic antibiotic susceptibility. We found both loci whose removal increased general antibiotic tolerance as well as pathways whose down-regulation increased tolerance to specific drugs and drug classes. The beneficial mutations identified span multiple pathways, and we identified pairs of mutations that individually provide only minor decreases in antibiotic susceptibility but that combine to provide higher tolerance. Conclusions/Significance Our results illustrate that a wide-range of mutations can modulate the activity of many cellular resistance processes and demonstrate that E. coli has a large mutational target size for increasing antibiotic tolerance. Furthermore, the work suggests that clinical levels of antibiotic resistance might develop through the sequential accumulation of chromosomal mutations of small individual effect. PMID:19462005

Tavazoie, Saeed

2009-01-01

13

Genetics and genomics of infectious disease susceptibility  

Microsoft Academic Search

Human genetic variation is a major determinant of susceptibility to many common infectious diseases. Malaria was the first disease to be studied extensively and many susceptibility and resistance loci have been identified. However, genes for other diseases such as HIV\\/AIDS and mycobacterial infections are now being identified using a variety of approaches. A large number of genes appear to influence

Adrian Vs Hill

1999-01-01

14

[Genetic susceptibility to norovirus infection].  

PubMed

Norovirus (NoV) are the most common cause of acute gastroenteritidis in humans worldwide. They are transmitted through consumption of contaminated food, or mostly by direct person-to-person contact. However, susceptibility to NoV infection is variable. NoVs recognize carbohydrate ligand, including A, B, H and Lewis histoblood group antigen (HBGAs) for attachment to human epithelial cells. Synthesis of these HBGAs requires various glycosyltransferase encoded by the ABO, FUT2, FUT3 genes. The presence of distinct carbohydrates structures dependent upon the combined polymorphism at the FUT2, FUT3 and ABO loci influences susceptibility to NoV infection. NoV-glycan interactions studies show that different strains recognize specific HBGAs. Together with herd immunity, HBGAs play a major role in the epidemiology and evolution of NoVs. PMID:23399413

Ruvoën, N; Le Pendu, J

2013-01-01

15

Genetic susceptibility to ischemic stroke  

PubMed Central

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

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

2014-01-01

16

Bladder cancer epidemiology and genetic susceptibility  

PubMed Central

Bladder cancer is the most common malignancy of the urinary system. The incidence of bladder cancer of men is higher than that of women (approximately 4:1). Here, we summarize the bladder cancer-related risk factors, including environmental and genetic factors. In recent years, although the mortality rate induced by bladder cancer has been stable or decreased gradually, the public health effect may be pronounced. The well-established risk factors for bladder cancer are cigarette smoking and occupational exposure. Genetic factors also play important roles in the susceptibility to bladder cancer. A recent study demonstrated that hereditary non-polyposis colorectal cancer is associated with increased risk of bladder cancer. Since 2008, genome-wide association study (GWAS) has been used to identify the susceptibility loci for bladder cancer. Further gene-gene or gene-environment interaction studies need to be conducted to provide more information for the etiology of bladder cancer. PMID:23720672

Chu, Haiyan; Wang, Meilin; Zhang, Zhengdong

2013-01-01

17

Genetic variation in Drosophila melanogaster pathogen susceptibility  

PubMed Central

SUMMARY Genetic variation in susceptibility to pathogens is a central concern both to evolutionary and medical biologists, and for the implementation of biological control programmes. We have investigated the extent of such variation in Drosophila melanogaster, a major model organism for immunological research. We found that within populations, different Drosophila genotypes show wide-ranging variation in their ability to survive infection with the entomopathogenic fungus Beauveria bassiana. Furthermore, striking divergence in susceptibility has occurred between genotypes from temperate and tropical African locations. We hypothesize that this may have been driven by adaptation to local differences in pathogen exposure or host ecology. Genetic variation within populations may be maintained by temporal or spatial variation in the costs and benefits of pathogen defence. Insect pathogens are employed widely as biological control agents and entomopathogenic fungi are currently being developed for reducing malaria transmission by mosquitoes. Our data highlight the need for concern about resistance evolution to these novel biopesticides in vector populations. PMID:16497252

TINSLEY, M. C.; BLANFORD, S.; JIGGINS, F. M.

2007-01-01

18

Genetic polymorphisms and susceptibility to lung disease.  

PubMed

Susceptibility to infection by bacterium such as Bacillus anthracis has a genetic basis in mice and may also have a genetic basis in humans. In the limited human cases of inhalation anthrax, studies suggest that not all individuals exposed to anthrax spores were infected, but rather, individuals with underlying lung disease, particularly asthma, sarcoidosis and tuberculosis, might be more susceptible. In this study, we determined if polymorphisms in genes important in innate immunity are associated with increased susceptibility to infectious and non-infectious lung diseases, particularly tuberculosis and sarcoidosis, respectively, and therefore might be a risk factor for inhalation anthrax. Examination of 45 non-synonymous polymorphisms in ten genes: p47phox (NCF1), p67phox (NCF2), p40phox (NCF4), p22phox (CYBA), gp91phox (CYBB), DUOX1, DUOX2, TLR2, TLR9 and alpha 1-antitrypsin (AAT) in a cohort of 95 lung disease individuals and 95 control individuals did not show an association of these polymorphisms with increased susceptibility to lung disease. PMID:16608528

Lee, Pauline L; West, Carol; Crain, Karen; Wang, Lei

2006-01-01

19

Genetic susceptibility to age related macular degeneration  

PubMed Central

Age related macular degeneration (AMD) is the leading cause of visual impairment in the elderly and a major cause of blindness in the developed world. The disease can take two forms, geographic atrophy and choroidal neovascularisation. The pathogenesis of AMD is poorly understood. There are undoubtedly environmental and other risk factors involved and the adverse effect of smoking is well established. Several studies have shown that genetic factors are important but leave uncertainty about the magnitude and nature of the genetic component and whether it varies with the type of AMD. Several hereditary retinal dystrophies show similarities to AMD and these genes are potential candidate susceptibility genes. Particular interest has focused on the ABCR gene which is responsible for autosomal recessive Stargardt macular dystrophy. It has been claimed that heterozygotes for ABCR mutations are predisposed to AMD but the data are conflicting. Studies of the genes responsible for autosomal dominant Sorsby fundus dystrophy, Doyne honeycomb retinal dystrophy, and Best disease have given negative results. In one large AMD family, linkage has been reported to markers in 1q25-q31. Recent data suggest that the ApoE ?4 allele may be associated with reduced risk of AMD. A better understanding of the genetic factors in AMD would contribute to understanding the pathogenesis. If those at risk could be identified it may be possible to modify lifestyle or develop novel therapies in the presymptomatic stage to prevent disease or decrease its severity.???Keywords: age related macular degeneration; genetic susceptibility PMID:10662806

Yates, J.; Moore, A.

2000-01-01

20

Personalized genetic testing and norovirus susceptibility  

PubMed Central

BACKGROUND: The availability of direct-to-consumer personalized genetic testing has enabled the public to access and interpret their own genetic information. Various genetic traits can be determined including resistance to norovirus through a nonsense mutation (G428A) in the FUT2 gene. Although this trait is believed to confer resistance to the most dominant norovirus genotype (GII.4), the spectrum of resistance to other norovirus strains is unknown. The present report describes a cluster of symptomatic norovirus GI.6 infection in a family identified to have norovirus resistance through personalized genetic testing. CASE PRESENTATION: In January 2013, four members of a family determined by a direct-to-consumer genetic test to be homozygous for the norovirus resistance trait (A/A genotype for single nucleotide polymorphism rs601338) developed symptoms consistent with acute viral gastroenteritis. Stool and vomitus samples were submitted for enteric viral pathogen testing. Samples were positive for norovirus GI.6 in three of the four cases. CONCLUSIONS: The present report is the first to describe norovirus GI.6 infection in patients with the G428A nonsense mutation in FUT2; this cluster of cases suggests that the G428A mutation in FUT2 may not confer resistance to norovirus GI.6. Direct-to-consumer genetic testing is empowering members of the public to identify novel associations with their genetic traits. Expert consultation is important for the interpretation of personalized genetic test results, and follow-up laboratory testing can confirm any potentially novel associations. PMID:25285128

Prystajecky, Natalie; Brinkman, Fiona SL; Auk, Brian; Isaac-Renton, Judith L; Tang, Patrick

2014-01-01

21

New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background  

Microsoft Academic Search

BACKGROUND: Few genetic factors predisposing to the sporadic form of amyotrophic lateral sclerosis (ALS) have been identified, but the pathology itself seems to be a true multifactorial disease in which complex interactions between environmental and genetic susceptibility factors take place. The purpose of this study was to approach genetic data with an innovative statistical method such as artificial neural networks

Silvana Penco; Massimo Buscema; Maria Cristina Patrosso; Alessandro Marocchi; Enzo Grossi

2008-01-01

22

Lung Cancer Susceptibility Model Based on Age, Family History and Genetic Variants  

Microsoft Academic Search

Background: Epidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer. Methodology\\/Principal Findings: We screened 157 candidate single nucleotide polymorphisms (SNP) in

Robert P. Young; Raewyn J. Hopkins; Bryan A. Hay; Michael J. Epton; Graham D. Mills; Peter N. Black; Heather D. Gardner; Richard Sullivan; Gregory D. Gamble

2009-01-01

23

Autism genetic database (AGD): a comprehensive database including autism susceptibility gene-CNVs integrated with known noncoding RNAs and fragile sites  

E-print Network

Background: Autism is a highly heritable complex neurodevelopmental disorder, therefore identifying its genetic basis has been challenging. To date, numerous susceptibility genes and chromosomal abnormalities have been ...

Matuszek, Gregory; Talebizadeh, Zohreh

2009-09-24

24

Role of genetic background in induced instability  

NASA Technical Reports Server (NTRS)

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.

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

2003-01-01

25

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...

26

Lung Cancer Susceptibility Model Based on Age, Family History and Genetic Variants  

Microsoft Academic Search

BackgroundEpidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer.Methodology\\/Principal FindingsWe screened 157 candidate single nucleotide polymorphisms (SNP) in a discovery cohort

Robert P. Young; Raewyn J. Hopkins; Bryan A. Hay; Michael J. Epton; Graham D. Mills; Peter N. Black; Heather D. Gardner; Richard Sullivan; Gregory D. Gamble; Iris Schrijver

2009-01-01

27

Genetic susceptibility to mycobacterial disease in humans  

Microsoft Academic Search

Mycobacterial disease remains a serious global health problem. Tuberculosis causes more than 2 million deaths a year, and leprosy is still a cause of severe disability in many parts of the world. As a result of the study of individuals with marked susceptibility to usually nonpathogenic mycobacteria, as well as case–control studies with candidate genes and genome-wide screens of affected

Suran L Fernando; Warwick J Britton

2006-01-01

28

Genetics of susceptibility to human helminth infection.  

PubMed

Recent studies have shown that host genetics is an important determinant of the intensity of infection and morbidity due to human helminths. Epidemiological studies of a number of parasite species have shown that the intensity of infection (worm burden) is a heritable phenotype. The proportion of variance in human worm burden explained by genetic effects varies from 0.21 to 0.44. Human genome scans have identified a locus responsible for controlling Schistosoma mansoni infection intensity on chromosome 5q31-q33, and loci controlling Ascaris lumbricoides intensity on chromosomes 1 and 13, although the genes involved have not yet been identified. There is also evidence for genetic control of pathology due to S. mansoni, and linkage has been reported to a region containing the gene for the interferon-gamma receptor 1 subunit. There is some evidence for genetic control of filarial infection, though little information on filarial disease. Association studies have provided evidence for major histocompatibility complex control of pathology in schistosomiasis and onchocerciasis. Recent candidate gene studies suggest a role of other immune response genes in controlling helminth infection and pathology, but require replication. Identification of the genetic loci involved may be important in the understanding of helminth epidemiology and the mechanisms of resistance and pathology. PMID:13678637

Quinnell, Rupert J

2003-09-30

29

Genetic Susceptibility and Survival: Application to Breast Cancer  

E-print Network

Genetic Susceptibility and Survival: Application to Breast Cancer Edwin S. IVERSEN, JR., Giovanni are known to confer an elevated risk of both breast and ovarian cancers. The effect of carrying such a mutation on survival after developing breast or ovarian cancer is less well understood. We investigate

West, Mike

30

Chloroquine Susceptibility and Reversibility in a Plasmodium falciparum Genetic Cross  

PubMed Central

Summary Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT), are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the Southeast Asia-derived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the pfcrt and pfmdr1 loci to influence CQR levels. Chemoreversal via a wide range of chemical structures operates through a direct pfcrt-based mechanism. Direct inhibition of parasite growth by these reversal agents is influenced by pfcrt mutations and additional loci. Direct labeling of purified recombinant PfMDR1 protein with a highly specific photoaffinity CQ analogue, and lack of competition for photolabeling by VP, supports our QTL predictions. We find no evidence that pfmdr1 copy number affects CQ response in the progeny, however, inheritance patterns indicate that an allele-specific interaction between pfmdr1 and pfcrt is part of the complex genetic background of CQR. PMID:20807203

Patel, Jigar J.; Thacker, Drew; Tan, John C.; Pleeter, Perri; Checkley, Lisa; Gonzales, Joseph M.; Deng, Bingbing; Roepe, Paul D.; Cooper, Roland A.; Ferdig, Michael T.

2011-01-01

31

Genetic variation for maternal effects on parasite susceptibility.  

PubMed

The expression of infectious disease is increasingly recognized to be impacted by maternal effects, where the environmental conditions experienced by mothers alter resistance to infection in offspring, independent of heritability. Here, we studied how maternal effects (high or low food availability to mothers) mediated the resistance of the crustacean Daphnia magna to its bacterial parasite Pasteuria ramosa. We sought to disentangle maternal effects from the effects of host genetic background by studying how maternal effects varied across 24 host genotypes sampled from a natural population. Under low-food conditions, females produced offspring that were relatively resistant, but this maternal effect varied strikingly between host genotypes, i.e. there were genotype by maternal environment interactions. As infection with P. ramosa causes a substantial reduction in host fecundity, this maternal effect had a large effect on host fitness. Maternal effects were also shown to impact parasite fitness, both because they prevented the establishment of the parasites and because even when parasites did establish in the offspring of poorly fed mothers, and they tended to grow more slowly. These effects indicate that food stress in the maternal generation can greatly influence parasite susceptibility and thus perhaps the evolution and coevolution of host-parasite interactions. PMID:21848987

Stjernman, M; Little, T J

2011-11-01

32

The Role of Host Genetics in Susceptibility to Influenza: A Systematic Review  

PubMed Central

Background The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380). Methods and Findings PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven. Conclusion The fundamental question “Is susceptibility to severe influenza in humans heritable?” remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies. PMID:22438897

Horby, Peter; Nguyen, Nhu Y.; Dunstan, Sarah J.; Baillie, J. Kenneth

2012-01-01

33

Genetic susceptibility testing for neurodegenerative diseases: Ethical and practice issues  

PubMed Central

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

Roberts, J. Scott; Uhlmann, Wendy R.

2013-01-01

34

Human genetic susceptibility and infection with Leishmania peruviana  

SciTech Connect

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.

Shaw, M.A.; Davis, C.R.; Collins, A. [and others

1995-11-01

35

Genetic Algorithms To provide a background and understanding of basic genetic  

E-print Network

Genetic Algorithms Objectives To provide a background and understanding of basic genetic algorithms and some of their applications. ·a basic genetic algorithm ·the basic discussion ·the applications of the algorithm #12;Genetic Algorithms 1859 Origin of the Species Survival of the Fittest #12;Genetic Algorithms

Qu, Rong

36

Duffy antigen receptor and genetic susceptibility of African Americans to acute rejection and delayed function  

Microsoft Academic Search

Duffy antigen receptor and genetic susceptibility of African Americans to acute rejection and delayed function.BackgroundThe unique distribution of the alleles for the Duffy antigen receptor complex (DARC) that binds to chemokines may be associated with the rates of acute rejection and delayed allograft function (DGF) among African Americans.MethodsA prospective, multicenter cohort study enrolled 222 African American recipients of cadaveric renal

Kevin C. Mange; ELINE LUNING PRAK; MALEK KAMOUN; YANGZHU DU; NOAH GOODMAN; THEODORE DANOFF; TRACEY HOY; MELISSA NEWMAN; Marshall M. Joffe; Harold I. Feldman

2004-01-01

37

Understanding susceptibility to breast cancer metastasis: the genetic approach  

PubMed Central

SUMMARY Metastasis is a complex phenotype that is not discrete, is polygenic, varies in range over the entire population and follows non-Mendelian inheritance. Recent evidence indicates that inherited susceptibility affects not only the development of the primary tumor, but is also an important factor in progression and metastasis. Since metastasis accounts for the majority of breast cancer deaths, identification and understanding of the genetic modifiers of metastasis underlies success of personalized therapy. Studies from our laboratory and others have now characterized several metastasis susceptibility factors. While an important step forward, these certainly do not describe the entire metastatic phenomenon and efforts continue to expand this knowledge. Here we review the complex metastatic process and current knowledge on the genetics of breast cancer metastasis, including germline polymorphisms that have been associated with the disease. PMID:25214894

Shukla, Anjali; Alsarraj, Jude; Hunter, Kent

2014-01-01

38

Perceptions About Genetic Testing for the Susceptibility to Alcohol Dependence and Other Multifactorial Diseases  

PubMed Central

Background Beliefs, attitudes, and preferences about the risk and benefits of genetic testing are important determinants of willingness to undergo testing. Aims: The purpose of this study was to evaluate the perceived importance of genetic testing for alcohol dependence compared with other multifactorial diseases among African Americans. Methods: Surveys were conducted with 258 participants using the Genetic Psycho-Social Implications (GPSI) questionnaire to evaluate several areas of hypothetical genetic testing for alcohol dependence. Respondents were divided into two groups: those who perceived testing for alcohol dependence to be equally important as testing for cancer and those who did not. Using chi-square, the groups' responses were compared for nine GPSI items measuring beliefs about the severity of alcohol dependence, general benefits of genetic testing, and specific benefits of genetic testing for diabetes, hypertension, or a disease affecting a family member. Results: Nearly 86% of respondents believed that genetic testing for alcoholism was equally as important as testing for cancer. Those who reported parity of importance of alcohol dependence and cancer screening were more likely to believe that alcoholism is a deadly disease (p<0.001) and genetic testing influences health (p<0.001). Conclusion: African Americans reported favorable attitudes and beliefs in possible availability of susceptibility genetic testing for alcohol dependence. The perceived importance of testing for alcohol dependence was associated with beliefs about the severity of alcoholism and certain benefits of genetic testing in general. PMID:22191677

Kalu, Nnenna; Kwagyan, John; Williams, Carla; Taylor, Robert E.; Scott, Denise M.

2012-01-01

39

Genetic susceptibility to feline infectious peritonitis in Birman cats.  

PubMed

Genetic factors are presumed to influence the incidence of feline infectious peritonitis (FIP), especially among pedigreed cats. However, proof for the existence of such factors has been limited and mainly anecdotal. Therefore, we sought evidence for genetic susceptibility to FIP using feline high density single nucleotide polymorphism (SNP) arrays in a genome-wide association study (GWAS). Birman cats were chosen for GWAS because they are highly inbred and suffer a high incidence of FIP. DNA from 38 Birman cats that died of FIP and 161 healthy cats from breeders in Denmark and USA were selected for genotyping using 63K SNPs distributed across the feline genome. Danish and American Birman cats were closely related and the populations were therefore combined and analyzed in two manners: (1) all cases (FIP) vs. all controls (healthy) regardless of age, and (2) cases 1½ years of age and younger (most susceptible) vs. controls 2 years of age and older (most resistant). GWAS of the second cohort was most productive in identifying significant genome-wide associations between case and control cats. Four peaks of association with FIP susceptibility were identified, with two being identified on both analyses. Five candidate genes ELMO1, RRAGA, TNFSF10, ERAP1 and ERAP2, all relevant to what is known about FIP virus pathogenesis, were identified but no single association was fully concordant with the disease phenotype. Difficulties in doing GWAS in cats and interrogating complex genetic traits were discussed. PMID:23619280

Golovko, Lyudmila; Lyons, Leslie A; Liu, Hongwei; Sørensen, Anne; Wehnert, Suzanne; Pedersen, Niels C

2013-07-01

40

Genetic Algorithms To provide a background and understanding of basic genetic  

E-print Network

and have been successfully applied to complex engineering optimisation problems. Genetic Algorithms1 Genetic Algorithms Objectives To provide a background and understanding of basic genetic algorithms and some of their applications. ·a basic genetic algorithm ·the basic discussion ·the applications

Qu, Rong

41

Identification of Multiple Genetic Susceptibility Loci in Takayasu Arteritis  

PubMed Central

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B?52. We genotyped ?200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r2 < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10?16) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10?9; and rs189754752, OR = 2.47, p = 4.22 × 10?9). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10?12). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10?8). PMID:23830517

Saruhan-Direskeneli, Güher; Hughes, Travis; Aksu, Kenan; Keser, Gokhan; Coit, Patrick; Aydin, Sibel Z.; Alibaz-Oner, Fatma; Kamal?, Sevil; Inanc, Murat; Carette, Simon; Hoffman, Gary S.; Akar, Servet; Onen, Fatos; Akkoc, Nurullah; Khalidi, Nader A.; Koening, Curry; Karadag, Omer; Kiraz, Sedat; Langford, Carol A.; McAlear, Carol A.; Ozbalkan, Zeynep; Ates, Askin; Karaaslan, Yasar; Maksimowicz-McKinnon, Kathleen; Monach, Paul A.; Ozer, Hüseyin T.; Seyahi, Emire; Fresko, Izzet; Cefle, Ayse; Seo, Philip; Warrington, Kenneth J.; Ozturk, Mehmet A.; Ytterberg, Steven R.; Cobankara, Veli; Onat, A. Mesut; Guthridge, Joel M.; James, Judith A.; Tunc, Ercan; Duzgun, Nur?en; B?cakc?gil, Muge; Yentür, Sibel P.; Merkel, Peter A.; Direskeneli, Haner; Sawalha, Amr H.

2013-01-01

42

Identification of multiple genetic susceptibility loci in Takayasu arteritis.  

PubMed

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)). PMID:23830517

Saruhan-Direskeneli, Güher; Hughes, Travis; Aksu, Kenan; Keser, Gokhan; Coit, Patrick; Aydin, Sibel Z; Alibaz-Oner, Fatma; Kamal?, Sevil; Inanc, Murat; Carette, Simon; Hoffman, Gary S; Akar, Servet; Onen, Fatos; Akkoc, Nurullah; Khalidi, Nader A; Koening, Curry; Karadag, Omer; Kiraz, Sedat; Langford, Carol A; McAlear, Carol A; Ozbalkan, Zeynep; Ates, Askin; Karaaslan, Yasar; Maksimowicz-McKinnon, Kathleen; Monach, Paul A; Ozer, Hüseyin T; Seyahi, Emire; Fresko, Izzet; Cefle, Ayse; Seo, Philip; Warrington, Kenneth J; Ozturk, Mehmet A; Ytterberg, Steven R; Cobankara, Veli; Onat, A Mesut; Guthridge, Joel M; James, Judith A; Tunc, Ercan; Duzgun, Nur?en; B?cakc?gil, Muge; Yentür, Sibel P; Merkel, Peter A; Direskeneli, Haner; Sawalha, Amr H

2013-08-01

43

Innate immunity and genetic determinants of urinary tract infection susceptibility  

PubMed Central

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

Godaly, Gabriela; Ambite, Ines; Svanborg, Catharina

2015-01-01

44

Edinburgh Research Explorer Genetic susceptibility to infectious disease in East African  

E-print Network

Edinburgh Research Explorer Genetic susceptibility to infectious disease in East African Shorthorn-Topping, M 2013, 'Genetic susceptibility to infectious disease in East African Shorthorn Zebu: a genome susceptibility to infectious disease in East African Shorthorn Zebu: a genome-wide analysis of the effect

Millar, Andrew J.

45

Evidence for a Shared Genetic Susceptibility to Migraine and Epilepsy  

PubMed Central

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

Winawer, Melodie R.; Connors, Robert

2012-01-01

46

Kawasaki Disease: Novel Insights into Etiology and Genetic Susceptibility  

PubMed Central

Kawasaki Disease is a vasculitis of young childhood that particularly affects the coronary arteries. Molecular analysis of the oligoclonal IgA response in acute KD led to production of synthetic KD antibodies. These antibodies identify intracytoplasmic inclusion bodies in acute KD tissues. Light and electron microscopic studies indicate that the inclusion bodies are consistent with aggregates of viral proteins and RNA. Advances in molecular genetic analysis and completion of the human genome project have sparked a worldwide effort to identify genes associated with KD. A polymorphism of one such gene, ITPKC, a negative regulator of T cell activation, confers susceptibility to KD in Japanese populations and increases the risk of developing coronary artery abnormalities in both Japanese and U.S children. Identification of the etiologic agent and of genes conferring KD susceptibility are the best means to improving diagnosis and therapy, and allow for prevention of this important disorder of childhood. PMID:20690826

Rowley, Anne H.

2010-01-01

47

Genetic Variability in Susceptibility to Occupational Respiratory Sensitization  

PubMed Central

Respiratory sensitization can be caused by a variety of substances at workplaces, and the health and economic burden linked to allergic respiratory diseases continues to increase. Although the main factors that affect the onset of the symptoms are the types and intensity of allergen exposure, there is a wide range of interindividual variation in susceptibility to occupational/environmental sensitizers. A number of gene variants have been reported to be associated with various occupational allergic respiratory diseases. Examples of genes include, but are not limited to, genes involved in immune/inflammatory regulation, antioxidant defenses, and fibrotic processes. Most of these variants act in combination with other genes and environmental factors to modify disease progression, severity, or resolution after exposure to allergens. Therefore, understanding the role of genetic variability and the interaction between genetic and environmental/occupational factors provides new insights into disease etiology and may lead to the development of novel preventive and therapeutic strategies. This paper will focus on the current state of knowledge regarding genetic influences on allergic respiratory diseases, with specific emphasis on diisocyanate-induced asthma and chronic beryllium disease. PMID:21747866

Yucesoy, Berran; Johnson, Victor J.

2011-01-01

48

Genetic variability in susceptibility to occupational respiratory sensitization.  

PubMed

Respiratory sensitization can be caused by a variety of substances at workplaces, and the health and economic burden linked to allergic respiratory diseases continues to increase. Although the main factors that affect the onset of the symptoms are the types and intensity of allergen exposure, there is a wide range of interindividual variation in susceptibility to occupational/environmental sensitizers. A number of gene variants have been reported to be associated with various occupational allergic respiratory diseases. Examples of genes include, but are not limited to, genes involved in immune/inflammatory regulation, antioxidant defenses, and fibrotic processes. Most of these variants act in combination with other genes and environmental factors to modify disease progression, severity, or resolution after exposure to allergens. Therefore, understanding the role of genetic variability and the interaction between genetic and environmental/occupational factors provides new insights into disease etiology and may lead to the development of novel preventive and therapeutic strategies. This paper will focus on the current state of knowledge regarding genetic influences on allergic respiratory diseases, with specific emphasis on diisocyanate-induced asthma and chronic beryllium disease. PMID:21747866

Yucesoy, Berran; Johnson, Victor J

2011-01-01

49

Advances in Susceptibility Genetics of Intervertebral Degenerative Disc Disease  

PubMed Central

The traditional view that the etiology of lumbar disc herniation is primarily due to age, gender, occupation, smoking and exposure to vehicular vibration dominated much of the last century. Recent research indicates that heredity may be largely responsible for the degeneration as well as herniation of intervertebral discs. Since 1998, genetic influences have been confirmed by the identification of several genes forms associated with disc degeneration. These researches are paving the way for a better understanding of the biologic mechanisms. Now, many researchers unanimously agree that lumbar disc herniation appears to be similar to other complex diseases, whose etiology has both environmental and hereditary influence, each with a part of contribution and relative risk. Then addressing the etiological of lumbar disc herniation, it is important to integrate heredity with the environment factors. For the purpose of this review, we have limited our discussion to several susceptibility genes associated with disc degeneration. PMID:18781226

Zhang, Yin'gang; Sun, Zhengming; Liu, Jiangtao; Guo, Xiong

2008-01-01

50

Contribution of environment and genetics to pancreatic cancer susceptibility.  

PubMed

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

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

51

Genetic Susceptibility for Alzheimer’s Disease Neuritic Plaque Pathology  

PubMed Central

Objective To investigate whether Alzheimer’s disease (AD) susceptibility loci from genome-wide association studies (GWAS) impact neuritic plaque pathology and to additionally identify novel risk loci for this trait. Design Candidate analysis of single nucleotide polymorphisms (SNPs) and GWAS in a joint clinicopathologic cohort study, followed by targeted validation in independent neuroimaging cohorts. Participants and Setting 725 deceased subjects from the Religious Orders and Rush Memory and Aging Project, two prospective, community-based studies of aging; the validation neuroimaging cohort consisted of 114 subjects from multiple clinical and research centers. Main Outcome Measures A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on ?-amyloid load by immunocytochemistry, and replication with fibrillar ?-amyloid Positron Emission Tomography (PET) imaging with Pittsburgh Compound B or florbetapir. Results Besides the previously reported APOE and CR1 loci, we find that ABCA7 (rs3764650, P=0.02) and CD2AP (rs9349407, P=0.03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our GWAS, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P=3.3×10?6). This polymorphism was associated with postmortem ?-amyloid load, as well as fibrillar ?-amyloid in two independent cohorts of adults with normal cognition. Conclusion These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, pre-symptomatic stages of AD. PMID:23836404

Shulman, Joshua M.; Chen, Kewei; Keenan, Brendan T.; Chibnik, Lori B.; Fleisher, Adam; Thiyyagura, Pradeep; Roontiva, Auttawut; McCabe, Cristin; Patsopoulos, Nikolaos A.; Corneveaux, Jason J.; Yu, Lei; Huentelman, Matthew J.; Evans, Denis A.; Schneider, Julie A.; Reiman, Eric M.; De Jager, Philip L.; Bennett, David A.

2013-01-01

52

Inherited genetic susceptibility to monoclonal gammopathy of unknown significance.  

PubMed

Monoclonal gammopathy of undetermined significance (MGUS) is present in ?2% of individuals age >50 years. The increased risk of multiple myeloma (MM) in relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common single-nucleotide polymorphisms (SNPs) at 2p23.3 (rs6746082), 3p22.1 (rs1052501), 3q26.2 (rs10936599), 6p21.33 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077), and 22q13.1 (rs877529) have recently been shown to influence MM risk. To examine the impact of these 7 SNPs on MGUS, we analyzed two case-control series totaling 492 cases and 7306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P < .02) for rs1052501, rs2285803, rs4487645, and rs4273077. SNP associations were independent, with risk increasing with a larger number of risk alleles carried (per allele odds ratio, 1.18; P < 10(-7)). Collectively these data are consistent with a polygenic model of disease susceptibility to MGUS. PMID:24449210

Weinhold, Niels; Johnson, David C; Rawstron, Andrew C; Försti, Asta; Doughty, Chi; Vijayakrishnan, Jayaram; Broderick, Peter; Dahir, Nasrin B; Begum, Dil B; Hosking, Fay J; Yong, Kwee; Walker, Brian A; Hoffmann, Per; Mühleisen, Thomas W; Langer, Christian; Dörner, Elisabeth; Jöckel, Karl-Heinz; Eisele, Lewin; Nöthen, Markus M; Hose, Dirk; Davies, Faith E; Goldschmidt, Hartmut; Morgan, Gareth J; Hemminki, Kari; Houlston, Richard S

2014-04-17

53

[The role of human genetic factors in susceptibility to tuberculosis].  

PubMed

Tuberculosis has been one of the most important illnesses in the history of the world, but it was never understood why only some people, and not others, develop the disease. It was assumed that human genetic factors play a role in susceptibility, but until the advent of molecular markers, it was never possible to convincingly separate inheritance from the compounding factors of environment and exposure to the bacillus. In recent years particular polymorphisms of several human genes have been shown to be correlated with susceptibility to TB: NRAMP1, Vitamin D receptor, Interferon gamma receptor, IL-12 and its receptor, several HLA haplotypes and there are probably several others that will be discovered. Nevertheless, no single gene appears to play a dominant role in the total TB burden of any population, and exposure of the individual to the bacillus and the environment and nutritional state of the individual also seem to play an important role in determining who will develop the disease. PMID:11899696

Takiff, H

2001-01-01

54

A Statistical Model for Assessing Genetic Susceptibility as a Risk Factor in Multifactorial Diseases: Lessons from Occupational Asthma  

PubMed Central

Background Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes. Objective The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk. Methods We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes. Results Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures. Conclusion The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment. PMID:17384770

Demchuk, Eugene; Yucesoy, Berran; Johnson, Victor J.; Andrew, Michael; Weston, Ainsley; Germolec, Dori R.; De Rosa, Christopher T.; Luster, Michael I.

2007-01-01

55

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

PubMed Central

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

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

2012-01-01

56

Genetic susceptibility to lupus: the biological basis of genetic risk found in B cell signaling pathways  

PubMed Central

Over 50 genetic variants have been statistically associated with the development of SLE (or lupus). Each genetic association is a key component of a pathway to lupus pathogenesis, the majority of which requires further mechanistic studies to understand the functional changes to cellular physiology. Whereas their use in clinical practice has yet to be established, these genes guide efforts to develop more specific therapeutic approaches. The BCR signaling pathways are rich in lupus susceptibility genes and may well provide novel opportunities for the understanding and clinical treatment of this complex disease. PMID:22753952

Vaughn, Samuel E.; Kottyan, Leah C.; Munroe, Melissa E.; Harley, John B.

2012-01-01

57

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

E-print Network

Evolutionary Determinants of Genetic Variation in Susceptibility to Infectious Diseases in Humans, USA Abstract Although genetic variation among humans in their susceptibility to infectious diseases with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative

Antonovics, Janis

58

Genetic susceptibility to lung cancer and co-morbidities  

PubMed Central

Lung cancer is a leading cause of cancer death and disease burden in many countries. Understanding of the biological pathways involved in lung cancer aetiology is required to identify key biomolecules that could be of significant clinical value, either as predictive, prognostic or diagnostic markers, or as targets for the development of novel therapies to treat this disease, in addition to smoking avoidance strategies. Genome-wide association studies (GWAS) have enabled significant progress in the past 5 years in investigating genetic susceptibility to lung cancer. Large scale, multi-cohort GWAS of mainly Caucasian, smoking, populations have identified strong associations for lung cancer mapped to chromosomal regions 15q [nicotinic acetylcholine receptor (nAChR) subunits: CHRNA3, CHRNA5], 5p (TERT-CLPTM1L locus) and 6p (BAT3-MSH5). Some studies in Asian populations of smokers have found similar risk loci, whereas GWAS in never smoking Asian females have identified associations in other chromosomal regions, e.g., 3q (TP63), that are distinct from smoking-related lung cancer risk loci. GWAS of smoking behaviour have identified risk loci for smoking quantity at 15q (similar genes to lung cancer susceptibility: CHRNA3, CHRNA5) and 19q (CYP2A6). Other genes have been mapped for smoking initiation and smoking cessation. In chronic obstructive pulmonary disease (COPD), which is a known risk factor for lung cancer, GWAS in large cohorts have also found CHRNA3 and CHRNA5 single nucleotide polymorphisms (SNPs) mapping at 15q as risk loci, as well as other regions at 4q31 (HHIP), 4q24 (FAM13A) and 5q (HTR4). The overlap in risk loci between lung cancer, smoking behaviour and COPD may be due to the effects of nicotine addiction; however, more work needs to be undertaken to explore the potential direct effects of nicotine and its metabolites in gene-environment interaction in these phenotypes. Goals of future genetic susceptibility studies of lung cancer should focus on refining the strongest risk loci in a wide range of populations with lung cancer, and integrating other clinical and biomarker information, in order to achieve the aim of personalised therapy for lung cancer. PMID:24163739

Holloway, John W.; Fong, Kwun M.

2013-01-01

59

Genetic susceptibility to non-polyposis colorectal cancer  

PubMed Central

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 ? 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

Lynch, H.; de la Chapelle, A.

1999-01-01

60

Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure.  

PubMed

Pleural malignant mesothelioma (MM) is a rare but extremely aggressive cancer. The limited impact of standard therapeutic treatments on survival rates makes the identification of factors that increase the individual risk a leading priority. The high proportion of cases explained by exposure to asbestos has guided intervention policies to an effective ban of this compound from our environment. However, MM cannot be solely attributed to this agent, and the role of predisposing factors and their interaction with asbestos exposure is increasingly studied. The role of mEH, GSTM1, GSTT1, NAT2, and CYP1A1 genotypes in modulating susceptibility to MM was examined in a case-control study of 80 subjects with a confirmed diagnosis of MM and 255 controls. Subjects with low mEH activity showed a significantly increased risk of MM (OR, 2.51; 95% CI, 1.11-5.68). The association was stronger in the group with low asbestos exposure (OR, 7.83; 95% CI, 0.98-62.60). A significant increased risk of MM was also found in NAT2 fast acetylators (OR, 1.74; 95% CI, 1.02-2.96). The presence of synergisms between genotypes, i.e., mEH and NAT2 (LRT for heterogeneity p<0.023), mEH and GSTM1 (LRT p<0.061), and NAT2 and GSTM1 (LRT p<0.049), combined with the interaction observed with exposure to asbestos, suggests the presence of gene-environment and gene-gene interactions in the development of MM, although the size of the study group does not allow to draw clearcut conclusions. Since genetic polymorphisms can also modify the extent of genetic damage occurring in subjects exposed to carcinogens, we measured the frequency of micronuclei in peripheral blood lymphocytes of a subgroup of MM cases. The limited number of cases (28) did not allow to observe significant effects. In conclusion, these results strengthen the hypothesis that individual susceptibility to MM can be modulated by the interaction between polymorphic genes involved in the metabolism and the intensity of asbestos exposure. PMID:15993904

Neri, Monica; Filiberti, Rosangela; Taioli, Emanuela; Garte, Seymour; Paracchini, Valentina; Bolognesi, Claudia; Canessa, Pier Aldo; Fontana, Vincenzo; Ivaldi, Giovanni Paolo; Verna, Anna; Bonassi, Stefano; Puntoni, Riccardo

2005-12-30

61

A New Scale Measuring Psychologic Impact of Genetic Susceptibility Testing for Alzheimer Disease  

Microsoft Academic Search

This paper describes the development and psycho- metric properties of a new scale for assessing the psychologic impact of genetic susceptibility testing for Alzheimer disease (AD). The new instrument, The REVEAL Impact of Genetic Testing for Alzheimer's disease (IGT-AD) was designed to examine the unique nature of genetic information and the disease course of AD. The scale was tested as

Winston W. Chung; Clara A. Chen; L. Adrienne Cupples; J. Scott Roberts; Susan C. Hiraki; Anil K. Nair; Robert C. Green; Robert A. Stern

2009-01-01

62

Rewiring of genetic networks in response to modification of genetic background.  

PubMed

Genome-scale genetic interaction networks are progressively contributing to map the molecular circuitry that determines cellular behavior. To what extent this mapping changes in response to different environmental or genetic conditions is, however, largely unknown. Here, we assembled a genetic network using an in silico model of metabolism in yeast to explicitly ask how separate genetic backgrounds alter network structure. Backgrounds defined by single deletions of metabolically active enzymes induce strong rewiring when the deletion corresponds to a catabolic gene, evidencing a broad redistribution of fluxes to alternative pathways. We also show how change is more pronounced in interactions linking genes in distinct functional modules and in those connections that present weak epistasis. These patterns reflect overall the distributed robustness of catabolism. In a second class of genetic backgrounds, in which a number of neutral mutations accumulate, we dominantly observe modifications in the negative interactions that together with an increase in the number of essential genes indicate a global reduction in buffering. Notably, neutral trajectories that originate considerable changes in the wild-type network comprise mutations that diminished the environmental plasticity of the corresponding metabolism, what emphasizes a mechanistic integration of genetic and environmental buffering. More generally, our work demonstrates how the specific mechanistic causes of robustness influence the architecture of multiconditional genetic interaction maps. PMID:25432942

Baji?, Djordje; Moreno-Fenoll, Clara; Poyatos, Juan F

2014-01-01

63

Genetic Susceptibility to Coronary Heart Disease in Type 2 Diabetes: Three Independent Studies  

PubMed Central

Objective To evaluate whether coronary heart disease (CHD)-susceptibility loci identified by genome-wide association studies of the general population also contribute to CHD in type 2 diabetes. Background No study has examined the effects of these genetic variants on CHD in diabetic patients. Methods We genotyped 15 genetic markers of 12 loci in three studies of diabetic patients: the prospective Nurses’ Health Study (309 CHD cases and 544 controls) and Health Professional Follow-up Study (345 CHD cases and 451 controls), and the cross-sectional Joslin Heart Study (422 CHD cases and 435 controls). Results Five SNPs, rs4977574 (CDKN2A/2B), rs12526453 (PHACTR1), rs646776 (CELSR2-PSRC1-SORT1), rs2259816 (HNF1A), and rs11206510 (PCSK9) showed directionally consistent associations with CHD in the three studies, with combined odds ratios (ORs) ranging from 1.17 to 1.25 (p=0.03 to 0.0002). None of the other SNPs reached significance in individual or combined analyses. A genetic risk score (GRS) was created by combining the risk alleles of the five significantly associated loci. The OR of CHD per GRS unit was 1.19 (95% confidence interval [CI] 1.13– 1.26; p<0.0001). Individuals with GRS ?8 (19% of diabetic subjects) had almost a two-fold increase in CHD risk (OR=1.94, 95% CI 1.60–2.35) as compared to individuals with GRS ?5 (30% of diabetic subjects). Prediction of CHD was significantly improved (p<0.001) when the GRS was added to a model including clinical predictors in the combined samples. Conclusions Our results illustrate the consistency and differences in the determinants of genetic susceptibility to CHD in diabetic patients and the general populations. PMID:22152955

Qi, Lu; Parast, Layla; Cai, Tianxi; Powers, Christine; Gervino, Ernest V.; Hauser, Thomas H.; Hu, Frank B.; Doria, Alessandro

2011-01-01

64

Genetic Background and Climatic Droplet Keratopathy Incidence in a Mapuche Population from Argentina  

PubMed Central

Purpose To determine whether the incidence of and susceptibility to climatic droplet keratopathy (CDK), an acquired, often bilateral degenerative corneal disease, is influenced by the genetic background of the individuals who exhibit the disorder. Methods To determine whether the disease expression was influenced by the genetic ancestry of CDK cases in native Mapuche of the northwest area of Patagonia in Argentina, we examined mitochondrial DNA and Y-chromosome variation in 53 unrelated individuals. Twenty-nine of them were part of the CDK (patient) population, while 24 were part of the control group. The analysis revealed the maternal and paternal lineages that were present in the two study groups. Results This analysis demonstrated that nearly all persons had a Native American mtDNA background, whereas 50% of the CDK group and 37% of the control group had Native American paternal ancestry, respectively. There was no significant difference in the frequencies of mtDNA haplogroups between the CDK patient and control groups. Although the Y-chromosome data revealed differences in specific haplogroup frequencies between these two groups, there was no statistically significant relationship between individual paternal genetic backgrounds and the incidence or stage of disease. Conclusions These results indicate a lack of correlation between genetic ancestry as represented by haploid genetic systems and the incidence of CDK in Mapuche populations. In addition, the mtDNA appears to play less of a role in CDK expression than for other complex diseases linked to bioenergetic processes. However, further analysis of the mtDNA genome sequence and other genes involved in corneal function may reveal the more precise role that mitochondria play in the expression of CDK. PMID:24040292

Schurr, Theodore G.; Dulik, Matthew C.; Cafaro, Thamara A.; Suarez, María F.

2013-01-01

65

Complex genetic background in a large family with Brugada syndrome.  

PubMed

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

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

66

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

Microsoft Academic Search

Classical twin studies and recent linkage analyses of African populations have revealed a potential involve- ment 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

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

2006-01-01

67

A Multidirectional Non-Cell Autonomous Control and a Genetic Interaction Restricting Tobacco Etch Virus Susceptibility in Arabidopsis  

PubMed Central

Background Viruses constitute a major class of pathogens that infect a variety of hosts. Understanding the intricacies of signaling during host-virus interactions should aid in designing disease prevention strategies and in understanding mechanistic aspects of host and pathogen signaling machinery. Methodology/Principal Findings An Arabidopsis mutant, B149, impaired in susceptibility to Tobacco etch virus (TEV), a positive strand RNA virus of picoRNA family, was identified using a high-throughput genetic screen and a counterselection scheme. The defects include initiation of infection foci, rate of cell-to-cell movement and long distance movement. Conclusions/Significance The defect in infectivity is conferred by a recessive locus. Molecular genetic analysis and complementation analysis with three alleles of a previously published mutant lsp1 (loss of susceptibility to potyviruses) indicate a genetic interaction conferring haploinsufficiency between the B149 locus and certain alleles of lsp1 resulting in impaired host susceptibility. The pattern of restriction of TEV foci on leaves at or near the boundaries of certain cell types and leaf boundaries suggest dysregulation of a multidirectional non-cell autonomous regulatory mechanism. Understanding the nature of this multidirectional signal and the molecular genetic mechanism conferring it should potentially reveal a novel arsenal in the cellular machinery. PMID:17912362

Gopalan, Suresh

2007-01-01

68

Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease.  

PubMed

BackgroundChronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.MethodsWe analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.ResultsFor CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR¿=¿1.93, P¿=¿4.99¿×¿10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR¿=¿1.88, P¿=¿4.99¿×¿10-7).ConclusionsWe found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.Trial registrationClinicalTrials.gov NCT00608764, NCT00292552. PMID:25241909

Lee, Jin; Cho, Michael H; Hersh, Craig P; McDonald, Merry-Lynn N; Crapo, James D; Bakke, Per S; Gulsvik, Amund; Comellas, Alejandro P; Wendt, Christine H; Lomas, David A; Kim, Victor; Silverman, Edwin K

2014-09-21

69

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

ERIC Educational Resources Information Center

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…

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

2007-01-01

70

Disclosing the Disclosure: Factors Associated With Communicating the Results of Genetic Susceptibility Testing for Alzheimer's Disease  

Microsoft Academic Search

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

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

2009-01-01

71

The BOADICEA model of genetic susceptibility to breast and ovarian cancer: updating, validation and predictions  

Cancer.gov

The BOADICEA model of genetic susceptibility to breast and ovarian cancer: updating, validation and predictions. Antonis C. Antoniou (1), Paul D.P Pharoah (2) and Douglas F Easton (1) on behalf of the Boadicea collaborators. (1) CR-UK Genetic Epidemiology

72

Systems genetics analysis of cancer susceptibility: from mouse models to humans  

Microsoft Academic Search

Genetic studies of cancer susceptibility have shown that most heritable risk cannot be explained by the main effects of common alleles. This may be due to unknown gene–gene or gene–environment interactions and the complex roles of many genes at different stages of cancer. Studies using mouse models of cancer suggest that methods that integrate genetic analysis and genomic networks with

David Quigley; Allan Balmain

2009-01-01

73

Copyright 2003 by the Genetics Society of America Effects of Genetic Background on Response to Selection in Experimental  

E-print Network

Copyright 2003 by the Genetics Society of America Effects of Genetic Background on Response received June 28, 2002 Accepted for publication September 9, 2002 ABSTRACT The extent to which genetic consequences. Using experimental populations of Arabidopsis thaliana and map-based population genetic data, we

Rieseberg, Loren

74

Removing Background Phase Variations in Susceptibility Weighted Imaging Using a Fast, Forward-Field Calculation  

PubMed Central

Purpose To estimate magnetic field variations induced from air-tissue interface geometry and remove their effects from susceptibility weighted imaging (SWI) data. Materials and Methods A Fourier-transform-based field estimation method is used to calculate the field deviation arising from air-tissue interface geometry. This is accomplished by, first, manually drawing or automatically detecting the sinuses, the mastoid cavity and the head geometry. The difference in susceptibility, ??, between brain tissue and air-spaces is then calculated using a residual-phase minimization approach. SWI data are corrected by subtracting the predicted phase from the original phase image. Resultant phase images are then used to perform the SWI post-processing. Results Significant improvement in the post-processed SWI data is demonstrated, most notably in the frontal and midbrain regions and to a lesser extent at the boundary of the brain. Specifically, there is much less dropout of signal after phase correction near air-tissue interfaces making it possible to see vessels and structures that were often incorrectly removed by the conventional SWI post-processing. Conclusion The Fourier-transform-based field estimation method is a powerful 3D background phase removal method for improving SW images, providing clearer images of the fore-brain and the mid-brain regions. PMID:19306433

Neelavalli, Jaladhar; Cheng, Yu-Chung N.; Jiang, Jing; Haacke, E. Mark

2009-01-01

75

T Helper Phenotype and Genetic Susceptibility in Experimental Lyme Disease  

Microsoft Academic Search

Summary Infection of inbred mice with Borrelia burgdorferi results in strain-specific variation in the severity of pathogen-induced arthritis: BALB\\/c mice develop only mild disease whereas C3H\\/HeJ mice develop severe arthritis. The immunologic basis for varying host susceptibility has yet to be defined. We modified experimental Lyme disease to facilitate measurement of antigen-specific cytokine production in resistant and susceptible mice. The

Jennifer E. Matyniak; Steven L. Reiner

76

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

PubMed

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

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

2015-02-01

77

Ethnic background and genetic variation in the evaluation of cancer risk: a systematic review.  

PubMed

The clinical use of genetic variation in the evaluation of cancer risk is expanding, and thus understanding how determinants of cancer susceptibility identified in one population can be applied to another is of growing importance. However there is considerable debate on the relevance of ethnic background in clinical genetics, reflecting both the significance and complexity of genetic heritage. We address this via a systematic review of reported associations with cancer risk for 82 markers in 68 studies across six different cancer types, comparing association results between ethnic groups and examining linkage disequilibrium between risk alleles and nearby genetic loci. We find that the relevance of ethnic background depends on the question. If asked whether the association of variants with disease risk is conserved across ethnic boundaries, we find that the answer is yes, the majority of markers show insignificant variability in association with cancer risk across ethnic groups. However if the question is whether a significant association between a variant and cancer risk is likely to reproduce, the answer is no, most markers do not validate in an ethnic group other than the discovery cohort's ancestry. This lack of reproducibility is not attributable to studies being inadequately populated due to low allele frequency in other ethnic groups. Instead, differences in local genomic structure between ethnic groups are associated with the strength of association with cancer risk and therefore confound interpretation of the implied physiologic association tracked by the disease allele. This suggest that a biological association for cancer risk alleles may be broadly consistent across ethnic boundaries, but reproduction of a clinical study in another ethnic group is uncommon, in part due to confounding genomic architecture. As clinical studies are increasingly performed globally this has important implications for how cancer risk stratifiers should be studied and employed. PMID:24901479

Jing, Lijun; Su, Li; Ring, Brian Z

2014-01-01

78

Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity  

PubMed Central

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome. PMID:12975475

Stratmann, Thomas; Martin-Orozco, Natalia; Mallet-Designe, Valérie; Poirot, Laurent; McGavern, Dorian; Losyev, Grigoriy; Dobbs, Cathleen M.; Oldstone, Michael B.A.; Yoshida, Kenji; Kikutani, Hitoshi; Mathis, Diane; Benoist, Christophe; Haskins, Kathryn; Teyton, Luc

2003-01-01

79

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

PubMed Central

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 – IL1?, IL1?, 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 IL1?, +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 IL1?, IL12RB1 and CISH genes and the susceptibility to leptospirosis infection. PMID:25255143

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

80

Genetic polymorphisms of cytochrome P450 2E1, glutathione S-transferase M1 and T1, and susceptibility to gastric carcinoma in Taiwan  

Microsoft Academic Search

Background and aims: Cytochrome P450 (CYP) and glutathione S-transferase (GST) enzymes are involved in activation and detoxification of many potential carcinogens. Genetic polymorphisms in these enzymes have been found to influence interindividual and interethnic susceptibility to cancer. Although CYP and GST enzymes are involved in the activation and detoxification of N-nitrosamines and related compound, studies on the relationship between genetic

Ming-Shiang Wu; Chien-Jen Chen; Ming-Tsan Lin; Hsiu-Po Wang; Chia-Tung Shun; Jin-Chuan Sheu; Jaw-Town Lin

2002-01-01

81

Interleukin-16 Gene Polymorphisms Are Considerable Host Genetic Factors for Patients' Susceptibility to Chronic Hepatitis B Infection  

PubMed Central

Host genetic background is known as an important factor in patients' susceptibility to infectious diseases such as viral hepatitis. The aim of this study was to determine the effect of genetic polymorphisms of interleukin-16 (IL-16) cytokine on susceptibility of hepatitis B virus (HBV) infected patients to develop chronic HBV infection. Genotyping was conducted using PCR followed by enzymatic digestion and RFLP (restriction fragment length polymorphism) analysis. We genotyped three single nucleotide polymorphisms (SNPs) in the Il-16 gene (rs11556218 T>G, rs4778889 T>C, and rs4072111 C>T) to test for relationship between variation at these loci and patients' susceptibility to chronic HBV infection. Allele frequency of Il-16 gene rs4072111 and rs11556218 was significantly different between chronic HBV patients and healthy blood donors. Genotype frequency of rs4778889 polymorphism of Il-16 gene was significantly different when chronic HBV patients and HBV clearance subjects were compared. Our results showed that Il-16 gene polymorphisms are considerable host genetic factors when we chase biomarkers for prognosis of HBV infected patients.

Romani, Sara; Hosseini, Seyed Masoud; Mohebbi, Seyed Reza; Kazemian, Shabnam; Derakhshani, Shaghayegh; Khanyaghma, Mahsa; Sharifian, Afsaneh; Zali, Mohammad Reza

2014-01-01

82

Empathy Is Moderated by Genetic Background in Mice  

PubMed Central

Empathy, as originally defined, refers to an emotional experience that is shared among individuals. When discomfort or alarm is detected in another, a variety of behavioral responses can follow, including greater levels of nurturing, consolation or increased vigilance towards a threat. Moreover, changes in systemic physiology often accompany the recognition of distressed states in others. Employing a mouse model of cue-conditioned fear, we asked whether exposure to conspecific distress influences how a mouse subsequently responds to environmental cues that predict this distress. We found that mice are responsive to environmental cues that predict social distress, that their heart rate changes when distress vocalizations are emitted from conspecifics, and that genetic background substantially influences the magnitude of these responses. Specifically, during a series of pre-exposure sessions, repeated experiences of object mice that were exposed to a tone-shock (CS-UCS) contingency resulted in heart rate deceleration in subjects from the gregarious C57BL/6J (B6) strain, but not in subjects from the less social BALB/cJ (BALB) strain. Following the pre-exposure sessions, subjects were individually presented with the CS-only for 5 consecutive trials followed by 5 consecutive pairings of the CS with the UCS. Pre-exposure to object distress increased the freezing responses of B6 mice, but not BALB mice, on both the CS-only and the CS-UCS trials. These physiological and behavioral responses of B6 mice to social distress parallel features of human empathy. Our paradigm thus has construct and face validity with contemporary views of empathy, and provides unequivocal evidence for a genetic contribution to the expression of empathic behavior. PMID:19209221

Lahvis, Garet P.

2009-01-01

83

A Genetic Lung Cancer Susceptibility Test may have a Positive Effect on Smoking Cessation.  

PubMed

Smoking increases the risk of developing lung cancer. Genetic loci have been identified which could form the basis of a lung cancer susceptibility test; but little is known whether such a test would interest or motivate those trying to quit smoking. To address this, we investigated the attitudes of people trying to quit smoking towards genetic susceptibility testing for lung cancer. Participant's attitudes to topics associated with lung cancer susceptibility testing were assessed; were they interested in genetic testing? What impact would a hypothetical high- or low- risk result have on smoking cessation? 680 self-completion questionnaires were given to individuals attending National Health Service stop smoking clinics in three different areas of the United Kingdom between 2011 and 2012. 139 questionnaires were returned, giving a 20 % response rate. Participants expressed an interest in a genetic susceptibility test for lung cancer and almost all reported that a high-risk result would increase their motivation to stop smoking. However, many participants had a neutral attitude towards a low-risk result. Most participants agreed their smoking habit could lead to lung cancer. Lung cancer susceptibility testing may be a useful incentive to help people quit smoking. This study suggests the need for genetic services to work with smoking cessation teams if routine testing becomes available in the future. PMID:25403897

Kammin, Tammy; Fenton, Andrew K; Thirlaway, Kathryn

2014-11-19

84

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

PubMed Central

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

Baker, Christi; Antonovics, Janis

2012-01-01

85

Genetic susceptibility to the respiratory effects of air pollution  

Microsoft Academic Search

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

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

2009-01-01

86

Mitochondrial DNA Haplogroup Confers Genetic Susceptibility to Nasopharyngeal Carcinoma in Chaoshanese from Guangdong, China  

PubMed Central

Recent studies have shown association of mtDNA background with cancer development. We analyzed mitochondrial DNA (mtDNA) control region variation of 201 patients with nasopharyngeal carcinoma (NPC) and of 201 normal controls from Chaoshan Han Chinese to discern mtDNA haplogroup effect on the disease onset. Binary logistic regression analysis with adjustment for gender and age revealed that the haplogroup R9 (P?=?0.011, OR?=?1.91, 95% CI?=?1.16–3.16), particularly its sub-haplogroup F1 (P?=?0.015, OR?=?2.43, 95% CI?=?1.18–5.00), were associated significantly with increased NPC risk. These haplogroups were further confirmed to confer high NPC risk in males and/or individuals ?40 years of age, but not in females or in subjects <40 years old. Our results indicated that mtDNA background confers genetic susceptibility to NPC in Chaoshan Han Chinese, and R9, particularly its sub-haplogroup F1, is a risk factor for NPC. PMID:24498198

Hu, Sheng-Ping; Du, Ju-Ping; Li, De-Rui; Yao, Yong-Gang

2014-01-01

87

Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome llq  

Microsoft Academic Search

LOCI in the major histocompatibility complex (MHC) on chromo-some 6 and the insulin (INS) region on chromosome 11 have been implicated in susceptibility to insulin-dependent diabetes mellitus (IDDM) through candidate gene investigations1-5, but they may account for less than 50% of genetic risk for the disease6. Genome-wide linkage studies have led to localization of more than 10 sus-ceptibility loci for

L. Hashimoto; C. Habita; J. P. Beressi; M. Delepine; C. Basse; A. Cambon-Thomsen; I. Deschamps; J. I. Rotter; S. Djoulah; M. R. James; P. Froguel; J. Weissenbach; G. M. Lathrop; C. Julier

1994-01-01

88

Genetic susceptibility to tuberculosis in Africans: A genome-wide scan  

Microsoft Academic Search

Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility

Richard Bellamy; Nulda Beyers; Keith P. W. J. McAdam; Cyril Ruwende; Robert Gie; Priscilla Samaai; Danite Bester; Mandy Meyer; Tumani Corrah; Matthew Collin; D. Ross Camidge; David Wilkinson; Eileen Hoal-van Helden; Hilton C. Whittle; William Amos; Paul van Helden; Adrian V. S. Hill

2000-01-01

89

Strain background effects and genetic modifiers of hearing in mice  

PubMed Central

Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positional-candidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23753A/G). This variant also was shown to modify hearing loss associated with the Atp2b2dfw-2J and Mass1frings mutations. The hearing modifier (Moth1) of tubby (Tubtub) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2dfw-2J–Cdh23753A/G interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans. PMID:16579977

Johnson, Kenneth R.; Zheng, Qing Yin; Noben-Trauth, Konrad

2010-01-01

90

Genetic Modifiers of Lepr fa Associated with Variability in Insulin Production and Susceptibility to NIDDM  

Microsoft Academic Search

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 obeseLeprfa\\/LeprfaF2 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

Wendy K. Chung; Min Zheng; Melvin Chua; Erin Kershaw; Loraine Power-Kehoe; Michael Tsuji; X. Sharon Wu-Peng; Julie Williams; Streamson C. Chua; Rudolph L. Leibel

1997-01-01

91

The influence of XRCC1 genetic variants on lung cancer susceptibility in Chinese Han population.  

PubMed

Growing evidence suggests that genetic variants of X-ray repair cross-complementing group 1 proteins (XRCC1) contribute to genetic effects on the development of lung cancer. This case-control study aims to evaluate the genetic effects of XRCC1 c.482C>T and c.1686C>G single nucleotide polymorphisms (SNPs) on lung cancer susceptibility. 391 lung cancer patients and 398 cancer-free controls were enrolled in this study. The genotypes of c.482C>T and c.1686C>G genetic variants were detected by the created restriction site-polymerase chain reaction (CRS-PCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods. The genetic effects on lung cancer susceptibility were evaluated using association analyses by the unconditional logistic regression model. Our data indicated that there were significant differences in the distribution of allelic and genotypic frequencies between lung cancer patients and cancer-free controls. The XRCC1 c.482C>T and c.1686C>G genetic variants were significantly associated with the susceptibility to lung cancer (for c.482C>T, TT versus (vs.) CC: OR=2.14, 95% CI 1.31-3.48, P=0.002; T vs. C: OR=1.37, 95% CI 1.10-1.69, P=0.004; for c.1686C>G, GG vs. CC: OR=2.53, 95% CI 1.46-4.38, P=0.001; G vs. C: OR=1.33, 95% CI 1.06-1.65, P=0.012). These preliminary results suggested that the XRCC1 c.482C>T and c.1686C>G genetic variants might play genetic effects on the susceptibility to lung cancer in the studied population. PMID:25433331

Wang, Yingyi; Ni, Jianjiao; Sun, Zhao; Chen, Shuchang; Jiao, Yuchen; Bai, Chunmei

2015-02-10

92

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis  

Microsoft Academic Search

The pathogenesis of viral myocarditis is a multifactorial process involving host genetics, viral genetics and the environment in which they interact. We have used a model of infection with coxsackievirus B3 (CVB3) to characterize the contribution of host genetics to viral myocarditis in mice of different genetic backgrounds but with a common H2 haplotype: A\\/J and B10.A-H2a. Here we have

M Aly; S Wiltshire; G Chahrour; J-C Loredo Osti; S M Vidal

2007-01-01

93

Knowledge gaining by human genetic studies on tuberculosis susceptibility  

Microsoft Academic Search

Tuberculosis (TB) is a serious health issue in the developing world. Lack of knowledge on the etiological mechanisms of TB hinders the development of effective strategies for the treatment or prevention of TB disease. Human genetic study is an indispensable approach to understand the molecular basis of common diseases. Numerous efforts were made to screen the human genome for TB

Hui-Qi Qu; Susan P Fisher-Hoch; Joseph B McCormick

2011-01-01

94

Host genetic background impacts modulation of the TLR4 pathway by RON in tissue-associated macrophages.  

PubMed

Toll-like receptors (TLRs) enable metazoans to mount effective innate immune responses to microbial and viral pathogens, as well as to endogenous host-derived ligands. It is understood that genetic background of the host can influence TLR responsiveness, altering susceptibility to pathogen infection, autoimmunity and cancer. Macrophage stimulatory protein (MSP), which activates the receptor tyrosine kinase recepteur d'origine nantais (RON), promotes key macrophage functions such as motility and phagocytic activity. MSP also acts via RON to modulate signaling by TLR4, which recognizes a range of pathogen or endogenous host-derived molecules. Here, we show that RON exerts divergent control over TLR4 activity in macrophages from different mouse genetic backgrounds. RON potently modulated the TLR4 response in macrophages from M2-prone FVB mice, as compared with M1-skewed C57Bl6 mice. Moreover, global expression analysis revealed that RON suppresses the TLR4-dependent type-I interferon gene signature only in FVB macrophages. This leads to attenuated production of the potent inflammatory mediator, tumor necrosis factor-?. Eliminating RON kinase activity markedly decreased carcinogen-mediated tumorigenesis in M2/Th2-biased FVB mice. We propose that host genetic background influences RON function, thereby contributing to the variability in TLR4 responsiveness in rodents and, potentially, in humans. These findings provide novel insight into the complex interplay between genetic context and immune function. PMID:23817579

Chaudhuri, Amitabha; Wilson, Nicholas S; Yang, Becky; Paler Martinez, Andres; Liu, Jinfeng; Zhu, Catherine; Bricker, Nicole; Couto, Suzana; Modrusan, Zora; French, Dorothy; Cupp, James; Ashkenazi, Avi

2013-08-01

95

RESEARCH ARTICLE Open Access Natural genetic variation determines susceptibility  

E-print Network

Deravaj1 , Jasmine Alexander-Floyd2 and Richard I Morimoto1 Abstract Background: Monogenic gain-of-function are caused by de novo gain-of-function mutations that result in expression of destabilized, aggregation

Morimoto, Richard

96

BIOM-252. Human genetics and genomics: Underpinnings of human disease and disease susceptibility (3 units)  

E-print Network

(Psychiatry) jkelsoe@ucsd.edu Genetics of Bipolar Disorder Gene Yeo, PhD (CMM) ewyeo@ucsd.edu RNA Binding in the Mammalian Genome Frank Furnari, PhD (Medicine) ffurnari@ucsd.edu Mutational Heterogeneity and Tumor Progression Richard Kolodner, PhD (Medicine) rkolodner@ucsd.edu DNA Repair Defects and Cancer Susceptibility

Gleeson, Joseph G.

97

Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits  

Microsoft Academic Search

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease, which affects quality of life for millions of elderly individuals worldwide. AMD is associated with a diverse spectrum of clinical phe- notypes, all of which include the death of photoreceptors in the central part of the human retina (called the macula). Tremendous progress has been made in identifying genetic susceptibility variants

Anand Swaroop; Kari EH Branham; Wei Chen; Goncalo Abecasis

2007-01-01

98

Genetics and asthma disease susceptibility in the US Latino population.  

PubMed

The US Latino population is heterogeneous with diversity in environmental exposures and socioeconomic status. Moreover, the US Hispanic population derives from numerous countries previously under Spanish rule, and many Hispanics have complex proportions of European, Native American, and African ancestry. Disparities in asthma severity and control are due to complex interactions between environmental exposures, socioeconomic factors, and genetic variations. In addition, diseases within the Latino community may also differ by country of origin. Although US Census data show low asthma rates in the Hispanic population as a whole, there is a lot of variability in the prevalence and morbidity of asthma, with a prevalence of 5.0% in Mexican Americans versus 17.0% in Puerto Ricans. The diversity and population admixture make the study of the genetics of asthma complex in Latino populations. However, an understanding of the genetics of asthma in all populations, including the Latino population, can enhance risk identification, help us to target pharmacological therapy, and guide environmental regulations, all of which can promote a reduction in health disparities. The inclusion of markers of ancestral diversity and the incorporation of techniques to adjust for stratification now make these studies feasible in complex populations, including the Latino population. To date, studies using linkage analyses, genome-wide associations, or candidate gene analyses have identified an association of asthma or asthma-related phenotypes with candidate genes, including interleukin 13, beta-2 adrenergic receptor, a disintegrin and metalloproteinase 33, orosomucoid 1-like 3, and thymic stromal lymphopoietin. As reviewed here, although these genes have been identified in diverse populations, limited studies have been performed in Latino populations, and they have had variable replication. There is a need for the development of registries with well-phenotyped pediatric and adult Latino populations and subgroups for inclusion in the rapidly expanding field of genetic studies, and these studies need to be used to reduce health disparities. PMID:20309924

Reibman, Joan; Liu, Mengling

2010-01-01

99

Genetic Susceptibility to Tuberculosis: From Monogenic to Polygenic Inheritance  

Microsoft Academic Search

Summary. Tuberculosis is re-emerging as a leading public health problem worldwide, largely due to the lack of a fully protective vaccine, the acquired immunodeficiency associated with HIV-co-infection and the increasing number of drug-resistant mycobacteria. There is substantial epidemiological evidence that the host genetic make-up affects the development of clinical tuberculosis in humans. Here we review population-based and patient-based molecular studies

Alexandre Alcaïs; Natascha Remus; Laurent Abel; Jean-Laurent Casanova

2001-01-01

100

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

SciTech Connect

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.

Classen, Aimee T [ORNL; Chapman, Samantha K. [Smithsonian Environmental Research Center, Edgewater, MD; Whitham, Thomas G [Northern Arizona University; Hart, Stephen C [Northern Arizona University; Koch, George W [Northern Arizona University

2007-01-01

101

Malignant transformation in a defined genetic background: proteome changes displayed by 2D-PAGE  

Microsoft Academic Search

BACKGROUND: Cancer arises from normal cells through the stepwise accumulation of genetic alterations. Cancer development can be studied by direct genetic manipulation within experimental models of tumorigenesis. Thereby, confusion by the genetic heterogeneity of patients can be circumvented. Moreover, identification of the critical changes that convert a pre-malignant cell into a metastatic, therapy resistant tumor cell, however, is one necessary

Stephanie M Pütz; Fotini Vogiatzi; Thorsten Stiewe; Albert Sickmann

2010-01-01

102

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

PubMed Central

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

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

2013-01-01

103

Genetic Susceptibility to Peripheral Arterial Disease: A Dark Corner in Vascular Biology  

PubMed Central

Peripheral arterial disease (PAD) is characterized by reduced blood flow to the limbs, usually as a consequence of atherosclerosis, and affects ?12 million Americans. It is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. Similar to other atherosclerotic diseases, such as coronary artery disease, PAD is the result of the complex interplay between injurious environmental stimuli and genetic predisposing factors of the host. Genetic susceptibility to PAD is likely contributed by sequence variants in multiple genes, each with modest effects. Although many of these variants probably alter susceptibility both to PAD and to coronary artery disease, it is likely that there exists a set of variants specifically to alter susceptibility to PAD. Despite the prevalence of PAD and its high societal burden, relatively little is known about such genetic variants. This review summarizes our limited present knowledge and gives an overview of recent, more powerful approaches to elucidating the genetic basis of PAD. We discuss the advantages and limitations of genetic studies and highlight the need for collaborative networks of PAD investigators for shedding light on this dark corner of vascular biology. PMID:17656669

Knowles, Joshua W.; Assimes, Themistocles L.; Li, Jun; Quertermous, Thomas; Cooke, John P.

2009-01-01

104

Post-Traumatic Brain Injury: Genetic Susceptibility to Outcome.  

PubMed

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

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

2014-07-24

105

Population Genetics of Drosophila Amylase. V. Genetic Background and Selection on Different Carbohydrates  

PubMed Central

Frequency changes in amylase allozymes and patterns of tissue-specific expression of amylase have been monitored in laboratory populations of Drosophila pseudoobscura maintained on media in which the only carbohydrate source was maltose or starch. Nonrandom changes occurred in patterns of expression, whereas no patterns in allozyme frequency changes were discernible. The nature of the pattern changes was similar to an identical study done on populations derived from a natural population several hundred miles from the population used in the present experiments. However, in the previous study nonrandom changes in allozyme frequencies were also noted. Evidently, selection on the Drosophila amylase system differs depending upon the genetic background of the population. Furthermore, the evolutionary dynamics of structural gene variants and those regions controlling its expression may be independent, a result consistent with DNA sequence data. PMID:17246202

Powell, Jeffrey R.; Amato, George D.

1984-01-01

106

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

NASA Astrophysics Data System (ADS)

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.

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

2013-03-01

107

Joint Genetic Susceptibility to Type 1 Diabetes and Autoimmune Thyroiditis: from Epidemiology to Mechanisms  

PubMed Central

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

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

2008-01-01

108

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

PubMed

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

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

2008-10-01

109

Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background  

PubMed Central

The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability. PMID:22389733

Decuypere, Saskia; Vanaerschot, Manu; Brunker, Kirstyn; Imamura, Hideo; Müller, Sylke; Khanal, Basudha; Rijal, Suman; Dujardin, Jean-Claude; Coombs, Graham H.

2012-01-01

110

PFAPA syndrome in siblings. Is there a genetic background?  

Microsoft Academic Search

“PFAPA syndrome” is an autoinflammatory entity composed of periodic fever, aphthous stomatitis, pharyngitis, and cervical\\u000a adenitis. There have been many reports of children with the disease, but only occasionally have been described in siblings,\\u000a and no specific genetic mutation has been determined yet. Corticosteroids are the mainstay in the treatment of the acute attacks.\\u000a The role of surgery in long-term

Pilar Antón-Martín; Roberto Ortiz Movilla; Sara Guillén Martín; Luis M. Allende; M. Teresa Cuesta Rubio; M. Fernanda López González; José Tomás Ramos Amador

111

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...

112

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

SciTech Connect

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.

Morgan, K.; Liu, J.; Boothroyd, L. [McGill Univ., Quebec (Canada)] [and others

1994-09-01

113

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

PubMed Central

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

2014-01-01

114

Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study  

PubMed Central

Summary Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF. Methods First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10?8) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes. Findings In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r2=0.07], rs5743894 [r2=0.16], and rs5743890 [r2=0.01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1.72 [95% CI 1.24–2.38]; p=0.0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0.097), 40% in those with the minor allele of rs111521887 (p=3.0 × 10?4), and 50% in those with the minor allele of rs5743894 (p=2.93 × 10?5) compared with homozygous carriers of common alleles for these SNPs. Interpretation Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease. Funding National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III. PMID:24429156

Flores, Carlos; Barber, Mathew; Huang, Yong; Broderick, Steven M; Wade, Michael S; Hysi, Pirro; Scuirba, Joseph; Richards, Thomas J; Juan-Guardela, Brenda M; Vij, Rekha; Han, MeiLan K; Martinez, Fernando J; Kossen, Karl; Seiwert, Scott D; Christie, Jason D

2013-01-01

115

Joint Genetic Susceptibility to Type 1 Diabetes and Autoimmune Thyroiditis: from Epidemiology to Mechanisms  

Microsoft Academic Search

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)). Epi- demiological data point to a strong genetic influence on the shared susceptibility to T1D and

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

2008-01-01

116

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...

117

Genetic Variation and Susceptibilities to Protease Inhibitors among Subtype B and F Isolates in Brazil  

Microsoft Academic Search

The genetic variation of the human immunodeficiency virus type 1 (HIV-1) protease gene (prt) permits the classification of HIV-1 strains into five distinct protease subtypes, which follow the gag subtyping patterns. The susceptibilities of non-B-subtype strains to protease inhibitors (PIs) and other antiretroviral drugs remain largely unknown. Subtype F is the main non-B strain contributing to the Brazilian epidemic, accounting

AMILCAR TANURI; ANA C. P. VICENTE; KOKO OTSUKI; CARLOS A. RAMOS; ORLANDO C. FERREIRA; MAURO SCHECHTER; LUIS M. JANINI; DANUTA PIENIAZEK; MARK A. RAYFIELD

118

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection  

Microsoft Academic Search

Cryptococcus neoformans is a major cause of fungal pneumonia, meningitis and disseminated disease in the immune compromised host. Here we have used a clinically relevant model to investigate the genetic determinants of susceptibility to progressive cryptococcal pneumonia in C57BL\\/6J and CBA\\/J inbred mice. At 5 weeks after infection, the lung fungal burden was over 1000-fold higher in C57BL\\/6J compared to

S F Carroll; J C Loredo Osti; L Guillot; K Morgan; S T Qureshi

2008-01-01

119

Genetic testing in asymptomatic minorsBackground considerations towards ESHG Recommendations  

Microsoft Academic Search

Although various guidelines and position papers have discussed, in the past, the ethical aspects of genetic testing in asymptomatic minors, the European Society of Human Genetics had not earlier endorsed any set of guidelines exclusively focused on this issue. This paper has served as a background document in preparation of the development of the policy recommendations of the Public and

Pascal Borry; Gerry Evers-Kiebooms; Martina C Cornel; Angus Clarke; Kris Dierickx

2009-01-01

120

Cellular basis of the genetic susceptibility of murine experimental allergic encephalomyelitis  

SciTech Connect

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.

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

1986-03-01

121

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

PubMed

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

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

2014-08-01

122

Phlebotomus orientalis Sand Flies from Two Geographically Distant Ethiopian Localities: Biology, Genetic Analyses and Susceptibility to Leishmania donovani  

PubMed Central

Background Phlebotomus orientalis Parrot (Diptera: Psychodidae) is the main vector of visceral leishmaniasis (VL) caused by Leishmania donovani in East Africa. Here we report on life cycle parameters and susceptibility to L. donovani of two P. orientalis colonies originating from different sites in Ethiopia: a non-endemic site in the lowlands - Melka Werer (MW), and an endemic focus of human VL in the highlands - Addis Zemen (AZ). Methodology/Principal Findings Marked differences in life-cycle parameters between the two colonies included distinct requirements for larval food and humidity during pupation. However, analyses using Random Amplified Polymorphic DNA (RAPD) PCR and DNA sequencing of cytB and COI mitochondrial genes did not reveal any genetic differences. F1 hybrids developed successfully with higher fecundity than the parental colonies. Susceptibility of P. orientalis to L. donovani was studied by experimental infections. Even the lowest infective dose tested (2×103 per ml) was sufficient for successful establishment of L. donovani infections in about 50% of the P. orientalis females. Using higher infective doses, the infection rates were around 90% for both colonies. Leishmania development in P. orientalis was fast, the presence of metacyclic promastigotes in the thoracic midgut and the colonization of the stomodeal valve by haptomonads were recorded in most P. orientalis females by day five post-blood feeding. Conclusions Both MW and AZ colonies of P. orientalis were highly susceptible to Ethiopian L. donovani strains. As the average volume of blood-meals taken by P. orientalis females are about 0.7 µl, the infective dose at the lowest concentration was one or two L. donovani promastigotes per sand fly blood-meal. The development of L. donovani was similar in both P. orientalis colonies; hence, the absence of visceral leishmaniasis in non-endemic area Melka Werer cannot be attributed to different susceptibility of local P. orientalis populations to L. donovani. PMID:23638207

Seblova, Veronika; Volfova, Vera; Dvorak, Vit; Pruzinova, Katerina; Votypka, Jan; Kassahun, Aysheshm; Gebre-Michael, Teshome; Hailu, Asrat; Warburg, Alon; Volf, Petr

2013-01-01

123

Am. J. Hum. Genet. 74:160167, 2004 Mapping Multiple Sclerosis Susceptibility to the HLA-DR Locus in African  

E-print Network

Am. J. Hum. Genet. 74:160­167, 2004 160 Report Mapping Multiple Sclerosis Susceptibility to the HLA, CA; 3 Multiple Sclerosis Center, Department of Neurology, Wayne State University School of Medicine susceptibility exists in multiple sclerosis (MS), and an association with the HLA- DRB1*1501-DQB1*0602 haplotype

Reich, David

124

Am. J. Hum. Genet. 67:11541162, 2000 A Second-Generation Genomewide Screen for Asthma-Susceptibility  

E-print Network

Am. J. Hum. Genet. 67:1154­1162, 2000 1154 A Second-Generation Genomewide Screen for Asthma of South Dakota Medical School, Sioux Falls A genomewide screen for asthma- and atopy-susceptibility loci on asthma and atopy phenotypes in diverse populations. Introduction The identification of susceptibility

Cox, Nancy J.

125

Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population.  

PubMed

Genome-wide association studies in patients with testicular germ-cell tumors (TGCT) from Great Britain and the United States have identified six susceptibility loci in or near biologically plausible candidate genes. However, these loci have not been replicated in an independent European sample. We performed a genetic replication study of previously identified TGCT susceptibility loci in a Croatian case-control sample and performed additional analyses as concerning histological subtypes or tumor staging. We analyzed six single-nucleotide polymorphisms [rs2900333 (ATF7IP), rs210138 (BAK1), rs755383 (DMRT1), rs995030 (KITLG), rs4624820 (SPRY4), and rs4635969 (TERT/CLPTM1L)], each representing one of the published susceptibility loci/genes. Five susceptibility loci were found to be also associated in the Croatian population with P-values between 2.1e-10 (rs995030; odds ratio [OR] 3.08) and 0.01739 (rs4635969; OR 1.37), which remained statistically significant after correction for multiple testing. Although rs2900333 near ATF7IP just showed borderline association with all-TGCT (OR 1.24, P = 0.062), it showed significant association with the more aggressive forms of the tumor (OR 1.51, P = 0.0067)-a clinically interesting finding, which however has to be replicated in an independent sample. Assessment of cumulative risks revealed that men with at least seven risk alleles have a more than 2.5-fold increased disease risk (OR = 2.73, 95% confidence interval = 1.98-3.79). In summary, we independently replicated the majority of TGCT susceptibility loci identified previously in a Croatian sample and suggested a possible role of genetic variation near ATF7IP in regulating disease progression. PMID:22745383

Lessel, Davor; Gamulin, Marija; Kulis, Tomislav; Toliat, Mohammad Reza; Grgic, Mislav; Friedrich, Katrin; Zunec, Renata; Balija, Melita; Nürnberg, Peter; Kastelan, Zeljko; Högel, Josef; Kubisch, Christian

2012-08-01

126

Genetics and Susceptibility to Toxic Chemicals: Do You (or Should You) Know Your Genetic Profile?  

Microsoft Academic Search

This review is based on a symposium\\/roundtable session, sponsored by the Division of Toxicology of the American Soci- ety for Pharmacology and Experimental Therapeutics, that was held at the 2002 Experimental Biology meeting in New Orleans, LA. The focus is on the role of pharmacogenomics in determin- ing individual susceptibility to chemically induced toxicity. An individual's risk of disease from

LAWRENCE H. LASH; RONALD N. HINES; FRANK J. GONZALEZ; TIMOTHY R. ZACHAREWSKI; MARK A. ROTHSTEIN

2003-01-01

127

Anopheles gambiae pathogen susceptibility: The intersection of genetics, immunity and ecology  

PubMed Central

Mosquitoes are the major arthropod vectors of human diseases such as malaria and viral encephalitis. However, each mosquito species does not transmit every pathogen, due to reasons that include specific evolutionary histories, mosquito immune system structure, and ecology. Even a competent vector species for a pathogen displays a wide range of variation between individuals for pathogen susceptibility, and therefore efficiency of disease transmission. Understanding the molecular and genetic mechanisms that determine heterogeneities in transmission efficiency within a vector species could help elaborate new vector control strategies. This review discusses mechanisms of host-defense in Anopheles gambiae, and sources of genetic and ecological variation in the operation of these protective factors. Comparison is made between functional studies using Plasmodium or fungus, and we call attention to the limitations of generalizing gene phenotypes from experiments done in a single genetically simple colony. PMID:22538050

Mitri, Christian; Vernick, Kenneth D.

2012-01-01

128

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

PubMed Central

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

2011-01-01

129

Causes and consequences of genetic background effects illuminated by integrative genomic analysis.  

PubMed

The phenotypic consequences of individual mutations are modulated by the wild-type genetic background in which they occur. Although such background dependence is widely observed, we do not know whether general patterns across species and traits exist or about the mechanisms underlying it. We also lack knowledge on how mutations interact with genetic background to influence gene expression and how this in turn mediates mutant phenotypes. Furthermore, how genetic background influences patterns of epistasis remains unclear. To investigate the genetic basis and genomic consequences of genetic background dependence of the scalloped(E3) allele on the Drosophila melanogaster wing, we generated multiple novel genome-level datasets from a mapping-by-introgression experiment and a tagged RNA gene expression dataset. In addition we used whole genome resequencing of the parental lines-two commonly used laboratory strains-to predict polymorphic transcription factor binding sites for SD. We integrated these data with previously published genomic datasets from expression microarrays and a modifier mutation screen. By searching for genes showing a congruent signal across multiple datasets, we were able to identify a robust set of candidate loci contributing to the background-dependent effects of mutations in sd. We also show that the majority of background-dependent modifiers previously reported are caused by higher-order epistasis, not quantitative noncomplementation. These findings provide a useful foundation for more detailed investigations of genetic background dependence in this system, and this approach is likely to prove useful in exploring the genetic basis of other traits as well. PMID:24504186

Chandler, Christopher H; Chari, Sudarshan; Tack, David; Dworkin, Ian

2014-04-01

130

Susceptibility Genetic  

Microsoft Academic Search

P R O J E C T O V E R V I E W Young children are thought to be more sensitive than adults to the toxic effects of certain pesticides (Eskenazi et al 1999, Faust- man et al 2000). Increasingly, research indicates that in young an- imals, lower metabolism is a major determinant of an increased sensitivity to

Lucio Costa; Clem Furlong; Toby Cole; Christina Pettan-Brewer; Rebecca Richter

131

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...

132

Genetic Background Affects Human Glial Fibrillary Acidic Protein Promoter Activity  

PubMed Central

The human glial fibrillary acidic protein (hGFAP) promoter has been used to generate numerous transgenic mouse lines, which has facilitated the analysis of astrocyte function in health and disease. Here, we evaluated the expression levels of various hGFAP transgenes at different ages in the two most commonly used inbred mouse strains, FVB/N (FVB) and C57BL/6N (B6N). In general, transgenic mice maintained on the B6N background displayed weaker transgene expression compared with transgenic FVB mice. Higher level of transgene expression in B6N mice could be regained by crossbreeding to FVB wild type mice. However, the endogenous murine GFAP expression was equivalent in both strains. In addition, we found that endogenous GFAP expression was increased in transgenic mice in comparison to wild type mice. The activities of the hGFAP transgenes were not age-dependently regulated. Our data highlight the importance of proper expression analysis when non-homologous recombination transgenesis is used. PMID:23826164

Bai, Xianshu; Saab, Aiman S.; Huang, Wenhui; Hoberg, Isolde K.; Kirchhoff, Frank; Scheller, Anja

2013-01-01

133

Salmonella penetration through eggshells of chickens of different genetic backgrounds.  

PubMed

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

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

2013-09-01

134

Genetics of canine diabetes mellitus: are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs?  

PubMed

Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population. PMID:23265864

Catchpole, Brian; Adams, Jamie P; Holder, Angela L; Short, Andrea D; Ollier, William E R; Kennedy, Lorna J

2013-02-01

135

THE MITOCHONDRIAL PARADIGM FOR CARDIOVASCULAR DISEASE SUSCEPTIBILITY AND CELLULAR FUNCTION: A COMPLEMENTARY CONCEPT TO MENDELIAN GENETICS  

PubMed Central

While there is general agreement that cardiovascular disease (CVD) development is influenced by a combination of genetic, environmental, and behavioral contributors, the actual mechanistic basis of how these factors initiate or promote CVD development in some individuals while others with identical risk profiles do not, is not clearly understood. This review considers the potential role for mitochondrial genetics and function in determining CVD susceptibility from the standpoint that the original features that molded cellular function were based upon mitochondrial-nuclear relationships established millions of years ago and were likely refined during prehistoric environmental selection events that today, are largely absent. Consequently, contemporary risk factors that influence our susceptibility to a variety of age-related diseases, including CVD were probably not part of the dynamics that defined the processes of mitochondrial – nuclear interaction, and thus, cell function. In this regard, the selective conditions that contributed to cellular functionality and evolution should be given more consideration when interpreting and designing experimental data and strategies. Finally, future studies that probe beyond epidemiologic associations are required. These studies will serve as the initial steps for addressing the provocative concept that contemporary human disease susceptibility is the result of selection events for mitochondrial function that increased chances for prehistoric human survival and reproductive success. PMID:21647091

Kryzwanski, David M.; Moellering, Douglas; Fetterman, Jessica L.; Dunham-Snary, Kimberly J.; Sammy, Melissa J.; Ballinger, Scott W.

2013-01-01

136

The mitochondrial paradigm for cardiovascular disease susceptibility and cellular function: a complementary concept to Mendelian genetics.  

PubMed

While there is general agreement that cardiovascular disease (CVD) development is influenced by a combination of genetic, environmental, and behavioral contributors, the actual mechanistic basis of how these factors initiate or promote CVD development in some individuals while others with identical risk profiles do not, is not clearly understood. This review considers the potential role for mitochondrial genetics and function in determining CVD susceptibility from the standpoint that the original features that molded cellular function were based upon mitochondrial-nuclear relationships established millions of years ago and were likely refined during prehistoric environmental selection events that today, are largely absent. Consequently, contemporary risk factors that influence our susceptibility to a variety of age-related diseases, including CVD were probably not part of the dynamics that defined the processes of mitochondrial-nuclear interaction, and thus, cell function. In this regard, the selective conditions that contributed to cellular functionality and evolution should be given more consideration when interpreting and designing experimental data and strategies. Finally, future studies that probe beyond epidemiologic associations are required. These studies will serve as the initial steps for addressing the provocative concept that contemporary human disease susceptibility is the result of selection events for mitochondrial function that increased chances for prehistoric human survival and reproductive success. PMID:21647091

Krzywanski, David M; Moellering, Douglas R; Fetterman, Jessica L; Dunham-Snary, Kimberly J; Sammy, Melissa J; Ballinger, Scott W

2011-08-01

137

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

PubMed Central

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

2013-01-01

138

Genetic markers of host resistance and/or susceptibility to the lethal effects of radiation and combined radiation-burn injuries. Technical report, 2 March 1984-31 October 1985  

SciTech Connect

The results suggest that strains of rats of differing genetic backgrounds differ widely in their susceptibility to the lethal effects of ionizing radiation. Just as has been observed in the same species with thermal injury, the capacity of rats to withstand the lethal effects of irradiation appear to be governed by genetic factors. The 8 inbred and 2 randomly bred strains of rats tested could be grouped (on the basis of LD50/30 determinations) into three categories, ranging from highly susceptible (ACI and BN) strains to 5 strains of intermediate susceptibility (W, OM, SD, LEW DA) and to 3 highly resistant, i.e., least susceptible strains (WF, F344, BUF). As observed earlier with thermal injury, females of the same strain were more susceptible to the lethal effects of radiation; this effect was particularly marked in pigmented strains. Two inbred pigmented strains bearing train hi/hi (homozygous recessive Irish gene for coat color) were the most susceptible to radiation vis-a-vis 7 other albino strains and one other pigmented strain (DA), which lacks the hi/hi gene. There may therefore be an association between skin pigmentation and/or coat color and the genetic determinants of susceptibility to the lethal effects of radiation. Comparison of the susceptibility of the same strains to the lethal effects of severe thermal injury provides no evidence of a parallel influence of skin pigmentation or coat color upon such susceptibility. While one pigmented strain (ACI) was most highly susceptible, the other pigmented strain (BN) was in the least susceptible category. The evidence also points to the probability that MHC factors are not involved in conditioning host susceptibility to severe radiation injury.

Rapaport, F.T.

1985-12-01

139

Effect of murine cytomegalovirus infection on mitogen responses in genetically resistant and susceptible mice.  

PubMed Central

Suppression of the blastogenic response of spleen cells was found during murine cytomegalovirus infection of the genetically susceptible BALB/c and also the more resistant BALB.K strains of mice. These results were observed for both the T-cell mitogen concanavalin A and the B-cell mitogen lipopolysaccharide. As the viral inoculum was increased, there was greater immunosuppression within each strain, the time of maximum depression coinciding with peak virus titers in the spleen. Although both strains developed similar splenic virus titers and exhibited a similar decrease in the proportion of splenic T-lymphocytes, there was greater suppression of the mitogenic response during sublethal infection of the more susceptible BALB/c strain. The suppression could not be readily accounted for by the presence of suppressor cells or by a change in sensitivity to mitogen. The results suggest that the extent of immunosuppression induced by murine cytomegalovirus is determined in part by host genotype. PMID:6281188

Allan, J E; Shellam, G R; Grundy, J E

1982-01-01

140

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

PubMed

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. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID:25347540

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

2014-12-01

141

A genetic model for evaluation of susceptibility to ozone-induced inflammation  

SciTech Connect

We examined ozone-induced airway inflammatory responses in inbred mice, and progeny of crosses between them, to investigate genetic susceptibility to ozone. Nine strains of male mice (18-23 g, 5-7 wk) were exposed for 3 h to 2 ppm ozone (O3) or filtered air (control), and pulmonary inflammation was assessed 2, 6, and 24 h after exposure by inflammatory cell counts and total protein content in bronchoalveolar lavage (BAL). The time course of the response to O3 was consistent between the strains. The maximum change in polymorphonuclear leukocytes (PMNs) was detected 6 h after O3, and the maximum increase in BAL protein occurred 24 h postexposure. Air controls exhibited no detectable changes in the parameters of inflammation at any time. The phenotypes of the C57BL/6J (B6, termed susceptible) and C3H/HeJ (C3, termed resistant) strains were easily distinguished by the magnitude of their inflammatory responses to O3. A 22-fold difference in PMNs was detected between the two strains 2 h after O3 (P less than 0.001), and a sixfold difference was found 6 h after O3 (P less than 0.001). Total BAL proteins were also significantly different between the B6 and C3 strains 6 h (P less than 0.01) and 24 h after O3 (P less than 0.001). To further evaluate the potential genetic contribution to the inflammatory response, the F1, F2, and backcross progeny from crosses between B6 and C3 strains were examined. The phenotypes of these progeny were consistent with the hypothesis that a single autosomal recessive gene at the Inf locus confers susceptibility to acute O3-induced influx of PMNs, but the genetic control of altered permeability is not clear.

Kleeberger, S.R.; Bassett, D.J.; Jakab, G.J.; Levitt, R.C. (Johns Hopkins Medical Institutions, Baltimore, MD (USA))

1990-06-01

142

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

PubMed

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

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; Lebrão, 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

143

Admixture mapping of end stage kidney disease genetic susceptibility using estimated mutual information ancestry informative markers  

Microsoft Academic Search

ABSTRACT: BACKGROUND: The question of a genetic contribution to the higher prevalence and incidence of end stage kidney disease (ESKD) among African Americans (AA) remained unresolved, until recent findings using admixture mapping pointed to the association of a genomic locus on chromosome 22 with this disease phenotype. In the current study we utilize this example to demonstrate the utility of

Liran I Shlush; Sivan Bercovici; Walter G Wasser; Guennady Yudkovsky; Alan Templeton; Dan Geiger; Karl Skorecki

2010-01-01

144

Susceptibility to ozone-induced inflammation. I. Genetic control of the response to subacute exposure  

SciTech Connect

We demonstrated previously that C57BL/6J (B6) inbred mice are susceptible and C3H/HeJ (C3) mice are resistant to airway inflammation that is induced by acute (3 h) exposure to 2 parts per million (ppm) ozone (O3). In the present study we tested the hypothesis that B6 and C3 mice are also differentially susceptible to the airway inflammatory responses to subacute (72 h) exposure to environmentally relevant concentrations of O3 (0.12 and 0.30 ppm). Male mice (20-25 g, 5-7 wk) were exposed continuously to 0.12 ppm O3, 0.30 ppm O3, or filtered air (control). Pulmonary inflammation was assessed after 24, 48, and 72 h by differential cell count and total protein in bronchoalveolar lavage (BAL) returns. Exposure to 0.12 ppm O3 caused significant influx of alveolar macrophages, polymorphonuclear leukocytes (PMNs), lymphocytes, and total BAL protein in both strains, but no differences in the magnitude of the responses were found between B6 and C3 mice. In contrast to the effect of 0.12 ppm O3, exposure to 0.30 ppm O3 elicited significantly greater numbers of inflammatory cells and BAL protein concentration in B6 mice relative to C3 mice. The phenotypes of the B6 and C3 mice were termed susceptible and resistant, respectively. To further evaluate the potential genetic contribution to the inflammatory response to 0.30 ppm O3, the F1, F2, and backcross progeny from B6 and C3 progenitors were examined. The ratios of susceptible and resistant phenotypes of these progeny support the hypothesis that a single autosomal recessive gene confers susceptibility to subacute O3-induced inflammation.

Kleeberger, S.R.; Levitt, R.C.; Zhang, L.Y. (Johns Hopkins Medical Institutions, Baltimore, MD (United States))

1993-01-01

145

Fine-Mapping and Phenotypic Analysis of the Ity3 Salmonella Susceptibility Locus Identify a Complex Genetic Structure  

PubMed Central

Experimental animal models of Salmonella infections have been widely used to identify genes important in the host immune response to infection. Using an F2 cross between the classical inbred strain C57BL/6J and the wild derived strain MOLF/Ei, we have previously identified Ity3 (Immunity to Typhimurium locus 3) as a locus contributing to the early susceptibility of MOLF/Ei mice to infection with Salmonella Typhimurium. We have also established a congenic strain (B6.MOLF-Ity/Ity3) with the MOLF/Ei Ity3 donor segment on a C57BL/6J background. The current study was designed to fine map and characterize functionally the Ity3 locus. We generated 12 recombinant sub-congenic strains that were characterized for susceptibility to infection, bacterial load in target organs, cytokine profile and anti-microbial mechanisms. These analyses showed that the impact of the Ity3 locus on survival and bacterial burden was stronger in male mice compared to female mice. Fine mapping of Ity3 indicated that two subloci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. The Ity3.1 sublocus controls NADPH oxidase activity and is characterized by decreased ROS production, reduced inflammatory cytokine response and increased bacterial burden, thereby supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying this sublocus. The Ity3.2 sub-locus is characterized by a hyperresponsive inflammatory cytokine phenotype after exposure to Salmonella. Overall, this research provides support to the combined action of hormonal influences and complex genetic factors within the Ity3 locus in the innate immune response to Salmonella infection in wild-derived MOLF/Ei mice. PMID:24505352

Khan, Rabia T.; Yuki, Kyoko E.; Malo, Danielle

2014-01-01

146

Genetic factors on mouse chromosome 18 affecting susceptibility to testicular germ cell tumors and permissiveness to embryonic stem cell derivation  

PubMed Central

Despite strong heritability, little is known about the genetic control of susceptibility to testicular germ cell tumors (TGCTs) in humans or mice. Although the mouse model of spontaneous TGCTs has been extensively studied, conventional linkage analysis has failed to locate the factors that control both teratocarcinogenesis in the susceptible 129 family of inbred strains. As an alternative approach, we used both chromosome substitution strains (CSSs) to identify individual chromosomes that harbor susceptibility genes, and a panel of congenic strains derived from a selected CSS to determine the number and location of susceptibility variants on the substituted chromosome. We showed that 129-Chr 18MOLF males are resistant to spontaneous TGCTs and that at least four genetic variants control susceptibility in males with this substituted chromosome. In addition, early embryonic cells from this strain fail to establish embryonic stem (ES) cell lines as efficiently as those from the parental 129/Sv strain. For the first time, 129-derived genetic variants that control TGCT susceptibility and fundamental aspects of ES cell biology have been localized in a genetic context where the genes can be identified and functionally characterized. PMID:19934337

Anderson, Philip D.; Nelson, Vicki R.; Tesar, Paul J.; Nadeau, Joseph H.

2009-01-01

147

Susceptibility of the QCD vacuum to CP-odd electromagnetic background fields.  

PubMed

We investigate two flavor quantum chromodynamics (QCD) in the presence of CP-odd electromagnetic background fields and determine, by means of lattice QCD simulations, the induced effective ? term to first order in E[over ?] · B[over ?]. We employ a rooted staggered discretization and study lattice spacings down to 0.1 fm and Goldstone pion masses around 480 MeV. In order to deal with a positive measure, we consider purely imaginary electric fields and real magnetic fields, and then exploit the analytic continuation. Our results are relevant to a description of the effective pseudoscalar quantum electrodynamics-QCD interactions. PMID:23473133

D'Elia, Massimo; Mariti, Marco; Negro, Francesco

2013-02-22

148

Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity.  

PubMed

By means of large twin cohorts, it has been possible to provide relatively valid and unbiased data regarding the influence of genetic and to some extent epigenetic factors in the aetiology of thyroid autoimmunity. The comparison of concordance rates between monozygotic and dizygotic twins provides irrefutable evidence of a genetic component in the aetiology of both Graves' disease and Hashimoto's thyroiditis, as well as for harbouring thyroid autoantibodies. Biometric modelling shows that approximately 75% of the total phenotypic variance in autoimmune thyroid disease is due to genetic effects. Despite the well known gender difference in the prevalence of autoimmune thyroid disease, the analyzes suggest that it is the same set of genes that operate in males and females. The lack of complete phenotypic concordance in monozygotic twin pairs indicates that also environmental and/or epigenetic factors are of importance. The impact of specific environmental and epigenetic exposures can be evaluated by investigating disease discordant twin pairs. Our studies show that skewed X chromosome inactivation is associated with clinically overt AITD but not with the presence of TPOAb in euthyroid individuals. It is now recognized that twin studies offer several features that uniquely enhance our ability to localize genes and understand their function. Future twin studies will incorporate information on genetic and epigenetic variation making it possible to quantify the precise effect of specific susceptibility genes and/or epigenetic variation on estimates of heritability. PMID:21511236

Brix, T H; Hegedüs, L

2011-04-01

149

Assessing the quality of studies supporting genetic susceptibility and outcomes of ARDS  

PubMed Central

The acute respiratory distress syndrome (ARDS) is a severe inflammatory disease manifested as a result of pulmonary and systemic responses to several insults. It is now well accepted that genetic variation influences these responses. However, little is known about the genes that are responsible for patient susceptibility and outcome of ARDS. Methodological flaws are still abundant among genetic association studies with ARDS and here, we aimed to highlight the quality criteria where the standards have not been reached, to expose the associated genes to facilitate replication attempts, and to provide quick-reference guidance for future studies. We conducted a PubMed search from January 2008 to September 2012 for original articles. Studies were considered if a statistically significant association was declared with either susceptibility or outcomes of all-cause ARDS. Fourteen criteria were used for evaluation and results were compared to those from a previous quality assessment report. Significant improvements affecting study design and statistical analysis were detected. However, major issues such as adjustments for the underlying population stratification and replication studies remain poorly addressed. PMID:24567738

Acosta-Herrera, Marialbert; Pino-Yanes, Maria; Perez-Mendez, Lina; Villar, Jesús; Flores, Carlos

2014-01-01

150

Genetic susceptibility to MS: a second stage analysis in Canadian MS families.  

PubMed

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis. PMID:11523565

Dyment, D A; Willer, C J; Scott, B; Armstrong, H; Ligers, A; Hillert, J; Paty, D W; Hashimoto, S; Devonshire, V; Hooge, J; Kastrukoff, L; Oger, J; Metz, L; Warren, S; Hader, W; Power, C; Auty, A; Nath, A; Nelson, R; Freedman, M; Brunet, D; Paulseth, J E; Rice, G; O'Connor, P; Duquette, P; Lapierre, Y; Francis, G; Bouchard, J P; Murray, T J; Bhan, V; Maxner, C; Pryse-Phillips, W; Stefanelli, M; Sadovnick, A D; Risch, N; Ebers, G C

2001-07-01

151

The Adjuvant Effect of Particles – Importance of Genetic Background and Pre-Sensitisation  

Microsoft Academic Search

Background: We have previously reported that simple and well-characterised particles, such as polystyrene particles (PSP), have an IgE adjuvant effect in mice. The purpose of this study was to explore the importance of genetic background concerning the adjuvant effect of PSP in different strains of mice. Methods: Inbred NIH\\/Ola, BALB\\/c and C3H\\/HeJ mice were given two intraperitoneal injections with either

Berit Granum; Per Ivar Gaarder; Åse Eikeset; Berit A. Stensby; Martinus Løvik

2000-01-01

152

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

PubMed Central

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

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

153

Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection.  

PubMed

Interindividual variability in susceptibility to HIV-1 infection, its transmission, disease progression, and response to antiviral therapy has been attributed to host determinants and variability in multiple genes. Although most people exposed to the virus go on to develop full-blown disease at variable intervals, a proportion of them, labeled as long-term nonprogressors or exposed uninfected, possess 'natural resistance' to infection. A better understanding of genetic and immunologic basis of such a natural resistance to infection would bear important implications in designing therapeutic vaccine designs. The genetic variants that could influence susceptibility to HIV-1 and limit AIDS vary in different populations and among individuals. Meta-analyses of large cohort studies have identified numerous 'AIDS restriction genes' that regulate HIV cell entry (particularly chemokine coreceptors and their ligands), acquired and innate immunity (major histocompatibility complex, killer cell immunoglobulin-like receptor, and cytokines), and others [tripartite interaction motif 5 alpha (TRIM5alpha) and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G] that influence outcome of HIV infection. Studies carried out in the Indian population with regard to genetic polymorphisms in chemokine receptors have shown that (i) the protective CCR5 Delta32 variant is rare, (ii) CCR5HHE carrying *59402A is associated with increased likelihood of infection and development of AIDS, and (iii) the Indian population generally has low CCL3L1 copy numbers (approximately 2.3). These data have implications in developing screening tests that could identify people at higher or lower risk of infection and rate of disease progression, predict vaccine responsiveness in clinical trials and understand the pathogenic mechanisms. PMID:19317737

Kaur, G; Mehra, N

2009-04-01

154

Testing hypotheses about the genetic background of individuals and populations using ancestry-informative markers  

Microsoft Academic Search

Testing hypotheses about the genetic background of individuals and populations is equivalent to comparing models of parental admixture. Formally, the strength of evi- dence favouring one model over another is given by the Bayes factor (ratio of marginal likelihoods). We have extended the ADMIXMAP program to calculate Bayes factors between dierent models of parental admixture, and demonstrate applications to in-

Paul M. McKeigue; David O'Donnell; Clive J. Hoggart; Ray Fysh; Gerome Breen; Camila Guindalini

155

Determination of the transmission frequency of chromosome 4S (l) of Aegilops sharonensis in a range of wheat genetic backgrounds.  

PubMed

The transmission of chromosome 4S (l) from Aegilops sharonensis was observed in a range of wheat genetic backgrounds. Chromosome 4S (l) was transmitted at a very high frequency (at least 97.8%) in all crosses. The genetic background appears to only have a small effect on transmission. The frequency of transmission of chromosome 4S (l) was the same in each genetic background through both the male and female gametes. PMID:24221318

King, I P; Miller, T E; Koebner, R M

1991-04-01

156

Genetic Variation between Biomphalaria alexandrina Snails Susceptible and Resistant to Schistosoma mansoni Infection  

PubMed Central

Much effort has been made to control schistosomiasis infection in Egypt. However, enduring effects from such strategies have not yet been achieved. In this study, we sought to determine the genetic variability related to the interaction between Biomphalaria alexandrina snails and Schistosoma mansoni. Using RAPD-PCR with eight (10?mers) random primers, we were able to determine the polymorphic markers that differed between snails susceptible and resistant to Schistosoma mansoni infection using five primers out of the eight. Our results suggest that the RAPD-PCR technique is an efficient means by which to compare genomes and to detect genetic variations between schistosomiasis intermediate hosts. The RAPD technique with the above-noted primers can identify genomic markers that are specifically related to the Biomphalaria alexandrina/Schistosoma mansoni relationship in the absence of specific nucleotide sequence information. This approach could be used in epidemiologic surveys to investigate genetic diversity among Biomphalaria alexandrina snails. The ability to determine resistant markers in Biomphalaria alexandrina snails could potentially lead to further studies that use refractory snails as agents to control the spread of schistosomiasis. PMID:23878796

El-Nassery, Suzanne M. F.; Abou-El-Naga, Iman F.; Allam, Sonia R.; Shaat, Eman A.; Mady, Rasha F. M.

2013-01-01

157

Genome-wide meta-analysis of genetic susceptible genes for Type 2 Diabetes  

PubMed Central

Background Many genetic studies, including single gene studies and Genome-wide association studies (GWAS), aim to identify risk alleles for genetic diseases such as Type II Diabetes (T2D). However, in T2D studies, there is a significant amount of the hereditary risk that cannot be simply explained by individual risk genes. There is a need for developing systems biology approaches to integrate comprehensive genetic information and provide new insight on T2D biology. Methods We performed comprehensive integrative analysis of Single Nucleotide Polymorphisms (SNP's) individually curated from T2D GWAS results and mapped them to T2D candidate risk genes. Using protein-protein interaction data, we constructed a T2D-specific molecular interaction network consisting of T2D genetic risk genes and their interacting gene partners. We then studied the relationship between these T2D genes and curated gene sets. Results We determined that T2D candidate risk genes are concentrated in certain parts of the genome, specifically in chromosome 20. Using the T2D genetic network, we identified highly-interconnected network "hub" genes. By incorporating T2D GWAS results, T2D pathways, and T2D genes' functional category information, we further ranked T2D risk genes, T2D-related pathways, and T2D-related functional categories. We found that highly-interconnected T2D disease network “hub” genes most highly associated to T2D genetic risks to be PI3KR1, ESR1, and ENPP1. The well-characterized TCF7L2, contractor to our expectation, was not among the highest-ranked T2D gene list. Many interacted pathways play a role in T2D genetic risks, which includes insulin signalling pathway, type II diabetes pathway, maturity onset diabetes of the young, adipocytokine signalling pathway, and pathways in cancer. We also observed significant crosstalk among T2D gene subnetworks which include insulin secretion, regulation of insulin secretion, response to peptide hormone stimulus, response to insulin stimulus, peptide secretion, glucose homeostasis, and hormone transport. Overview maps involving T2D genes, gene sets, pathways, and their interactions are all reported. Conclusions Large-scale systems biology meta-analyses of GWAS results can improve interpretations of genetic variations and genetic risk factors. T2D genetic risks can be attributable to the summative genetic effects of many genes involved in a broad range of signalling pathways and functional networks. The framework developed for T2D studies may serve as a guide for studying other complex diseases. PMID:23281828

2012-01-01

158

Role of Genetic Variants of Autophagy Genes in Susceptibility for Non-Medullary Thyroid Cancer and Patients Outcome  

PubMed Central

Autophagy is a central process in regulation of cell survival, cell death and proliferation and plays an important role in carcinogenesis, including thyroid carcinoma. Genetic variation in autophagy components has been demonstrated to influence the capacity to execute autophagy and is associated with disease susceptibility, progression and outcome. In the present study, we assessed whether genetic variation in autophagy genes contributes to susceptibility to develop thyroid carcinoma, disease progression and/or patient outcome. The results indicate that patients carrying the ATG5 single nucleotide polymorphisms rs2245214 have a higher probability to develop thyroid carcinoma (OR 1.85 (95% CI 1.04–3.23), P?=?0.042). In contrast, no significant differences could be observed for the other genetic variants studied in terms of thyroid carcinoma susceptibility. Furthermore, none of the selected genetic variants were associated with clinical parameters of disease progression and outcome. In conclusion, genetic variation in ATG5, a central player in the autophagy process, is found to be associated with increased susceptibility for thyroid carcinoma, indicating a role for autophagy in thyroid carcinogenesis. PMID:24739953

Plantinga, Theo S.; van de Vosse, Esther; Huijbers, Angelique; Netea, Mihai G.; Joosten, Leo A. B.; Smit, Jan W. A.; Netea-Maier, Romana T.

2014-01-01

159

Background  

E-print Network

Chronic Obstructive Pulmonary Disease (COPD) is a lung disease characterized by chronic inflammation of the airways. The primary risk factor for COPD is cigarette smoking; other risk factors include long-term exposure to environmental lung irritants and certain genetic conditions. 1 COPD is also found to be associated with significant comorbidities, including heart disease, kidney disease, asthma, and arthritis, as well as various types of cancer. 2 A large-scale study, using electronic primary care records of more than 1.2 million patients, found that COPD was associated with significantly higher odds of cardiovascular disease, stroke, and diabetes mellitus. 3 There is growing evidence to suggest that systemic inflammation is potentially a common pathway for multiple chronic conditions found among adults with COPD. 4 COPD can adversely affect one’s quality of life (QoL). Depression has often been associated with COPD. In an observational study of 35,722 patients with COPD, the incidence rate of new-onset diagnoses of depression was significantly higher in the COPD group, compared to the COPD-free group. 5 Sleeping difficulties and physical inactivity are also common among those with COPD. 6,7 The aim of this report is to enumerate the prevalence and risk of secondary chronic diseases, and poor quality of life, among North Carolina adults with COPD.

unknown authors

2011-01-01

160

The influence of genetic background versus commercial breeding programs on chicken immunocompetence.  

PubMed

Immunocompetence of livestock plays an important role in farm profitability because it directly affects health maintenance. Genetics significantly influences the immune system, and the genotypic structure of modern fast-growing chickens has been changed, particularly after decades of breeding for higher production. Therefore, this study was designed to help determine if intensive breeding programs have adversely affected immunocompetence or whether the immune response profiles are controlled to greater extent by genetic background. Thus, 3 indigenous chicken populations from different genetic backgrounds and 2 globally available modern broiler strains, Ross 308 and Cobb 500, were evaluated for various aspects of immune response. These included antibody responses against sheep red blood cells and Brucella abortus antigen, as well as some aspects of cell-mediated immunocompetence by toe web swelling test and in vitro blood mononuclear cell proliferation. Significant differences (P < 0.05) in antibody responses to both antigens and cellular proliferation were observed among populations but not consistently between modern commercial strains versus the indigenous populations. In fact, the immune response profiles of Cobb 500 were similar to the indigenous populations, but varied compared with the other commercial strain. In addition, considerable variation was recorded between indigenous populations for all responses measured in this study. The results of this study suggest that the variation observed in immune responses between these strains of chickens is most likely due to differences in the genetic background between each strain of chicken rather than by commercial selection programs for high production. PMID:24570426

Emam, Mehdi; Mehrabani-Yeganeh, Hassan; Barjesteh, Neda; Nikbakht, Gholamreza; Thompson-Crispi, Kathleen; Charkhkar, Saeid; Mallard, Bonnie

2014-01-01

161

Genetics of Transfusion Recipient Alloimmunization: Can Clues from Susceptibility to Autoimmunity Pave the Way?  

PubMed Central

Summary The search for genetic determinants of alloimmunization in sickle cell disease transfusion recipients was based on two premises: i) that polymorphisms responsible for stronger immune and/or inflammatory responses and hemoglobin ?S mutation were co-selected by malaria; and ii) that stronger responder status contributes to development of lupus. We found a marker of alloimmunization in the gene encoding for Ro52 protein, also known as Sjögren syndrome antigen 1 (SSA1) and TRIM21. Surprisingly, the nature of the association was opposite of that with lupus; the same variant of a polymorphism (rs660) that was associated with lupus incidence was also associated with induction of tolerance to red blood cell antigens during early childhood. The dual function of Ro52 can explain this apparent contradiction. We propose that other lupus/autoimmunity susceptibility loci may reveal roles of additional molecules in various aspects of alloimmunization induced by transfusion as well as during pregnancy.

Tatari-Calderone, Zohreh; Luban, Naomi L.C.; Vukmanovic, Stanislav

2014-01-01

162

Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.  

PubMed

A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of >/=1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs. PMID:12439739

Acuña, Gonzalo; Foernzler, Dorothee; Leong, Diane; Rabbia, Michael; Smit, Ralf; Dorflinger, Ernest; Gasser, Rodolfo; Hoh, Josephine; Ott, Jürg; Borroni, Edilio; To, Zung; Thompson, Annick; Li, Jia; Hashimoto, Lara; Lindpaintner, Klaus

2002-01-01

163

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

PubMed

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 have been widely reported, with females usually exhibiting a higher prevalence and severity of disease across all ages. The cause for this sex bias is currently uncertain, although it may be partly due to the differential effects of genetic factors between the sexes: gene-by-sex interactions. In this family based study (N = 2,663; 740 families; ages 1-93 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. © 2015 S. Karger AG, Basel. PMID:25612913

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

2015-01-01

164

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

PubMed Central

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

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

165

Better the Devil You Know? High-Risk Individuals’ Anticipated Psychological Responses to Genetic Testing for Melanoma Susceptibility  

Microsoft Academic Search

\\u000a Purpose: The psychological consequences of genetic testing for mutations among individuals at increased risk of developing melanoma remain unexamined. The present study aimed to explore anticipated emotional, behavioral, cognitive, and familial responses to hypothetical genetic testing for melanoma susceptibility. Methods: Forty semi-structured interviews were undertaken with affected (n=20) and unaffected (n=20) individuals at either high or average risk of developing

Nadine A. Kasparian; Bettina Meiser; Phyllis N. Butow; R. F. Soames Job; Graham J. Mann

2006-01-01

166

Association between the APC gene D1822V variant and the genetic susceptibility of colorectal cancer.  

PubMed

Adenomatous polyposis coli (APC) gene polymorphisms are believed to contribute to tumor susceptibility. However, the association between genetic variants (A/T) in the APC gene D1822V polymorphism and colorectal cancer (CRC) susceptibility remains unknown. To determine this association, a case-control study was performed. The genotype of the APC gene D1822V variants was analyzed by DNA sequencing in blood samples collected from 196 patients with CRC and 279 healthy subjects. There were no significant associations between the case and control groups in the distribution of AT [odds ratio (OR), 0.604; 95% confidence interval (CI), 0.355-1.029) and TT genotypes (OR, 0.438; 95% CI, 0.045-4.247) relative to the AA genotype. The ratio of the T allele was significantly lower (P=0.047) in the case group compared with the control group (OR, 0.611; 95% CI, 0.374-0.997), indicating that the T allele conferred a protective effect in CRC. The frequency of the AT genotype among the subjects diagnosed at >45 years of age was lower than those diagnosed at a younger age (P<0.05). The present study demonstrates that the T allele of the D1822V polymorphism may exert a protective effect against CRC, however, these findings require further validation in a larger sample size. PMID:24959234

Feng, Maohui; Fang, Xiping; Yang, Qian; Ouyang, Gang; Chen, Daping; Ma, Xiang; Li, Huachi; Xie, Wei

2014-07-01

167

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

PubMed Central

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

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

2013-01-01

168

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

PubMed Central

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

2013-01-01

169

Association of Eleven Common, Low-Penetrance Colorectal Cancer Susceptibility Genetic Variants at Six Risk Loci with Clinical Outcome  

PubMed Central

Background Low-penetrance genetic variants have been increasingly recognized to influence the risk of tumor development. Risk variants for colorectal cancer (CRC) have been mapped to chromosome positions 8q23.3, 8q24, 9p24.1, 10p14, 11q23, 14q22.2, 15q13, 16q22.1, 18q21, 19q13.1 and 20p12.3. In particular, the 8q24 single nucleotide polymorphism (SNP), rs6983267, has reproducibly been associated with the risk of developing CRC. As the CRC risk SNPs may also influence disease outcome, thus in this study, we evaluated whether they influence patient survival. Methodology/Principal Findings DNA samples from 583 CRC patients enrolled in the prospective, North Carolina Cancer Care Outcomes Research and Surveillance Consortium Study (NC CanCORS) were genotyped for 11 CRC susceptibility SNPs at 6 CRC risk loci. Relationships between genotypes and patient survival were examined using Cox regression analysis. In multivariate analysis, patients homozygous for the CRC risk allele of rs7013278 or rs7014346 (both at 8 q24) were only nominally significant for poorer overall survival compared to patients homozygous for the protective allele (hazard ratio?=?2.20 and 1.96, respectively; P<0.05). None of these associations, however, remained statistically significant after correction for multiple testing. The other nine susceptibility SNPs tested were not significantly associated with survival. Conclusions/Significance We did not find evidence of association of CRC risk variants with patient survival. PMID:22848671

Keku, Temitope O.; Galanko, Joseph A.; Martin, Christopher F.; Coleman, Clint A.; Wolfe, Michelle; Sandler, Robert S.; McLeod, Howard L.

2012-01-01

170

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

SciTech Connect

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.

Mortensen, Holly M., E-mail: mortensen.holly@epa.gov [Office of Research and Development, US Environmental Protection Agency, National Center for Computational Toxicology, US EPA, 109 TW Alexander Dr., Mailcode B205-01, Research Triangle Park, NC 27711 (United States); Euling, Susan Y. [Office of Research and Development, US Environmental Protection Agency, National Center for Environmental Assessment, US EPA, 1200 Pennsylvania Ave., NW, Mail Code 8623P, Washington, DC 20460 (United States)

2013-09-15

171

Role of a Genetic Variant on the 15q25.1 Lung Cancer Susceptibility Locus in Smoking-Associated Nasopharyngeal Carcinoma  

PubMed Central

Background The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC). Methods In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Results We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR?=?1.52; 95% CI, 1.16–2.00), especially among ever smokers (adjusted OR?=?2.07; 95% CI, 1.23–3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR?=?4.35; 95% CI, 2.57–7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P?=?0.011). Conclusions Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts. PMID:25329654

Ji, Xuemei; Zhang, Weidong; Gui, Jiang; Fan, Xia; Zhang, Weiwei; Li, Yafang; An, Guangyu; Zhu, Dakai; Hu, Qiang

2014-01-01

172

Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10  

Microsoft Academic Search

Hypertension is a significant risk factor for heart attack and stroke and represents a major public health burden because of its high prevalence (e.g. 15-20% of the European and American populations). Although blood pressure is known to have a strong genetic determi- nation, the genes responsible for susceptibility to essential hypertension are mostly unknown. Loci involved in blood pressure regulation

Cécile Julier; Marc Delépine; Bernard Keavney; Joseph Terwilliger; S. Davis; Thuan Bui; Xavier Jeunemaître; Gilberto Velho; Philippe Froguel; Peter Ratcliffe; Pierre Corvol; Florent Soubrier; G. Mark Lathrop

1997-01-01

173

Genetic polymorphisms of NQO1, CYP1A1 and TPMT and susceptibility to acute lymphoblastic leukemia  

E-print Network

Genetic polymorphisms of NQO1, CYP1A1 and TPMT and susceptibility to acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is the major pediatric cancer in developed countries. The etiology related to environmental exposures. Keywords Leukemia Á Tunisia Á TPMT Á NQO1 Á CYP1A1 Introduction Acute

Paris-Sud XI, Université de

174

THE IN VITRO SUSCEPTIBILITY OF MACROPHAGES TO PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME VIRUS VARIES BETWEEN GENETICALLY DIVERSE LINES OF PIGS  

Technology Transfer Automated Retrieval System (TEKTRAN)

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 thi...

175

Public interest in predictive genetic testing, including direct-to-consumer testing, for susceptibility to major depression: preliminary findings  

Microsoft Academic Search

The past decade has seen rapid advances in the identification of associations between candidate genes and a range of common multifactorial disorders. This paper evaluates public attitudes towards the complexity of genetic risk prediction in psychiatry involving susceptibility genes, uncertain penetrance and gene–environment interactions on which successful molecular-based mental health interventions will depend. A qualitative approach was taken to enable

Alex Wilde; Bettina Meiser; Philip B Mitchell; Peter R Schofield

2010-01-01

176

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...

177

Host genetic factors affect susceptibility to norovirus infections in Burkina Faso.  

PubMed

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 (Le(a-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

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

2013-01-01

178

Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-? immunity.  

PubMed

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-?-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-?. 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-?-dependent immunity. PMID:25453225

Bustamante, Jacinta; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent

2014-12-01

179

Genetic background of Prop1(df) mutants provides remarkable protection against hypothyroidism-induced hearing impairment.  

PubMed

Hypothyroidism is a cause of genetic and environmentally induced deafness. The sensitivity of cochlear development and function to thyroid hormone (TH) mandates understanding TH action in this sensory organ. Prop1(df) and Pou1f1(dw) mutant mice carry mutations in different pituitary transcription factors, each resulting in pituitary thyrotropin deficiency. Despite the same lack of detectable serum TH, these mutants have very different hearing abilities: Prop1(df) mutants are mildly affected, while Pou1f1(dw) mutants are completely deaf. Genetic studies show that this difference is attributable to the genetic backgrounds. Using embryo transfer, we discovered that factors intrinsic to the fetus are the major contributor to this difference, not maternal effects. We analyzed Prop1(df) mutants to identify processes in cochlear development that are disrupted in other hypothyroid animal models but protected in Prop1(df) mutants by the genetic background. The development of outer hair cell (OHC) function is delayed, but Prestin and KCNQ4 immunostaining appear normal in mature Prop1(df) mutants. The endocochlear potential and KCNJ10 immunostaining in the stria vascularis are indistinguishable from wild type, and no differences in neurofilament or synaptophysin staining are evident in Prop1(df) mutants. The synaptic vesicle protein otoferlin normally shifts expression from OHC to IHC as temporary afferent fibers beneath the OHC regress postnatally. Prop1(df) mutants exhibit persistent, abnormal expression of otoferlin in apical OHC, suggesting delayed maturation of synaptic function. Thus, the genetic background of Prop1(df) mutants is remarkably protective for most functions affected in other hypothyroid mice. The Prop1(df) mutant is an attractive model for identifying the genes that protect against deafness. PMID:22143287

Fang, Qing; Giordimaina, Alicia M; Dolan, David F; Camper, Sally A; Mustapha, Mirna

2012-04-01

180

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

PubMed Central

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

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

2009-01-01

181

Genetic susceptibility and loss of Nr4a1 enhances macrophage-mediated renal injury in CKD.  

PubMed

Nuclear hormone receptors of the NR4A subgroup have been implicated in cancer, atherosclerosis, and metabolic disease. However, little is known about the role of these receptors in kidney health or disease. Nr4a1-deficient rats (Nr4a1(-/-)) developed on a genetic background susceptible to kidney injury (fawn-hooded hypertensive rat [FHH]) were evaluated for BP, proteinuria, renal function, and metabolic parameters from 4 to 24 weeks-of-age. By week 24, Nr4a1(-/-) rats exhibited significantly higher proteinuria (approximately 4-fold) and decreased GFR compared with FHH controls. The severity of tubular atrophy, tubular casts, and interstitial fibrosis increased significantly in Nr4a1(-/-) rats and was accompanied by a large increase in immune cell infiltration, predominantly macrophages and to a lesser extent T cells and B cells. Global transcriptome and network analyses at weeks 8, 16, and 24 identified several proinflammatory genes and pathways differentially regulated between strains. Bone marrow crosstransplantation studies demonstrated that kidney injury in Nr4a1(-/-) rats was almost completely rescued by bone marrow transplanted from FHH controls. In vitro, macrophages isolated from Nr4a1(-/-) rats demonstrated increased immune activation compared with FHH-derived macrophages. In summary, the loss of Nr4a1 in immune cells appears to cause the increased kidney injury and reduced renal function observed in the Nr4a1(-/-) model. PMID:24722447

Westbrook, Lindsey; Johnson, Ashley C; Regner, Kevin R; Williams, Jan M; Mattson, David L; Kyle, Patrick B; Henegar, Jeffery R; Garrett, Michael R

2014-11-01

182

SELECTIVE NEUTRALITY OF GPGD ALLOZYMES IN E. COLZ AND THE EFFECTS OF GENETIC BACKGROUND  

Microsoft Academic Search

We have used gluconate-limited chemostats to study selective differences between isogenic strains of Escherichia coli RI2 into which four naturally occurring alleles coding for allozymes of 6-phosphogluconate dehydrogenase (6PGD) had been transferred. The limit of detectability of selection with our procedures is a selection coefficient of 0.5%. In the normal E. coli K12 genetic background, all alleles are selectively neutral

DANIEL DYKHUIZEN; DANIEL L. HARTL

1980-01-01

183

Genetic Susceptibility Factors on Genes Involved in the Steroid Hormone Biosynthesis Pathway and Progesterone Receptor for Gastric Cancer Risk  

PubMed Central

Background The objective of the study was to investigate the role of genes (HSD3B1, CYP17A1, CYP19A1, HSD17B2, HSD17B1) involved in the steroid hormone biosynthesis pathway and progesterone receptor (PGR) in the etiology of gastric cancer in a population-based two-phase genetic association study. Methods In the discovery phase, 108 candidate SNPs in the steroid hormone biosynthesis pathway related genes and PGR were analyzed in 76 gastric cancer cases and 322 controls in the Korean Multi-Center Cancer Cohort. Statistically significant SNPs identified in the discovery phase were re-evaluated in an extended set of 386 cases and 348 controls. Pooled- and meta-analyses were conducted to summarize the results. Results Of the 108 SNPs in steroid hormone biosynthesis pathway related genes and PGR analyzed in the discovery phase, 23 SNPs in PGR in the recessive model and 10 SNPs in CYP19A1 in the recessive or additive models were significantly associated with increased gastric cancer risk (p<0.05). The minor allele frequencies of the SNPs in both the discovery and extension phases were not statistically different. Pooled- and meta-analyses showed CYP19A1 rs1004982, rs16964228, and rs1902580 had an increased risk for gastric cancer (pooled OR [95% CI]?=?1.22 [1.01–1.48], 1.31 [1.03–1.66], 3.03 [1.12–8.18], respectively). In contrast, all PGR SNPs were not statistically significantly associated with gastric cancer risk. Conclusions Our findings suggest CYP19A1 that codes aromatase may play an important role in the association of gastric cancer risk and be a genetic marker for gastric cancer susceptibility. PMID:23110082

Cho, Lisa Y.; Yang, Jae Jeong; Ko, Kwang-Pil; Ma, Seung Hyun; Shin, Aesun; Choi, Bo Youl; Han, Dong Soo; Song, Kyu Sang; Kim, Yong Sung; Chang, Soung-Hoon; Shin, Hai-Rim; Kang, Daehee; Yoo, Keun-Young; Park, Sue K.

2012-01-01

184

Role of genetic heterogeneity and epistasis in bladder cancer susceptibility and outcome: a learning classifier system approach  

PubMed Central

Background and objective Detecting complex patterns of association between genetic or environmental risk factors and disease risk has become an important target for epidemiological research. In particular, strategies that provide multifactor interactions or heterogeneous patterns of association can offer new insights into association studies for which traditional analytic tools have had limited success. Materials and methods To concurrently examine these phenomena, previous work has successfully considered the application of learning classifier systems (LCSs), a flexible class of evolutionary algorithms that distributes learned associations over a population of rules. Subsequent work dealt with the inherent problems of knowledge discovery and interpretation within these algorithms, allowing for the characterization of heterogeneous patterns of association. Whereas these previous advancements were evaluated using complex simulation studies, this study applied these collective works to a ‘real-world’ genetic epidemiology study of bladder cancer susceptibility. Results and discussion We replicated the identification of previously characterized factors that modify bladder cancer risk—namely, single nucleotide polymorphisms from a DNA repair gene, and smoking. Furthermore, we identified potentially heterogeneous groups of subjects characterized by distinct patterns of association. Cox proportional hazard models comparing clinical outcome variables between the cases of the two largest groups yielded a significant, meaningful difference in survival time in years (survivorship). A marginally significant difference in recurrence time was also noted. These results support the hypothesis that an LCS approach can offer greater insight into complex patterns of association. Conclusions This methodology appears to be well suited to the dissection of disease heterogeneity, a key component in the advancement of personalized medicine. PMID:23444013

Urbanowicz, Ryan John; Andrew, Angeline S; Karagas, Margaret Rita; Moore, Jason H

2013-01-01

185

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

PubMed Central

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

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

2003-01-01

186

Genetic analysis with calcium-induced calcium release test in Japanese malignant hyperthermia susceptible (MHS) families.  

PubMed

Some genetic studies have shown a linkage between malignant hyperthermia susceptibility (MHS) and chromosome 19q or the skeletal muscle ryanodine receptor (RYR1) gene. Some types of MHS seem to be caused by an abnormality of calcium-induced calcium release (CICR). We analyzed the linkage of RYR1 gene polymorphisms in Japanese MHS families and investigated the correlation between genetic evidence of RYR1 gene mutations and an accelerated rate of CICR. We studied 63 subjects who were referred to our institute for investigation of MHS. CICR rates were measured by the skinned fiber method in 23 subjects. DNA samples were collected from 63 individuals belonging to 22 unrelated families. Restriction fragment length polymorphism (RFLP) analyses on the RYR1 locus and hypervariable microsatellite analysis were performed. We found one family with a linkage between acceleration of the CICR mechanism and a group of RFLPs. In CICR tests, ten of the 11 patients who had presented with fulminant MH showed accelerated rates of CICR. Analysis for the mutation C1840T, which was performed in 63 samples, did not demonstrate an alteration in any of the patients. Although we found heterozygotes in RFLP studies, we did not recognize a specific relationship between the acceleration of CICR and the RFLPs. We suggest a linkage between the acceleration of CICR and an abnormal human RYR1 gene in MHS. These results also suggest that heterogeneity exists for MH. We conclude that genetic tests cannot replace CICR tests or caffeine-halothane contracture tests with muscle biopsy as a diagnosing test for MH in the near future. PMID:10213958

Maehara, Y; Mukaida, K; Hiyama, E; Morio, M; Kawamoto, M; Yuge, O

1999-03-01

187

Longevity effect of IGF-1R+/? mutation depends on genetic background-specific receptor activation  

PubMed Central

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

Xu, Jie; Gontier, Géraldine; Chaker, Zayna; Lacube, Philippe; Dupont, Joëlle; Holzenberger, Martin

2014-01-01

188

HLA-DRB1*13:01 allele in the genetic susceptibility to colorectal carcinoma.  

PubMed

Increasing evidence suggests that HLA-DRB1 alleles reduce or increase the risk of developing ulcerative colitis-associated colorectal carcinoma (CRC) tumors. However, the role of HLA-DRB1 locus on the susceptibility to develop CRC tumor, in the absence of a history of inflammatory bowel diseases (IBDs), is unclear. The aim of our study was to determine whether HLA-DRB1 alleles are associated with IBD-independent CRC tumor. HLA-DRB1 allele polymorphisms were identified by sequence-based typing method in 53 CRC patients and 57 sex- and age-matched healthy Caucasian controls. Pearson's chi-squared analysis with Yate's correction or Fisher's exact test with Bonferroni's correction, as appropriate, were used to compare the allele frequency (AF) differences of HLA-DRB1 in patients and controls. A total of 29 HLA-DRB1 alleles were recognized. A detailed study of these alleles allowed to identify DRB1*13:01 and DRB1*11:01 alleles that were significantly associated with an increased and reduced risk to develop CRC tumor, respectively. AF of DRB1*13:01, in CRC patients, was significantly higher than that of healthy controls, even following Bonferroni's correction (p?=?0.029). In contrast, the presence of the DRB1*11:01 allele was negatively associated with CRC tumor as evidenced by the significantly lower AF in CRC patients than that of healthy controls (p?=?0.005). However, following Bonferroni's correction, the AF of DRB*11:01 lost its statistical significance. These results suggest that HLA-DRB1*13:01 allele could be a potential marker for predicting genetic susceptibility to CRC tumor. In contrast, the protective role of DRB1*11:01 remains unclear. PMID:25346274

Aureli, Anna; Canossi, Angelica; Del Beato, Tiziana; Franceschilli, Luana; Buonomo, Oreste; Papola, Franco; De Sanctis, Flavio; Lanzilli, Giulia; Sileri, Pierpaolo; Coppola, Andrea; Caratelli, Sara; Arriga, Roberto; Orlandi, Augusto; Lauro, Davide; Rossi, Piero; Sconocchia, Giuseppe

2014-10-23

189

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

PubMed Central

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

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

1999-01-01

190

MicroRNAs related polymorphisms and genetic susceptibility to esophageal squamous cell carcinoma.  

PubMed

Esophageal cancer (EC) is the sixth leading cause of cancer-associated death worldwide and the incidence and mortality in China are the highest. The single nucleotide polymorphisms (SNPs) related to microRNAs could lead to alteration in microRNA expression and contribute to the susceptibility of cancer. To evaluate the association between microRNA-related SNPs and EC, a case-control study including 381 patients with esophageal squamous cell carcinoma (ESCC) and 426 gender, age-matched controls was carried out to investigate the genetic susceptibility of five microRNA-related SNPs (rs2910164 in microRNA-146a, rs11614913 in microRNA-196a-2, rs7813 in GEMIN4, rs1595066 and rs16845990 in ErbB4) as well as the interactions of gene-gene and gene-environment in the development of ESCC. Variant homozygote genotype of rs11614913 in microRNA-196a-2 and rs1595066 in ErbB4 were significantly associated with reduced ESCC risk (OR(adjusted): 0.62, 95 % CI: 0.39-0.99 and OR(adjusted): 0.38, 95 % CI: 0.24-0.61). The analysis of haplotypes in ErbB4 gene showed significant increased ESCC risk in G(rs1595066)C(rs16845990) and G(rs1595066)T(rs16845990) haplotypes (OR(adjusted): 1.46, 95 % CI: 1.08-1.99 and OR(adjusted): 1.33, 95 % CI: 1.10-1.62), and inversely reduced ESCC risk in A(rs1595066)C(rs16845990) and A(rs1595066)T(rs16845990) haplotypes with OR (95 % CI) of 0.75 (0.60-0.94) and 0.65 (0.49-0.86), respectively. These findings suggest that the polymorphisms in the microRNA-related genes may affect susceptibility of ESCC in Chinese Han population and the gene-gene interactions play vital roles in the progression on esophageal cancer. Future studies with larger sample and different ethnic populations are required to support and validate our findings. PMID:24916311

Qu, Yanhong; Qu, Honghong; Luo, Manli; Wang, Peng; Song, Chunhua; Wang, Kaijuan; Zhang, Jianying; Dai, Liping

2014-12-01

191

Genetic susceptibility to type 2 diabetes: a global meta-analysis studying the genetic differences in Tunisian populations.  

PubMed

The present study is the first meta-analysis to evaluate type 2 diabetes (T2D)- associated polymorphisms in cohorts originated from several Tunisian regions. In fact, we evaluated the effect of seven polymorphisms in the following genes-PPARg (Pro12Ala), TNF? (-308A/G), ENPP1(K121Q), TCF7L2(rs7903146°C/T), MTHFR(C677T), ACE(I/D), and CAPN10(3R/2R)-on T2D risk, through a meta-analysis combining data of previous studies performed on Tunisian populations originating from the north, center, or south of the country. R statistics version 2.12.1 software was used to estimate the heterogeneity between studies. Pooled odds ratios were computed by the fixed-effects method of Mantel-Haenszel if no heterogeneity between studies exists. Despite the similarities founded in a number of loci, the Woolf test reported that the contributions of ENPP1 and ACE loci in T2D risk are dependent on the geographic origin of concerned groups, and this heterogeneity could be attributed not only to the variable contribution of the variant in T2D risk but also to diversities of genetic background between tested groups. Interestingly, observed heterogeneity highlighted founding concerning Y chromosome and the mitochondrial DNA about the genetic structure of Tunisian population and proves once again that Tunisians, like the north-Africans, are a mosaic of subpopulations, with significant differences in genetic structure. In homogeneous groups, we replicated the association of single-nucleotide polymorphisms of TCF7L2, MTHFR, CAPN 10, TNF?, and ACE genes with a T2D risk in the Tunisian population with OR ranging from 1.43 to 6.72. However, we reported an absence of the association of PPARg with T2D in the Tunisian population. PMID:23249316

Berhouma, Rym; Kouidhi, Soumaya; Ammar, Mariem; Abid, Hafawa; Baroudi, Thouraya; Ennafaa, Hajer; Benammar-Elgaaied, Amel

2012-08-01

192

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

PubMed Central

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 ?1 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 ?1 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

2013-01-01

193

Genetically determined inflammatory-response related cytokine and chemokine transcript profiles between mammary carcinoma resistant and susceptible rat strains.  

PubMed

Multiple human breast and rat mammary carcinoma susceptibility (Mcs) alleles have been identified. Wistar Kyoto (WKY) rats are resistant to developing mammary carcinomas, while Wistar Furth (WF) females are susceptible. Gene transcripts at Mcs5a1, Mcs5a2, and Mcs5c are differentially expressed between resistant WKY and susceptible WF alleles in immune-system tissues. We hypothesized that immune-related gene transcript profiles are genetically determined in mammary carcinoma resistant and susceptible mammary glands. Low-density QPCR arrays were used to compare inflammation related genes between mammary carcinoma resistant WKY and susceptible WF females. Mammary gland gene transcript levels predicted to be different based on arrays were tested in independent samples. In total, 20 females per strain were exposed to 7,12-dimethylbenz(a)anthracene (DMBA) to induce mammary carcinogenesis. Twelve age-matched controls per strain without DMBA were included to determine main effects of DMBA-exposure. Significant (ANOVA P ? 0.01) effects of strain on mammary gland transcript level were observed for Cx3cl1, Il11ra, Il4, C3, Ccl20, Ccl11, Itgb2, Cxcl12, and Cxcr7. Significant effects of DMBA-exposure were observed for Cx3cl1, Il11ra, Cxcr4, Il4ra, and Il4. Strain and DMBA-exposure interaction effects were significant for Cx3cl1. Transcript levels of Cxcr7 relative to Cxcr4 were modified differently by DMBA in mammary carcinoma resistant and susceptible strains. In conclusion, several genetically-determined differences in cytokine, chemokine, and receptor gene transcript levels were identified between mammary carcinoma susceptible and resistant mammary glands, which may be indicative of cell populations and activities that suppress mammary carcinogenesis in resistant genotypes. PMID:22609213

Devapatla, Bharat; Sanders, Jennifer; Samuelson, David J

2012-08-01

194

Genetic relatedness between methicillin-susceptible and methicillin-resistant Staphylococcus aureus: results of a national survey  

Microsoft Academic Search

Methods: We determined by PFGE, spa typing, multi-locus sequence typing (MLST) and agr group analysis the genetic relatedness of 103 MSSA and 511 MRSA strains from a national survey of patients admitted to 112 Belgian hospitals in 2003. Results: The 103 MSSA strains presented very diverse genetic backgrounds, they were distributed into 40 distinct PFGE types and clustered in 15

M. Hallin; O. Denis; A. Deplano; R. De Mendonca; R. De Ryck; S. Rottiers; M. J. Struelens

2007-01-01

195

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

PubMed Central

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

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

196

Genetics and Biomarkers of Moyamoya Disease: Significance of RNF213 as a Susceptibility Gene  

PubMed Central

Moyamoya disease is characterized by a progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is still unknown, recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene of moyamoya disease among East Asian population. A polymorphism in c.14576G>A in RNF213 was identified in 95% of familial patients with moyamoya disease and 79% of sporadic cases, and patients having this polymorphism were found to have significantly earlier disease onset and a more severe form of moyamoya disease, such as the presentation of cerebral infarction and posterior cerebral artery stenosis. The exact mechanism by which the RNF213 abnormality relates to moyamoya disease remains unknown, while recent reports using genetically engineered mice lacking RNF213 by homologous recombination provide new insight for the pathogenesis of this rare entity. Regarding biomarkers of moyamoya disease, moyamoya disease is characterized by an increased expression of angiogenic factors and pro-inflammatory molecules such as vascular endothelial growth factors and matrix metalloproteinase-9, which may partly explain its clinical manifestations of the pathologic angiogenesis, spontaneous hemorrhage, and higher incidence of cerebral hyperperfusion after revascularization surgery. More recently, blockade of these pro-inflammatory molecules during perioperative period is attempted to reduce the potential risk of surgical complication including cerebral hyperperfusion syndrome. In this review article, we focus on the genetics and biomarkers of moyamoya disease, and sought to discuss their clinical implication. PMID:24949311

Sonobe, Shinya; Nishijima, Yasuo; Niizuma, Kuniyasu; Sakata, Hiroyuki; Kure, Shigeo; Tominaga, Teiji

2014-01-01

197

Mouse genetic background is associated with variation in secondary complications after subarachnoid hemorrhage.  

PubMed

Spontaneous subarachnoid hemorrhage (SAH) is a form of hemorrhagic stroke that accounts for approximately 7 % of all strokes worldwide and is associated with mortality in approximately 35 % of cases and morbidity in many of the survivors. Studies have suggested that genetic variations may affect the pathophysiology of SAH. The goal of this study was to investigate the effect of mouse genetic background on brain injury and large artery vasospasm after SAH. SAH was induced in seven inbred strains of mice, and the degree of large artery vasospasm and brain injury was assessed. After 48 h, SAH mice showed a significant reduction in middle cerebral artery diameter and increased neuronal injury in the cerebral cortex compared with sham-operated controls. Mouse strains also demonstrated variable degrees of vasospasm and brain injury. This data suggests that different genetic factors influence how much brain injury and vasospasm occur after SAH. Future investigations may provide insight into the causes of these differences between strains and into which genetic contributors may be responsible for vasospasm and brain injury after SAH. PMID:25366595

D'Abbondanza, Josephine A; Lass, Elliot; Ai, Jinglu; Macdonald, R Loch

2015-01-01

198

Molecular characterization, genetic diversity and antibacterial susceptibility of Escherichia coli encoding Shiga toxin 2f in domestic pigeons.  

PubMed

This study aimed to evaluate prevalence, characteristics, genotypic diversity and antibacterial susceptibility of Escherichia coli encoding Shiga toxin 2f in domestic pigeons in different provinces of Iran. A total of 117 faecal samples were collected from pigeons and were subjected to molecular detection of stx2f. In total, 20, 25·8, 21·4 and 9% of pigeons from Tehran, Ferdows, Garmsar and Babol cities carried stx2f+ isolates, respectively. Of the 460 E. coli isolates examined, 43 were stx2f+ and most also carried eae (95·3%) and astA (97·7%) genes. Some of the stx2f+ isolates harboured cnf (9·3%), but all were negative for stx1, stx2 (other subtypes) and ehly. Most Strains (90%) were assigned to B1 phylogroup and possessed Intimin-?. Fingerprinting of the stx2f+ isolates using either enterobacterial repetitive intergenic consensus sequences (ERIC) or random amplified polymorphic DNA (RAPD)-polymerase chain reaction revealed seven distinct profiles by each method, with one prevailing (65·1 and 46·5%, respectively). By the combination of methods, 10 profiles were recognized. Ten isolates from different profiles were shown to belong to O20, O78 and O115 serogroups, and eight were 100% identical in the stx2f gene sequence. The strains were consistently resistant to amoxicillin and lincospectin and commonly resistant to tetracycline (88·4%) and doxycycline (74·4%). Overall, the results indicate a limited degree of genetic diversity in stx2f-harbouring E. coli from pigeons. Significance and impact of the study: Carriage of stx2f gene tends to be underreported in pigeon Escherichia coli isolates because most routine genetic and phenotypic tests cannot efficiently target this gene or detect the toxin. Nevertheless, pigeons frequently carry E. coli strains that are stx2f-positive, and this situation is not limited to any distinct geographical area. The current results suggest that genetic background of stx2f-encoding E. coli is distinct from most Shiga toxin-producing E. coli strains. However, the factors that contribute to host preferences and pathogenicity remain unclear. These findings have public health significance that should be addressed in future research. PMID:24863542

Askari Badouei, M; Zahraei Salehi, T; Koochakzadeh, A; Kalantari, A; Tabatabaei, S

2014-10-01

199

The genetic background effect on domesticated species: a mouse evolutionary perspective.  

PubMed

Laboratory mouse strains are known for their large phenotypic diversity and serve as a primary mammalian model in genotype-phenotype association studies. One possible attempt to understand the reason for this diversity could be addressed by careful investigation of the unique evolutionary history of their wild-derived founders and the consequence that it may have on the genetic makeup of the laboratory mouse strains during the history of human fancy breeding. This review will summarize recently published literature that endeavors to unravel the genetic background of laboratory mouse strains, as well as give new insights into novel evolutionary approaches. I will explain basic concepts of molecular evolution and the reason why it is important in order to infer function even among closely related wild and domesticated species. I will also discuss future frontiers in the field and how newly emerging sequencing technologies could help us to better understand the relationship between genotype and phenotype. PMID:21336458

Reuveni, Eli

2011-01-01

200

Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.  

PubMed

Fanconi anemia is an inherited disease characterized by bone marrow failure, congenital malformations, and predisposition to cancer. The breast cancer susceptibility gene BRCA2 was recently found to be associated with Fanconi anemia complementation group D1 (FA-D1). We examined four kindreds afflicted with Fanconi anemia for the presence of germline BRCA2 mutations. One kindred, of Ashkenazi Jewish ancestry, had five members who were diagnosed with breast cancer and two cousins who were BRCA2*6174delT/C3069X compound heterozygotes and had Fanconi anemia and brain tumors. In another kindred of Ashkenazi Jewish and Lithuanian Catholic ancestry, a child with Fanconi anemia and a medulloblastoma was a BRCA2*6174delT/886delGT compound heterozygote. Two other kindreds each contained a Fanconi anemia-afflicted child who developed medulloblastoma; one child was of Latin American ancestry and a compound heterozygote for BRCA2*I2490T/ 5301insA and the other was African American and a compound heterozygote for BRCA2*Q3066X/E1308X. Median age of the Fanconi anemia-afflicted children at brain tumor diagnosis was 3.5 years. The co-occurrence of brain tumors, Fanconi anemia, and breast cancer observed in one of these kindreds constitutes a new syndromic association. Individuals who carry a germline BRCA2 mutation and who plan to have children with a partner of Ashkenazi Jewish descent should consider undergoing genetic counseling. PMID:14559878

Offit, Kenneth; Levran, Orna; Mullaney, Brian; Mah, Katherine; Nafa, Khedoudja; Batish, Sat Dev; Diotti, Raffaella; Schneider, Hildegard; Deffenbaugh, Amie; Scholl, Thomas; Proud, Virginia K; Robson, Mark; Norton, Larry; Ellis, Nathan; Hanenberg, Helmut; Auerbach, Arleen D

2003-10-15

201

Genetic variants of GRIA1 are associated with susceptibility to schizophrenia in Korean population.  

PubMed

The ?-amino-3-hydroxy-5-methyl-4-propionic acid (AMPA) receptors are important for glutamate synaptic transmission in the central nervous system. Glutamate receptor, ionotropic, AMPA receptor 1 gene (GRIA1) belongs to the family of AMPA receptors. There is increasing evidence that AMPA receptors dysfunction may be related to an increased susceptibility to schizophrenia. The aim of this study was therefore to investigate whether genetic polymorphisms of GRIA1 are associated with schizophrenia and their clinical symptoms (hallucinations and delusions) in Korean population. Five single nucleotide polymorphisms (rs1428920, rs1552834, rs1422889, rs10035143, and rs2926835) of the GRIA1 were genotyped in 218 schizophrenia patients and 380 healthy controls, using a direct sequencing. All patients were evaluated by the Operational Criteria Checklist for Psychotic Illness. The genotype and allelic frequencies of rs1428920 and rs2926835 showed significant association between schizophrenia and controls (rs1428920, permutation p = 0.008, 0.008; rs2926835, permutation p = 0.038, 0.041, respectively). A significantly increased risk of schizophrenia was associated with the A allele of rs1428920 and rs2926835 of GRIA1. Furthermore, we found that rs1428920 was weakly associated with hallucinations of schizophrenia, but this significance disappeared after multiple testing (permutation p = 0.119). These results suggest that GRIA1 polymorphism may have influence upon the risk of developing schizophrenia. PMID:23053966

Kang, Won Sub; Park, Jin Kyung; Kim, Su Kang; Park, Hae Jeong; Lee, Sang Min; Song, Ji Young; Chung, Joo-Ho; Kim, Jong Woo

2012-12-01

202

A systematic mammalian genetic interaction map reveals pathways underlying ricin susceptibility.  

PubMed

Genetic interaction (GI) maps, comprising pairwise measures of how strongly the function of one gene depends on the presence of a second, have enabled the systematic exploration of gene function in microorganisms. Here, we present a two-stage strategy to construct high-density GI maps in mammalian cells. First, we use ultracomplex pooled shRNA libraries (25 shRNAs/gene) to identify high-confidence hit genes for a given phenotype and effective shRNAs. We then construct double-shRNA libraries from these to systematically measure GIs between hits. A GI map focused on ricin susceptibility broadly recapitulates known pathways and provides many unexpected insights. These include a noncanonical role for COPI, a previously uncharacterized protein complex affecting toxin clearance, a specialized role for the ribosomal protein RPS25, and functionally distinct mammalian TRAPP complexes. The ability to rapidly generate mammalian GI maps provides a potentially transformative tool for defining gene function and designing combination therapies based on synergistic pairs. PMID:23394947

Bassik, Michael C; Kampmann, Martin; Lebbink, Robert Jan; Wang, Shuyi; Hein, Marco Y; Poser, Ina; Weibezahn, Jimena; Horlbeck, Max A; Chen, Siyuan; Mann, Matthias; Hyman, Anthony A; Leproust, Emily M; McManus, Michael T; Weissman, Jonathan S

2013-02-14

203

Mechanisms of genetic resistance to Friend virus leukemia. III. Susceptibility of mitogen-responsive lymphocytes mediated by T cells.  

PubMed

Friend leukemia virus (FV) suppressed the proliferative responses of spleen, lymph node, marrow, and thymus cell populations to various T- and B-cell mitogens. Cells taken from mice, e.g. BALB/c genetically susceptible to leukemogenesis in vivo were much more susceptible to suppression of mitogenesis in vitro than similar cells from genetically resistant mice, e.g., C57BL/6. Nylon wool-purified splenic T cells from BALB/c and C3H mice lost susceptibility to FV-induced suppression of mitogenesis but became suppressible by addition of 10% unfiltered spleen cell. Thus, FV mediates in vitro suppression of lymphocyte proliferation indirectly by "activating" a suppressor cell. The suppressor cell adhered to nylon wool but not to glass wool or rayon wool columns. Pretreatment of spleen cells with carbonyl iron and a magnet did not abrogate the suppressor cell function. Suppressor cells were not eliminated by treatment with rabbit antimouse immunoglobulin (7S) and complement (C). However, high concentrations of anti-Thy-1 plus C destroyed suppressor cells of the spleen; thymic suppressor cells were much more susceptible to anti-Thy-1 serum. Nude athymic mice were devoid of suppressor cells and their B-cell proliferation was relatively resistant to FV-induced suppression in vitro. The suppressor cells in the thymus (but not in the spleen) were eliminated by treatment of mice with cortisol. Thus, FV appears to mediate its suppressive effect on mitogen-responsive lymphocytes by affecting "T-suppressor cells." Spleen cells from C57BL/6 mice treated with 89Sr to destroy marrow-dependent (M) cells were much more suppressible by FV in virto than normal C57BL/6 spleen cells. However, nylon-filtered spleen cells of 89Sr-treated C57BL/6 mice were resistant to FV-induced suppression in vitro, indicating that the susceptibility of spleen cells from 89Sr-treated B6 mice is also mediated by suppressor cells. Normal B6 splenic T cells were rendered susceptible to FV-induced suppression of mitogenesis by addition of 10% spleen cells from 89Sr-treated B6 mice. Thus, M cells appear to regulate the numbers and/or functions of T-suppressor cells which in turn mediate the immunosuppressive effects of FV in vitro. Neither mitogen-responsive lymphocytes nor T-suppressor cells are genetically resistant or susceptible to FV. The genetic resistance to FV is apparently a function of M cells, both in vitro as well as in vivo. PMID:1082914

Kumar, V; Caruso, T; Bennett, M

1976-04-01

204

Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region  

Microsoft Academic Search

OBJECTIVES--To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes. DESIGN--Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically.

E Tuomilehto-Wolf; J Tuomilehto; G A Hitman; A Nissinen; J Stengård; J Pekkanen; P Kivinen; E Kaarsalo; M J Karvonen

1993-01-01

205

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

PubMed Central

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

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

2001-01-01

206

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

PubMed Central

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

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

207

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

SciTech Connect

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.

Chung, W.K.; Zheng, M.; Chua, M. [Rockefeller Univ., New York, NY (United States)] [and others] [Rockefeller Univ., New York, NY (United States); and others

1997-05-01

208

Genetic backgrounds of the Plasmodium falciparum chloroquine resistant transporter (pfcrt) alleles in Pakistan.  

PubMed

Chloroquine (CQ) resistance in Plasmodium falciparum has been associated with point mutations in the P. falciparum CQ resistance transporter gene (pfcrt). Previous studies have shown 4-5 independent origins for CQ resistant pfcrt alleles globally, two in South America, one each in Southeast Asia, Papua New Guinea (PNG) and Philippines. In Asia, at least two different alleles corresponding to amino acids 72-76 (CVIET and SVMNT) have been found. The CVIET allele originated in Southeast Asia and then spread to Asia and Africa as well. The SVMNT allele, originating from PNG, has been found in India. This study was undertaken to investigate the genetic background of the CQ resistant pfcrt haplotypes in Pakistan. We genotyped microsatellite markers surrounding the pfcrt gene (six different markers at -12.3, -4.8, -1, 1.5, 3.9, 18.8 kb) in 114 clinical isolates of P. falciparum collected from different regions in Pakistan. Microsatellite analysis showed a significant reduction in genetic variation among the mutant SVMNT pfcrt alleles when compared to wild type alleles. The predominant SVMNT haplotype found in this study shared the same microsatellite haplotype found in both PNG and India. Two isolates with CVIET haplotypes showed similar microsatellite background to those found in Africa and Asia. In conclusion, this study suggests that CQ resistant SVMNT haplotypes in India and Pakistan have a common ancestral origin similar to that of Papua New Guinean isolates. PMID:22138496

Rawasia, Wasiq Faraz; Sridaran, Sankar; Patel, Jaymin C; Abdallah, Joseph; Ghanchi, Najia Karim; Barnwell, John W; Escalante, Ananias A; Udhayakumar, Venkatachalam; Beg, Mohammad Asim

2012-03-01

209

Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis.  

PubMed

Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility. PMID:24130809

Sisay, Sofia; Pryce, Gareth; Jackson, Samuel J; Tanner, Carolyn; Ross, Ruth A; Michael, Gregory J; Selwood, David L; Giovannoni, Gavin; Baker, David

2013-01-01

210

Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice.  

PubMed

Consumer use of herbal and dietary supplements has recently grown in the United States and, with increased use, reports of rare adverse reactions have emerged. One such supplement is green tea extract, containing the polyphenol epigallocatechin gallate (EGCG), which has been shown to be hepatotoxic at high doses in animal models. The Drug-Induced Liver Injury Network has identified multiple patients who have experienced liver injury ascribed to green tea extract consumption and the relationship to dose has not been straightforward, indicating that differences in sensitivity may contribute to the adverse response in susceptible people. The Diversity Outbred (DO), a genetically heterogeneous mouse population, provides a potential platform for study of interindividual toxicity responses to green tea extract. Within the DO population, an equal exposure to EGCG (50?mg/kg; daily for three days) was found to be tolerated in the majority of mice; however, a small fraction of the animals (16%; 43/272) exhibited severe hepatotoxicity (10-86.8% liver necrosis) that is analogous to the clinical cases. The data indicate that the DO mice may provide a platform for informing risk of rare, adverse reactions that may occur in consumer populations upon ingestion of concentrated herbal products. PMID:25446466

Church, Rachel J; Gatti, Daniel M; Urban, Thomas J; Long, Nanye; Yang, Xi; Shi, Qiang; Eaddy, J Scott; Mosedale, Merrie; Ballard, Shawn; Churchill, Gary A; Navarro, Victor; Watkins, Paul B; Threadgill, David W; Harrill, Alison H

2015-02-01

211

An Image-Based Genetic Assay Identifies Genes in T1D Susceptibility Loci Controlling Cellular Antiviral Immunity in Mouse  

PubMed Central

The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-?) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-?. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines. PMID:25268627

Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Doan, Aivi; Sokol, Harry; Bauer, Hermann; Herrmann, Bernhard G.; Lassen, Kara G.; Xavier, Ramnik J.

2014-01-01

212

Genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region.  

PubMed

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

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

213

Penicillin-resistant, ampicillin-susceptible Enterococcus faecalis of hospital origin: pbp4 gene polymorphism and genetic diversity.  

PubMed

Despite the spread of penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) isolates in diverse countries, the mechanisms leading to this unusual resistance phenotype have not yet been investigated. The aim of this study was to evaluate whether polymorphism in the pbp4 gene is associated with penicillin resistance in PRASEF isolates and to determine their genetic diversity. E. faecalis isolates were recovered from different clinical specimens of hospitalized patients from February 2006 to June 2010. The ?-lactam minimal inhibitory concentrations (MICs) were determined by E-test®. The PCR-amplified pbp4 gene was sequenced with an automated sequencer. The genetic diversities of the isolates were established by PFGE (pulsed-field gel electrophoresis) and MLST (multilocus sequencing typing). Seventeen non-producing ?-lactamase PRASEF and 10 penicillin-susceptible, ampicillin-susceptible E. faecalis (PSASEF) strains were analyzed. A single-amino-acid substitution (Asp-573?Glu) in the penicillin-binding domain was significantly found in all PRASEF isolates by sequencing of the pbp4 gene but not in the penicillin-susceptible isolates. In contrast to the PSASEF isolates, a majority of the PRASEFs had similar PFGE profiles. Six representative PRASEF isolates were resolved by MLST into ST9 and ST524 and belong to the globally dispersed clonal complex 9 (CC9). In conclusion, it appears quite likely that the amino acid alteration (Asp-573?Glu) found in the PBP4 of the Brazilian PRASEF isolates may account for their reduced susceptibility to penicillin, although other resistance mechanisms remain to be investigated. PMID:25445645

Conceição, Natália; da Silva, Lucas Emanuel Pinheiro; Darini, Ana Lúcia da Costa; Pitondo-Silva, André; de Oliveira, Adriana Gonçalves

2014-12-01

214

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

PubMed

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

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

2013-11-01

215

Genetic Background and GxE Interactions Modulate the Penetrance of a Naturally Occurring Wing Mutation in Drosophila melanogaster  

PubMed Central

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

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

2013-01-01

216

Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis  

Microsoft Academic Search

Susceptibility to infectious disease is influenced by multiple host genes, most of which are low penetrance QTLs that are difficult to map in humans. Leishmaniasis is a well-studied infectious disease with a variety of symptoms and well-defined immunological features. Mouse models of this disease have revealed more than 20 QTLs as being susceptibility genes, studies of which have made important

Peter Demant; Marie Lipoldová

2006-01-01

217

Evaluation of genetic susceptibility to childhood allergy and asthma in an African American urban population  

PubMed Central

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 high risk groups are variable and replication of genetic associations in African Americans is warranted. Methods We evaluated 41 single nucleotide polymorphisms (SNP) and a deletion corresponding to 11 genes demonstrating association with asthma in the literature, for association with asthma, atopy, testing positive for food allergens, eosinophilia, and total serum IgE among 141 African American children living in Detroit, Michigan. Independent SNP and haplotype associations were investigated for association with each trait, and subsequently assessed in concert using a genetic risk score (GRS). Results Statistically significant associations with asthma were observed for SNPs in GSTM1, MS4A2, and GSTP1 genes, after correction for multiple testing. Chromosome 11 haplotype CTACGAGGCC (corresponding to MS4A2 rs574700, rs1441586, rs556917, rs502581, rs502419 and GSTP1 rs6591256, rs17593068, rs1695, rs1871042, rs947895) was associated with a nearly five-fold increase in the odds of asthma (Odds Ratio (OR) = 4.8, p = 0.007). The GRS was significantly associated with a higher odds of asthma (OR = 1.61, 95% Confidence Interval = 1.21, 2.13; p = 0.001). Conclusions Variation in genes associated with asthma in predominantly non-African ethnic groups contributed to increased odds of asthma in this African American study population. Evaluating all significant variants in concert helped to identify the highest risk subset of this group. PMID:21320344

2011-01-01

218

Mupirocin-induced mutations in ileS in various genetic backgrounds of methicillin-resistant Staphylococcus aureus.  

PubMed

Topical mupirocin is widely used for the decolonization of methicillin-resistant Staphylococcus aureus (MRSA) carriers. We evaluated the capacity of various MRSA clonotypes to develop mutations in the ileS gene associated with low-level mupirocin resistance. Twenty-four mupirocin-sensitive MRSA isolates from a variety of genotypes (determined by a multilocus variable-number tandem-repeat assay) were selected. Mupirocin MICs were determined by Etest. The isolates were then incubated in subinhibitory concentrations of mupirocin for 7 to 14 days. Repeat MIC determinations and sequencing of the ileS gene were then performed. Doubling times of isolates exposed to mupirocin and of unexposed isolates were compared. We found that exposure to mupirocin led to rapid induction of low-level resistance (MICs of 8 to 24 ?g/ml) in 11 of 24 (46%) MRSA isolates. This phenomenon was observed in strains with diverse genetic backgrounds. Various mutations were detected in 18 of 24 (75%) MRSA isolates. Acquisition of mutations appeared to be a stepwise process during prolonged incubation with the drug. Among the five isolates exhibiting low-level resistance and the highest MICs, four tested sensitive after incubation in the absence of mupirocin but there was no reversion to the susceptible wild-type primary sequence. Resistance was not associated with significant fitness cost, suggesting that MRSA strains with low-level mupirocin resistance may have a selective advantage in facilities where mupirocin is commonly used. Our findings emphasize the importance of the judicious use of this topical agent and the need to closely monitor for the emergence of resistance. PMID:25122856

Lee, Andie S; Gizard, Yann; Empel, Joanna; Bonetti, Eve-Julie; Harbarth, Stephan; François, Patrice

2014-10-01

219

Mammographic texture synthesis: second-generation clustered lumpy backgrounds using a genetic algorithm.  

PubMed

Synthetic yet realistic images are valuable for many applications in visual sciences and medical imaging. Typically, investigators develop algorithms and adjust their parameters to generate images that are visually similar to real images. In this study, we used a genetic algorithm and an objective, statistical similarity measure to optimize a particular texture generation algorithm, the clustered lumpy backgrounds (CLB) technique, and synthesize images mimicking real mammograms textures. We combined this approach with psychophysical experiments involving the judgment of radiologists, who were asked to qualify the visual realism of the images. Both objective and psychophysical approaches show that the optimized versions are significantly more realistic than the previous CLB model. Anatomical structures are well reproduced, and arbitrary large databases of mammographic texture with visual and statistical realism can be generated. Potential applications include detection experiments, where large amounts of statistically traceable yet realistic images are needed. PMID:18545466

Castella, Cyril; Kinkel, Karen; Descombes, François; Eckstein, Miguel P; Sottas, Pierre-Edouard; Verdun, Francis R; Bochud, François O

2008-05-26

220

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.  

PubMed

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

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; Sigur?sson, Gunnar; Sijbrands, Eric; Silveira, Angela; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S; So, Wing Yee; Stan?áková, Alena; Stefansson, Kari; Steinbach, Gerald; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Strawbridge, Rona J; Stringham, Heather M; Sun, Qi; Suo, Chen

2014-03-01

221

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility  

PubMed Central

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

2014-01-01

222

Study of Associated Genetic Variants in Indian Subjects Reveals the Basis of Ethnicity Related Differences in Susceptibility to Venous Thromboembolism  

PubMed Central

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

Kumari, Babita; Srivastava, Swati; Chatterjee, Tathagat; Vardhan, Rig; Tyagi, Tarun; Gupta, Neha; Sahu, Anita; Chandra, Khem; Ashraf, Mohammad Zahid

2014-01-01

223

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

PubMed Central

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

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

2013-01-01

224

Genetic Background of Nontraumatic Osteonecrosis of the Femoral Head in the Korean Population  

PubMed Central

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. Level of Evidence: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID:18350352

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

2008-01-01

225

Genetic differential susceptibility in literacy-delayed children: A randomized controlled trial on emergent literacy in kindergarten.  

PubMed

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

Plak, Rachel D; Kegel, Cornelia A T; Bus, Adriana G

2015-02-01

226

Gene-environment interactions in determining differences in genetic susceptibility to cancer in subsites of the head and neck.  

PubMed

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. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc. PMID:25399842

Maurya, Shailendra S; Katiyar, Tridiv; Dhawan, Ankur; Singh, Sudhir; Jain, Swatantra K; Pant, Mohan C; Parmar, Devendra

2014-11-14

227

1998 Oxford University Press 13931398Human Molecular Genetics, 1998, Vol. 7, No. 9 Genome-wide search for asthma susceptibility loci in  

E-print Network

-wide search for asthma susceptibility loci in a founder population Carole Ober*, Nancy J. Cox1, Mark Abney, Stephanie Willadsen and Rodney Parry3 and the Collaborative Study on the Genetics of Asthma Department that are likely to be genetically heterogeneous. To identify genes that influence asthma and asthma

Abney, Mark

228

Induction of acute thrombocytopenia and infection of megakaryocytes by Rauscher murine leukemia virus reflect the genetic susceptibility to leukemogenesis  

PubMed Central

Acute thrombocytopenia and megakaryocyte infection have been investigated during the preleukemic phase of the disease induced by the Rauscher murine leukemia virus (RMuLV) in mice. Injection of RMuLV, either intravenously or intraperitoneally, rapidly induced thrombocytopenia, possibly as a result of direct interaction between platelets and viral particles. The susceptibility to this acute thrombocytopenia was genetically controlled and was inherited as a dominant trait. Murine strains with H-2d or H-2k haplotype, which are susceptible to the induction of leukemia by RMuLV, developed thrombocytopenia, whereas leukemia-resistant H-2b and H-2q strains of mice failed to develop thrombocytopenia. Using B10 H-2-congenic and intra-H-2-recombinant mice, it was shown that the susceptibility to RMuLV-induced thrombocytopenia was controlled by gene(s) in or closely linked to the D region of the H-2 complex. Megakaryocytes may be one of the first sites for the replication of RMuLV. Indeed, among bone marrow cells, only megakaryocytes expressed viral antigens gp70 and p30 during the initial phase of RMuLV infection. In addition, megakaryocytes from infected mice were able to transfer preleukemic thrombocytopenia as well as leukemia in syngeneic mice. The infection of megakaryocytes by RMuLV appears to be genetically controlled in a manner similar to the induction of thrombocytopenia, since only the megakaryocytes from mice developing thrombocytopenia were infected by RMuLV. These results indicate that the gene(s) governing the induction of thrombocytopenia by RMuLV may be the same gene(s) (or closely linked to the gene) that controls the susceptibility to leukemogenesis, and would be consistent with the expression of the gene product, presumably a receptor-like molecule for RMuLV, on platelet and megakaryocyte membranes. PMID:6833948

1983-01-01

229

Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury  

PubMed Central

Background Recent studies showed that overwhelming inflammatory response mediated by the toll-like receptor (TLR)-related pathway was important in the development of acute lung injury (ALI). The aim of this study was to determine whether common genetic variation in four genes of the TLR signaling pathway were associated with sepsis-induced ALI susceptibility and risk of death in Chinese Han population. Methods Fourteen tag single nucleotide polymorphisms (tagSNPs) in MyD88, IRAK1, IRAK4 and TRAF6 were genotyped in samples of sepsis-induced ALI (n?=?272) and sepsis alone patients (n?=?276), and tested for association in this case-control collection. Then, we investigated correlation between the associated SNP and the mRNA expression level of the corresponding gene. And we also investigated correlation between the associated SNP and tumor necrosis factor alpha (TNF-?) as well as interleukin-6 (IL-6) concentrations in peripheral blood mononuclear cells (PBMCs) exposed to lipopolysaccharides (LPS) ex vivo. The mRNA expression level was determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of TNF-? and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). Results The association analysis revealed that rs4755453, an intronic SNP of TRAF6, was significantly associated with susceptibility to sepsis-induced ALI. The C allele frequency of rs4755453 in the sepsis alone group was significantly higher than that in the sepsis-induced ALI group (P?=?0.00026, odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.37–0.74). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. TRAF6 mRNA expression levels in PBMCs from homozygotes of the rs4755453G allele were significantly higher than that in heterozygotes and homozygotes of the rs4755453C allele at baseline (P?=?0.012 and P?=?0.003, respectively) as well as after LPS stimulation (P?=?0.009 and P?=?0.005). Moreover, the concentrations of TNF-? and IL-6 in cell culture supernatants were also significantly higher in the subjects with rs4755453GG genotype than in subjects with CG and CC genotype. None of the 14 tagSNPs showed associations with risk of death and severity among ALI cases. Conclusions Our findings indicated that common genetic variants in TRAF6 were significantly associated with susceptibility to sepsis-induced ALI in Chinese Han population. This was the first genetic evidence supporting a role for TRAF6 in ALI. PMID:22901274

2012-01-01

230

NOS2 Variants Reveal a Dual Genetic Control of Nitric Oxide Levels, Susceptibility to Plasmodium Infection, and Cerebral Malaria  

PubMed Central

Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E–04 < P < 7.57E–04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E–05 < P < 7.90E–04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E–4 < P < 4.33E–02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes. PMID:24379293

Trovoada, Maria de Jesus; Martins, Madalena; Ben Mansour, Riadh; Sambo, Maria do Rosário; Fernandes, Ana B.; Antunes Gonçalves, Lígia; Borja, Artur; Moya, Roni; Almeida, Paulo; Costa, João; Marques, Isabel; Macedo, M. Paula; Coutinho, António; Narum, David L.

2014-01-01

231

Genome-Wide Association Study to Identify the Genetic Determinants of Otitis Media Susceptibility in Childhood  

PubMed Central

Background Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ?3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ?3 months) is 40–70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported. Methods and Findings Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR?=?1.90; 95%CI 1.47–2.45; Padj-PCA?=?8.3×10?7) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR?=?1.60; 95%CI 1.29–1.99; Padj-PCA?=?2.2×10?5) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (PGene?=?2×10?5) and BPIFA1 (PGene?=?1.07×10?4) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (Padj-PCA<10?5) in this GWAS, with pathway analysis showing a connection between top candidates and the TGF? pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. Conclusions This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes. PMID:23133572

Rye, Marie S.; Warrington, Nicole M.; Scaman, Elizabeth S. H.; Vijayasekaran, Shyan; Coates, Harvey L.; Anderson, Denise; Pennell, Craig E.; Blackwell, Jenefer M.; Jamieson, Sarra E.

2012-01-01

232

Genetic association of rs1520333 G/A polymorphism in the IL7 gene with multiple sclerosis susceptibility in Isfahan population  

PubMed Central

Background: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease in which the insulating membrane of central nervous system is damaged. The etiology of MS includes both genetic and environmental causes. A Genome — Wide Association Study (GWAS) recognized genetic single nucleotide polymorphisms (SNP) linked with MS predisposition among which immunologically related genes are considerably over signified. The purpose of the present study is to explore the association of rs1520333 C/T polymorphism in the IL7 gene variants with the risk of MS in a subset of Iranian population. Materials and Methods: In this case — control study, 110 cases with MS and 110 controls were contributed. DNA was extracted from blood samples and to amplify the fragment of interest contain rs1520333 SNP, polymerase chain reaction — restriction fragment length polymorphism method was implemented for genotyping of the DNA samples with a specific restriction enzyme (MwoI). SPSS for Windows software (version 18.0; SPSS, Chicago, IL, USA) was used for statistical analysis. Result: We demonstrated the important association between G allele [odds ratio (OR) =1.6614, confidence interval (CI) =1.12-2.47, P = 0.0124] and GG genotype (OR = 7.45, 95% CI = 2.13-25.97, P 0.0016) of the rs1520333 SNP for susceptibility to MS after adjustment for age, and gender. OR adjusted for age, gender, and body mass index has displayed similar outcomes. Conclusion: These results indicate that the rs1520333 SNP is a significant susceptibility gene variant for development of MS in the Iranian population. Nevertheless, functional studies are required to completely elucidate how this SNP contributed to MS pathogenesis. PMID:25538924

Ghavimi, Reza; Pourhossein, Meraj; Ghaedi, Kamran; Alesahebfosoul, Fereshteh; Honardoost, Mohamad Amin; Maracy, Mohamad Reza

2014-01-01

233

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

PubMed Central

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

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

234

Association of GST Genetic Polymorphisms with the Susceptibility to Hepatocellular Carcinoma (HCC) in Chinese Population Evaluated by an Updated Systematic Meta-Analysis  

PubMed Central

Background Due to the possible involvement of Glutathione S-transferase Mu-1 (GSTM1) and Glutathione S-transferase theta-1 (GSTT1) in the detoxification of environmental carcinogens, environmental toxins, and oxidative stress products, genetic polymorphisms of these two genes may play important roles in the susceptibility of human being to hepatocellular carcinoma. However, the existing research results are not conclusive. Methods A systematic literature search using databases (PubMed, Scopus, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wanfang Data, etc.) for the eligible studies meeting the inclusion criteria including case-control studies or cohort studies is evaluated using an updated systematic meta-analysis. Results Significant increase in the risk of HCC in the Chinese population is found in GSTM1 null genotype (OR?=?1.47, 95% CI: 1.21 to 1.79, P<0.001) and GSTT1 null genotype (OR?=?1.38, 95% CI: 1.14 to 1.65, P<0.001). Analysis using the random-effects model found an increased risk of HCC in GSTM1-GSTT1 dual null population (OR?=?1.79, 95% CI: 1.26 to 2.53, P<0.001). In addition, subgroup analyses showed a significant increase in the association of GST genetic polymorphisms (GSTM1, GSTT1, and GSTM1-GSTT1) with HCC in southeast and central China mainland. However, available data collected by this study fail to show an association between GST genetic polymorphisms and HCC in people from the Taiwan region (for GSTM1: OR?=?0.78, 95% CI: 0.60 to 1.01, P?=?0.06; for GSTT1: OR?=?0.94, 95% CI: 0.78 to 1.14, P?=?0.546; for GSTM1-GSTT1: OR?=?1.04, 95% CI: 0.81 to 1.32, P?=?0.77). Sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis. Conclusions Our results indicate that both GSTM1 and GSTT1 null genotypes are associated with an increased HCC risk in Chinese population. Peoples with dual null genotypes of GSTM1-GSTT1 are more susceptible to developing HCC. In conclusion, GST genetic polymorphisms play vital roles in the development of HCC in the Chinese population. PMID:23437305

Liu, Kui; Zhang, Lu; Lin, Xialu; Chen, Liangliang; Shi, Hongbo; Magaye, Ruth; Zou, Baobo; Zhao, Jinshun

2013-01-01

235

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

PubMed

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

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

2015-01-01

236

The mitochondrial paradigm for cardiovascular disease susceptibility and cellular function: a complementary concept to Mendelian genetics  

Microsoft Academic Search

While there is general agreement that cardiovascular disease (CVD) development is influenced by a combination of genetic, environmental, and behavioral contributors, the actual mechanistic basis of how these factors initiate or promote CVD development in some individuals while others with identical risk profiles do not, is not clearly understood. This review considers the potential role for mitochondrial genetics and function

David M Krzywanski; Douglas R Moellering; Jessica L Fetterman; Kimberly J Dunham-Snary; Melissa J Sammy; Scott W Ballinger

2011-01-01

237

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q  

Microsoft Academic Search

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic

Frances V. Elmslie; Michele Rees; Magali P. Williamson; Michael Kerr; Marianne J. Kjeldsen; Kiang An Pang; Anders Sundqvist; Mögens L. Friis; David Chadwick; Alan Richens; Athanasios Covanis; Manuela Santos; Alexis Arzimanoglou; Chrysostomos P. Panayiotopoulos; David Curtis; William P. Whitehouse; R. Mark Gardiner

1997-01-01

238

Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity  

Microsoft Academic Search

By means of large twin cohorts, it has been possible to provide relatively valid and unbiased data regarding the influence of genetic and to some extent epigenetic factors in the aetiology of thyroid autoimmunity. The comparison of concordance rates between monozygotic and dizygotic twins provides irrefutable evidence of a genetic component in the aetiology of both Graves’ disease and Hashimoto's

T. H. Brix; L. Hegedüs

2011-01-01

239

Genetic susceptibility to lung cancer--light at the end of the tunnel?  

PubMed

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

Marshall, Ariela L; Christiani, David C

2013-03-01

240

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...

241

Analysis of a p53 Mutation Associated with Cancer Susceptibility for Biochemistry and Genetic Laboratory Courses  

ERIC Educational Resources Information Center

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…

Soto-Cruz, Isabel; Legorreta-Herrera, Martha

2009-01-01

242

Genetic Analysis of Factors Affecting Susceptibility of Bacillus subtilis to Daptomycin? †  

PubMed Central

Daptomycin is the first of a new class of cyclic lipopeptide antibiotics used against multidrug-resistant, gram-positive pathogens. The proposed mechanism of action involves disruption of the functional integrity of the bacterial membrane in a Ca2+-dependent manner. We have used transcriptional profiling to demonstrate that treatment of Bacillus subtilis with daptomycin strongly induces the lia operon including the autoregulatory LiaRS two-component system (homologous to Staphylococcus aureus VraSR). The lia operon protects against daptomycin, and deletion of liaH, encoding a phage-shock protein A (PspA)-like protein, leads to threefold increased susceptibility. Since daptomycin interacts with the membrane, we tested mutants with altered membrane composition for effects on susceptibility. Deletion mutations of mprF (lacking lysyl-phosphatidylglycerol) or des (lipid desaturase) increased daptomycin susceptibility, whereas overexpression of MprF decreased susceptibility. Conversely, depletion of the cell for the anionic lipid phosphatidylglycerol led to increased resistance. Fluorescently labeled daptomycin localized to the septa and in a helical pattern around the cell envelope and was delocalized upon the depletion of phosphatidylglycerol. Together, these results indicate that the daptomycin-Ca2+ complex interacts preferentially with regions enriched in anionic phospholipids and leads to membrane stresses that can be ameliorated by PspA family proteins. PMID:19164152

Hachmann, Anna-Barbara; Angert, Esther R.; Helmann, John D.

2009-01-01

243

Host factors and genetic susceptibility to infections due to intracellular bacteria and fastidious organisms.  

PubMed

While genetic polymorphisms play a paramount role in tuberculosis (TB), less is known about their contribution to the severity of diseases caused by other intracellular bacteria and fastidious microorganisms. We searched electronic databases for observational studies reporting on host factors and genetic predisposition to infections caused by intracellular fastidious bacteria published up to 30 May 2014. The contribution of genetic polymorphisms was documented for TB. This includes genetic defects in the mononuclear phagocyte/T helper cell type 1 (Th1) pathway contributing to disseminated TB disease in children and genome-wide linkage analysis (GWAS) in reactivated pulmonary TB in adults. Similarly, experimental studies supported the role of host genetic factors in the clinical presentation of illnesses resulting from other fastidious intracellular bacteria. These include IL-6 -174G/C or low mannose-binding (MBL) polymorphisms, which are incriminated in chronic pulmonary conditions triggered by C. pneumoniae, type 2-like cytokine secretion polymorphisms, which are correlated with various clinical patterns of M. pneumoniae infections, and genetic variation in the NOD2 gene, which is an indicator of tubal pathology resulting from Chamydia trachomatis infections. Monocyte/macrophage migration and T lymphocyte recruitment defects are corroborated to ineffective granuloma formation observed among patients with chronic Q fever. Similar genetic polymorphisms have also been suggested for infections caused by T. whipplei although not confirmed yet. In conclusion, this review supports the paramount role of genetic factors in clinical presentations and severity of infections caused by intracellular fastidious bacteria. Genetic predisposition should be further explored through such as exome sequencing. PMID:25366416

Asner, S A; Morré, S A; Bochud, P-Y; Greub, G

2014-12-01

244

Minority mating advantage of certain eye color mutants of Drosophila melanogaster . III. Female discrimination and genetic background  

Microsoft Academic Search

A repetition of certain experiments done 2 years previously with two eye color mutants,brown andscarlet, inDrosophila melanogaster was undertaken to reconfirm results; however, initial tests revealed that strains or conditions had changed so that females were less discriminating. Testing was undertaken with changes in genetic background and certain laboratory conditions, with single females courted by equal numbers of two eye

Eliot B. Spiess

1982-01-01

245

Genetic susceptibility to male infertility: news from genome-wide association studies.  

PubMed

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

Aston, K I

2014-05-01

246

Prenatal exposure of mice to the human liver carcinogen aflatoxin B1 reveals a critical window of susceptibility to genetic change.  

PubMed

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

Chawanthayatham, Supawadee; Thiantanawat, Apinya; Egner, Patricia A; Groopman, John D; Wogan, Gerald N; Croy, Robert G; Essigmann, John M

2015-03-15

247

Genetic Susceptibility to Type 2 Diabetes and Obesity: Follow-Up of Findings from Genome-Wide Association Studies  

PubMed Central

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

Basile, Kevin J.; Johnson, Matthew E.; Xia, Qianghua; Grant, Struan F. A.

2014-01-01

248

Antimicrobial susceptibility patterns, emm type distribution and genetic diversity of Streptococcus pyogenes recovered in Brazil.  

PubMed

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

Arêas, Glauber P; Schuab, Rôde B B; Neves, Felipe P G; Barros, Rosana R

2014-11-01

249

Antimicrobial susceptibility patterns, emm type distribution and genetic diversity of Streptococcus pyogenes recovered in Brazil.  

PubMed

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:25351379

Arêas, Glauber P; Schuab, Rôde Bb; Neves, Felipe Pg; Barros, Rosana R

2014-10-28

250

Antimicrobial Susceptibility and Genetic Characterisation of Burkholderia pseudomallei Isolated from Malaysian Patients  

PubMed Central

Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to many antibiotics. Ceftazidime (CAZ), the synthetic ?-lactam, is normally used as the first-line antibiotic therapy for treatment of melioidosis. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, leading to mortality if therapy is not switched to a different antibiotic(s) in a timely manner. In this study, susceptibilities of 81 B. pseudomallei isolates to nine different antimicrobial agents were determined using the disk diffusion method, broth microdilution test and Etest. Highest percentage of susceptibility was demonstrated to CAZ, amoxicillin/clavulanic acid, meropenem, imipenem, and trimethoprim/sulfamethoxazole. Although these drugs demonstrated the highest percentage of susceptibility in B. pseudomallei, the overall results underline the importance of the emergence of resistance in this organism. PCR results showed that, of the 81 B. pseudomallei, six multidrug resistant (MDR) isolates carried bpeB, amrB, and BPSS1119 and penA genes. Genotyping of the isolates using random amplified polymorphic DNA analysis showed six different PCR fingerprinting patterns generated from the six MDR isolates clusters (A) and eight PCR fingerprinting patterns generated for the remaining 75 non-MDR isolates clusters (B). PMID:25379514

Khosravi, Yalda; Mariappan, Vanitha; Ng, Shet-Lee

2014-01-01

251

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 ...

252

Genetic, epidemiological and biological analysis of interleukin-10 promoter single-nucleotide polymorphisms suggests a definitive role for ?819C\\/T in leprosy susceptibility  

Microsoft Academic Search

Leprosy is a complex infectious disease influenced by genetic and environmental factors. The genetic contributing factors are considered heterogeneous and several genes have been consistently associated with susceptibility like PARK2, tumor necrosis factor (TNF), lymphotoxin-? (LTA) and vitamin-D receptor (VDR). Here, we combined a case–control study (374 patients and 380 controls), with meta-analysis (5 studies; 2702 individuals) and biological study

A C Pereira; V N Brito-de-Souza; C C Cardoso; I M F Dias-Baptista; F P C Parelli; J Venturini; F R Villani-Moreno; A G Pacheco; M O Moraes; MO Moraes

2009-01-01

253

Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus  

PubMed Central

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

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

254

Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.  

PubMed

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

Bell, Christopher G; Finer, Sarah; Lindgren, Cecilia M; 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

255

HYPOBARIC HYPOXIA IN ASCITES RESISTANT AND SUSCEPTIBLE BROILER GENETIC LINES INFLUENCES GUT MORPHOLOGY  

Technology Transfer Automated Retrieval System (TEKTRAN)

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 (26.0% ascites mortality, RES...

256

The 3? region of the DRD2 gene is involved in genetic susceptibility to schizophrenia  

Microsoft Academic Search

The gene coding for the D2 dopamine receptor (DRD2) is considered as one of the most relevant candidate genes in schizophrenia. Previous genetic studies focusing on this gene yielded conflicting results, for example because of differences in methodology (linkage versus association studies) and variability in the loci analyzed (the DRD2 gene having many polymorphic sites). We used a progressive strategy

Caroline Dubertret; Laurent Gouya; Naima Hanoun; Jean-Charles Deybach; Jean Adès; Michel Hamon; Philip Gorwood

2004-01-01

257

Aedes aegypti in Brazil: genetically differentiated populations with high susceptibility to dengue and yellow fever viruses  

Microsoft Academic Search

Aedes aegypti was eliminated from Brazil in 1955, but re-infested the country in the 1970s. Dengue outbreaks have occurred since 1981 and became endemic in several cities in Brazil after 1986. Urban yellow fever has not occurred since 1942, and only jungle yellow fever cases have been reported. A population genetic analysis using isoenzyme variation combined with an evaluation of

R Lourenço-de-Oliveira; M Vazeille; A. M. B de Filippis; A. B Failloux

2004-01-01

258

5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression  

Microsoft Academic Search

Carriers of the short allele of a functional 5? promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele

Lukas Pezawas; Andreas Meyer-Lindenberg; Emily M Drabant; Beth A Verchinski; Karen E Munoz; Bhaskar S Kolachana; Michael F Egan; Venkata S Mattay; Ahmad R Hariri; Daniel R Weinberger

2005-01-01

259

Genetic susceptibility to different clinical forms of tuberculosis in the Peruvian population  

Microsoft Academic Search

Racial variation, twin studies, segregation analyses, linkage and association studies all suggest that genetic factors play an important role in predisposition to tuberculosis. Many previous studies have been performed with pulmonary TB patients, as the most prevalent form of clinical TB (nearly 95%), and very few of them have considered extrapulmonary TB. The present study evaluates the effects of variation

C. A. Taype; S. Shamsuzzaman; R. A. Accinelli; J. R. Espinoza; M.-A. Shaw

2010-01-01

260

Genetic susceptibility to radiation E.J. Hall *, D.J. Brenner, B. Worgul, L. Smilenov  

E-print Network

protection standards, radiotherapy protocols for cancer patients which are seldom customized of early onset breast cancer patients in the women who survived the A-bombs in WWII, the genetic basis, there is the troubling fact that a few per- cent of radiotherapy patients suffer severe late effects quite out

Brenner, David Jonathan

261

Vascular endothelial growth factor genetic polymorphisms and susceptibility to age-related macular degeneration in Tunisian population  

PubMed Central

Purpose Three VEGF SNPs (?2578) C/A, (+405) G/C and (+936) C/T were investigated in Tunisian exudative AMD patients in order to determine their association with the disease susceptibility and their influence to intravitreal bevacizumab therapy response. Methods 145 AMD patients and 207 age-matched controls were included. 68 patients were treated with intravitreal bevacizumab. SNPs genotyping were performed using direct sequencing. The serum VEGF was assayed by ELISA (R&D). Results The (+405) CC and (+936) TT genotypes were higher in AMD patients than in controls (p?=?5?×?10?6 and p?=?0.021, respectively). The mean plasma levels of VEGF were statistically higher in AMD patients (84.22 pg/ml) than in controls (15 pg/ml). Three months after bevacizumab treatment, 52 patients (85.6%) were classified as good responders (GR) and 16 (14.4%) as poor responders (PR). The mean plasmatic-VEGF levels in GR patients was higher (86.61?±?80.30 pg/ml) than in PR patients (47.12?±?45.74 pg/ml) (p?=?0.086). The patients with genotype homozygous TT (+936) would be PR compared to those carrying CT and CC genotypes. Whereas, those with AA (?2578) genotype would be GR compared with others genotypes (p?=?0.014; p?=?0.042 respectively). Conclusions Our results show that VEGF genetic variants may contribute to the susceptibility to neovascular AMD in Tunisian patients. PMID:25165559

2014-01-01

262

Genetic Susceptibility, Colony Size, and Water Temperature Drive White-Pox Disease on the Coral Acropora palmata  

PubMed Central

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

Muller, Erinn M.; van Woesik, Robert

2014-01-01

263

Genetic Variation in the Extended Major Histocompatibility Complex and Susceptibility to Childhood Acute Lymphoblastic Leukemia: A Review of the Evidence  

PubMed Central

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

Urayama, Kevin Y.; Thompson, Pamela D.; Taylor, Malcolm; Trachtenberg, Elizabeth A.; Chokkalingam, Anand P.

2013-01-01

264

Potato plants genetically modified to produce N-acylhomoserine lactones increase susceptibility to soft rot erwiniae.  

PubMed

Many gram-negative bacteria employ N-acylhomoserine lactones (AHL) to regulate diverse physiological processes in concert with cell population density (quorum sensing [QS]). In the plant pathogen Erwinia carotovora, the AHL synthesized via the carI/expI genes are responsible for regulating the production of secreted plant cell wall-degrading exoenzymes and the antibiotic carbapen-3-em carboxylic acid. We have previously shown that targeting the product of an AHL synthase gene (yenI) from Yersinia enterocolitica to the chloroplasts of transgenic tobacco plants caused the synthesis in planta of the cognate AHL signaling molecules N-(3-oxohexanoyl)-L-homoserine lactone (3-oxo-C6-HSL) and N-hexanoylhomoserine lactone (C6-HSL), which in turn, were able to complement a carI-QS mutant. In the present study, we demonstrate that transgenic potato plants containing the yenI gene are also able to express AHL and that the presence and level of these AHL in the plant increases susceptibility to infection by E. carotovora. Susceptibility is further affected by both the bacterial level and the plant tissue under investigation. PMID:15305609

Toth, I K; Newton, J A; Hyman, L J; Lees, A K; Daykin, M; Ortori, C; Williams, P; Fray, R G

2004-08-01

265

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 ...

266

Effect of T-lymphocyte suppression on the parasite burden in Leishmania major-infected, genetically susceptible BALB/c mice.  

PubMed Central

Treatment of Leishmania major-infected, genetically susceptible BALB/c mice with the T-lymphocyte-immunosuppressive drug cyclosporin A (CyA) resulted in a significantly reduced parasite burden in the local site of infection and in the draining lymph nodes. These data indicate that T cells are pivotal for the propagation of L. major in vivo. PMID:3491051

Solbach, W; Forberg, K; Röllinghoff, M

1986-01-01

267

Genetic susceptibility to a complex disease: the key role of functional redundancy.  

PubMed

Complex diseases involve both a genetic component and a response to environmental factors or lifestyle changes. Recently, genome-wide association studies (GWAS) have succeeded in identifying hundreds of polymorphisms that are statistically associated with complex diseases. However, the association is usually weak and none of the associated allelic forms is either necessary or sufficient for the disease occurrence. We argue that this promotes a network view, centred on functional redundancy. We adapted reliability theory to the concerned sub-network, modelled as a parallel array of functional modules. In our model, as long as one module remains active, the function correlated with the respective disease is ensured and disease does not occur. Genetic factors reduce the initial number of available modules while environment, contingent surroundings, personal history, epigenetics, and some intrinsic stochasticity influence their persistence time. This model reproduces age-specific incidence curves and explains the influence of environmental changes. It offers a new paradigm, according to which disease occurs due to a lack of functional elements, depending on many idiosyncratic factors. Genetic risk assessed from GWAS is only a statistical notion with no direct interpretation at the individual level. However, genomic profiling could be useful at population level in devising models to guide decisions in health care policy. PMID:22662507

Debret, Gaëlle; Jung, Camille; Hugot, Jean-Pierre; Pascoe, Leigh; Victor, Jean-Marc; Lesne, Annick

2011-01-01

268

A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes  

PubMed Central

Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n?=?228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer. PMID:25411967

Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.

2014-01-01

269

Background Strain and the Differential Susceptibility of Podocyte-Specific Deletion of Myh9 on Murine Models of Experimental Glomerulosclerosis and HIV Nephropathy  

PubMed Central

We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition to glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investigators reported that podocyte-specific deletion of Myh9 (Pod?Myh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9flox alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in Pod?Myh9 mice vs control littermates (urine MAC ratio all p>0.05). We also tested C57BL/6 Pod?Myh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p<0.05 or less). In contrast, we found that Pod?Myh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that Pod?Myh9 results in a variable susceptibility to glomerulosclerosis in response to different models of glomerular injury. In addition, based on the lack of a spontaneous phenotype of glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh9 is not absolutely required in adult podocytes. PMID:23874454

Johnstone, Duncan B.; Ikizler, Omer; Zhang, Jidong; Holzman, Lawrence B.

2013-01-01

270

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis.  

PubMed

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

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

271

Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice  

Microsoft Academic Search

Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of age-related hearing loss (AHL) in mice. In linkage backcrosses, the recessive Cdh23 allele (ahl) of the C57BL\\/6J strain, when homozygous, confers increased susceptibility to AHL, while the dominant allele (Ahl+) of the CBA\\/CaJ strain confers resistance. To determine the isolated effects of these

Kelly L Kane; Chantal M Longo-Guess; Leona H Gagnon; Dalian Ding; Richard J Salvi; Kenneth R Johnson

2012-01-01

272

Genetic Background Strongly Modifies the Severity of Symptoms of Hirschsprung Disease, but Not Hearing Loss in Rats Carrying Ednrbsl Mutations  

PubMed Central

Hirschsprung disease (HSCR) is thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. However, it remains unknown whether the single complete deletion of important HSCR-associated genes is sufficient to result in HSCR disease. In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrbsl mutations. Moreover, we found that this mutation results in serious congenital sensorineural deafness, and these strains may be used as ideal models of Waardenburg Syndrome Type 4 (WS4). Furthermore, we evaluated how the same changed genetic background modifies three features of WS4 syndrome, aganglionosis, hearing loss, and pigment disorder in these congenic strains. We found that the same genetic background markedly changed the aganglionosis, but resulted in only slight changes to hearing loss and pigment disorder. This provided the important evidence, in support of previous studies, that different lineages of neural crest-derived cells migrating along with various pathways are regulated by different signal molecules. This study will help us to better understand complicated diseases such as HSCR and WS4 syndrome. PMID:21915282

Dang, Ruihua; Torigoe, Daisuke; Suzuki, Sari; Kikkawa, Yoshiaki; Moritoh, Kanako; Sasaki, Nobuya; Agui, Takashi

2011-01-01

273

Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis  

SciTech Connect

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.

Mulcahy, B.; Waldron-Lynch, F.; Adams, C.; O`Gara, F. [Cork Univ. Hospital (Ireland)] [and others

1996-09-01

274

Genetic Differences in Transcript Responses to Low-Dose Ionizing Radiation Identify Tissue Functions Associated with Breast Cancer Susceptibility  

PubMed Central

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGF?-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p?=?0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer. PMID:23077491

Snijders, Antoine M.; Marchetti, Francesco; Bhatnagar, Sandhya; Duru, Nadire; Han, Ju; Hu, Zhi; Mao, Jian-Hua; Gray, Joe W.; Wyrobek, Andrew J.

2012-01-01

275

Pathological Impact of Hepatitis B Virus Surface Proteins on the Liver Is Associated with the Host Genetic Background  

PubMed Central

Background While the immune pathogenesis caused by hepatitis B virus (HBV) infection has been studied extensively, little is known about direct pathogenic effects of HBV surface proteins. Here, we have investigated pathological cellular effects of HBV surface protein expression in the liver of transgenic mice with different genetic background. Methods The impact of HBV surface protein expression on the liver was studied in two mouse strains, BALB/c and C57BL/6. Histology and hydroxyproline assays were performed to investigate liver morphology and fibrosis. Gene expression and signaling were analyzed by microarray, qPCR and Western blotting. Results Expression of HBV surface proteins in the liver of transgenic mice induced activation of protein kinase-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2? (eIF2?) phosphorylation. Phosphorylation of eIF2? resulted in activation of the ER stress markers glucose regulated protein (GRP) 78 and pro-apoptotic C/EBP homologous protein (CHOP) in transgenic mice on BALB/c genetic background leading to stronger liver injury and fibrosis in comparison with transgenic mice on C57BL/6 background. Hepatic stellate cells represented the main collagen-producing liver cells in HBV transgenic mice. The key regulators of hepatocyte proliferation, transcription factors c-Jun and STAT3 were activated in HBV transgenic mice. Tumour incidence in transgenic mice was strain- and sex-dependent. Conclusions Extent of liver injury, fibrosis, and tumour development induced by hepatic HBV surface protein expression considerably depends on host genetic background. PMID:24594856

Stiefel, Johannes; Würger, Tilman; Schröder, Dirk; Matono, Tomomitsu; Mollenkopf, Hans-Joachim; Montalbano, Roberta; Pompaiah, Malvika; Reifenberg, Kurt; Zahner, Daniel; Ocker, Matthias; Gerlich, Wolfram; Glebe, Dieter; Roeb, Elke

2014-01-01

276

Comparison of Enterococcus faecium and Enterococcus faecalis Strains Isolated from Water and Clinical Samples: Antimicrobial Susceptibility and Genetic Relationships  

PubMed Central

Enterococci are part of the normal intestinal flora in a large number of mammals, and these microbes are currently used as indicators of fecal contamination in water and food for human consumption. These organisms are considered one of the primary causes of nosocomial and environmental infections due to their ability to survive in the environment and to their intrinsic resistance to antimicrobials. The aims of this study were to determine the biochemical patterns and antimicrobial susceptibilities of Enterococcus faecalis and E. faecium isolates from clinical samples and from water (groundwater, water from the Xochimilco wetland, and treated water from the Mexico City Metropolitan Area) and to determine the genetic relationships among these isolates. A total of 121 enterococcus strains were studied; 31 and 90 strains were isolated from clinical samples and water (groundwater, water from the Xochimilco wetland, and water for agricultural irrigation), respectively. Identification to the species level was performed using a multiplex PCR assay, and antimicrobial profiles were obtained using a commercial kit. Twenty-eight strains were analyzed by pulsed-field gel electrophoresis (PFGE). E. faecium strains isolated from water showed an atypical biochemical pattern. The clinical isolates showed higher resistance to antibiotics than those from water. Both the enterococci isolated from humans, and those isolated from water showed high genetic diversity according to the PFGE analysis, although some strains seemed to be closely related. In conclusion, enterococci isolated from humans and water are genetically different. However, water represents a potential route of transmission to the community and a source of antimicrobial resistance genes that may be readily transmitted to other, different bacterial species. PMID:23560050

Castillo-Rojas, Gonzalo; Mazari-Hiríart, Marisa; Ponce de León, Sergio; Amieva-Fernández, Rosa I.; Agis-Juárez, Raúl A.; Huebner, Johannes; López-Vidal, Yolanda

2013-01-01

277

Comparison of Enterococcus faecium and Enterococcus faecalis Strains isolated from water and clinical samples: antimicrobial susceptibility and genetic relationships.  

PubMed

Enterococci are part of the normal intestinal flora in a large number of mammals, and these microbes are currently used as indicators of fecal contamination in water and food for human consumption. These organisms are considered one of the primary causes of nosocomial and environmental infections due to their ability to survive in the environment and to their intrinsic resistance to antimicrobials. The aims of this study were to determine the biochemical patterns and antimicrobial susceptibilities of Enterococcus faecalis and E. faecium isolates from clinical samples and from water (groundwater, water from the Xochimilco wetland, and treated water from the Mexico City Metropolitan Area) and to determine the genetic relationships among these isolates. A total of 121 enterococcus strains were studied; 31 and 90 strains were isolated from clinical samples and water (groundwater, water from the Xochimilco wetland, and water for agricultural irrigation), respectively. Identification to the species level was performed using a multiplex PCR assay, and antimicrobial profiles were obtained using a commercial kit. Twenty-eight strains were analyzed by pulsed-field gel electrophoresis (PFGE). E. faecium strains isolated from water showed an atypical biochemical pattern. The clinical isolates showed higher resistance to antibiotics than those from water. Both the enterococci isolated from humans, and those isolated from water showed high genetic diversity according to the PFGE analysis, although some strains seemed to be closely related. In conclusion, enterococci isolated from humans and water are genetically different. However, water represents a potential route of transmission to the community and a source of antimicrobial resistance genes that may be readily transmitted to other, different bacterial species. PMID:23560050

Castillo-Rojas, Gonzalo; Mazari-Hiríart, Marisa; Ponce de León, Sergio; Amieva-Fernández, Rosa I; Agis-Juárez, Raúl A; Huebner, Johannes; López-Vidal, Yolanda

2013-01-01

278

Antimicrobial susceptibility of Neisseria gonorrhoeae isolates from symptomatic men attending the Nanjing sexually transmitted diseases clinic (2011¿2012): genetic characteristics of isolates with reduced sensitivity to ceftriaxone.  

PubMed

BackgroundEvolving gonococcal antimicrobial resistance (AMR) poses a serious threat to public health. The aim of this study was to: update antimicrobial susceptibility data of Neisseria gonorrhoeae recently isolated in Nanjing, China and identify specific deteminants of antimicrobial resistance and gentoypes of isolates with decreased sensitivity to ceftriaxone.Methods334¿N. gonorrhoeae isolates were collected consecutively from symptomatic men attending the Nanjing STD Clinic between April 2011 and December 2012. The minimum inhibitory concentrations (MICs) for penicillin, tetracycline, ciprofloxacin, spectinomycin and ceftriaxone were determined by agar plate dilution for each isolate. Penicillinase-producing N. gonorrhoeae (PPNG) and tetracycline-resistant N. gonorrhoeae (TRNG) were examined and typed for ß-lactamase and tetM encoding plasmids respectively. Isolates that displayed elevated MICs to ceftriaxone (MIC ¿0.125 mg/L) were also tested for mutations in penA, mtrR, porB1b, ponA and pilQ genes and characterized by Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST).Results98.8% (330/334) of N. gonorrhoeae isolates were resistant to ciprofloxacin; 97.9% (327/334) to tetracycline and 67.7% (226/334) to penicillin. All isolates were susceptible to ceftriaxone (MIC ¿0.25 mg/L) and spectinomycin (MIC ¿32 mg/L). Plasmid mediated resistance was exhibited by 175/334 (52%) of isolates: 120/334 (36%) of isolates were PPNG and 104/334 (31%) were TRNG. 90.0% (108/120) of PPNG isolates carried the Asia type ß-lactamase encoding plasmid and 96% (100/104) of TRNG isolates carried the Dutch type tetM containing plasmid. Elevated MICs for ceftriaxone were present in 15 (4.5%) isolates; multiple mutations were found in penA, mtrR, porB1b and ponA genes. The 15 isolates were distributed into diverse NG-MAST sequence types; four different non-mosaic penA alleles were identified, including one new type.Conclusions N. gonorrhoeae isolates in Nanjing generally retained similar antimicrobial resistance patterns to isolates obtained five years ago. Fluctuations in resistance plasmid profiles imply that genetic exchange among gonococcal strains is ongoing and is frequent. Ceftriaxone and spectinomycin remain treatments of choice of gonorrhea in Nanjing, however, decreased susceptibility to ceftriaxone and rising MICs for spectinomycin of N. gonorrhoeae isolates underscore the importance of maintaining surveillance for AMR (both phenotypic and genotypic). PMID:25427572

Li, Sai; Su, Xiaohong; Le, Wenjing; Jiang, Faxing; Wang, Baoxi; Rice, Peter A

2014-11-27

279

Associations of Genetic Variants in the PSCA, MUC1 and PLCE1 Genes with Stomach Cancer Susceptibility in a Chinese Population  

PubMed Central

Background Several genetic variants including PSCA rs2294008 C>T and rs2976392 G>A, MUC1 rs4072037 T>C, and PLCE1 rs2274223 A>G have shown significant association with stomach cancer risk in the previous genome-wide association studies (GWASs). Methods To evaluate associations of these SNPs in the Han Chinese, an independent hospital based case-control study was performed by genotyping these four polymorphisms in a total of 692 stomach cancer cases and 774 healthy controls acquired by using frequency matching for age and gender. False-positive report probability (FPRP) analysis was also performed to validate all statistically significant findings. Results In the current study, significant association with stomach cancer susceptibility was observed for all the four polymorphisms of interest. Specifically, a significant increased stomach cancer risk was associated with PSCA rs2294008 (CT vs. CC: adjusted OR = 1.37, 95% CI = 1.07–1.74, and CT/TT vs.CC: adjusted OR = 1.30, 95% CI = 1.03–1.63), PSCA rs2976392 (AG vs. GG: adjusted OR = 1.30, 95% CI = 1.02–1.65, and AG/AA vs. GG: adjusted OR = 1.26, 95% CI = 1.00–1.59), or PLCE1 rs2274223 (AG vs. AA: adjusted OR = 1.48, 95% CI = 1.15–1.90, and AG/GG vs. AA: adjusted OR = 1.45, 95% CI = 1.14–1.84), respectively. In contrast, MUC1 rs4072037 was shown to decrease the cancer risk (CT vs. TT: adjusted OR = 0.77, 95% CI = 0.60–0.98). Patients with more than one risk genotypes had significant increased risk to develop stomach cancer (adjusted OR = 1.30, 95% CI = 1.03–1.64), when compared with those having 0–1 risk genotypes. Stratified analysis indicated that the increased risk was more pronounced in younger subjects, men, ever smokers, smokers with pack years ? 27, patients with high BMI, or non-cardia stomach cancer. Conclusions This study substantiated the associations between four previous reported genetic variants and stomach cancer susceptibility in an independent Han Chinese population. Further studies with larger sample size and different ethnicities are warranted to validate our findings. PMID:25658482

Sun, Hongwei; Wu, Xiaoli; Wu, Fang; Li, Ying; Yu, Zhengping; Chen, Xiangrong; Chen, Yunzhi; Yang, Wenjun

2015-01-01

280

Genetic variants of vitamin D receptor and susceptibility to ischemic stroke.  

PubMed

Vitamin D receptor (VDR) is a potential candidate for cardiovascular disease. To date the genetic association of VDR with ischemic stroke has not been explored. In the present study we aimed to evaluate the association between VDR gene variants and ischemic stroke in Asian Indian population. Overall, 557 subjects were investigated that included 313 ischemic stroke patients and 244 control subjects. Four single nucleotide polymorphisms of the VDR gene termed as Fok I, Apa I, Taq I and Bsm I were genotyped by using PCR-RFLP method. The genotype distribution of Bsm I polymorphism was found to deviate from the Hardy-Weinberg equilibrium in control subjects, and hence excluded from the study. Apa I and Taq I polymorphisms were not found to be associated with ischemic stroke. However, presence of ff genotype of Fok I was found to confer 2.97-fold risk of ischemic stroke (95% CI=1.16-7.63, P=0.02) as compared to FF genotype. This association was found to be independent of various demographic and important biochemical covariates including age, gender, smoking, alcohol intake, BMI, and serum glucose, lipid profile, insulin and HOMA-IR, 25-hydroxyvitamin D and plasma NOx levels [OR=2.27, 95% CI=1.25-4.09, P=0.01]. However, adjustment for lipid metabolites attenuated the genetic association [OR=1.68, 95% CI=0.75-3.78, P=0.21]. Fok I polymorphism was also found to be associated with total cholesterol levels; ff genotype carriers were found to have significantly higher cholesterol levels (203.56±30.50mg/dl) as compared to FF carriers (177.38±47.90mg/dl) (P=0.04). On stratification by gender the genetic association between Fok I polymorphism and ischemic stroke remained significant in females only (OR=2.28, 95% CI=1.15-4.53, P=0.02). This genetic association was also found to attenuate on adjustment with lipid variables. In the present study we could associate the only known functional polymorphism of VDR i.e., Fok I, with ischemic stroke in a gender specific manner. Adjustment with lipid variables was found to attenuate this association indicating that impaired lipid metabolism may be the underlying mechanism of action of this polymorphism which leads to an increase in the risk of ischemic stroke. Further larger scale validations in other population are warranted in other population. PMID:25498546

Prabhakar, Puttachandra; Majumdar, Vijaya; Kulkarni, Girish Baburao; Christopher, Rita

2015-01-01

281

Genetic Variation in the IL7RA/IL7 Pathway Increases Multiple Sclerosis Susceptibility  

PubMed Central

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 8.29×10-6 and 3.48×10-7, 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 3.47×10-4 and BCL2 with p-values reaching 4.32×10-4. 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

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

282

The role of genetic breast cancer susceptibility variants as prognostic factors  

PubMed Central

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

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

283

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep?  

PubMed Central

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

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

284

High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.  

PubMed

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations. PMID:23143596

Eyre, Steve; Bowes, John; Diogo, Dorothée; Lee, Annette; Barton, Anne; Martin, Paul; Zhernakova, Alexandra; Stahl, Eli; Viatte, Sebastien; McAllister, Kate; Amos, Christopher I; Padyukov, Leonid; Toes, Rene E M; Huizinga, Tom W J; Wijmenga, Cisca; Trynka, Gosia; Franke, Lude; Westra, Harm-Jan; Alfredsson, Lars; Hu, Xinli; Sandor, Cynthia; de Bakker, Paul I W; Davila, Sonia; Khor, Chiea Chuen; Heng, Khai Koon; Andrews, Robert; Edkins, Sarah; Hunt, Sarah E; Langford, Cordelia; Symmons, Deborah; Concannon, Pat; Onengut-Gumuscu, Suna; Rich, Stephen S; Deloukas, Panos; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlsetig, Lisbeth; Martin, Javier; Rantapää-Dahlqvist, Solbritt; Plenge, Robert M; Raychaudhuri, Soumya; Klareskog, Lars; Gregersen, Peter K; Worthington, Jane

2012-12-01

285

Genome-Wide Identification of Susceptibility Alleles for Viral Infections through a Population Genetics Approach  

PubMed Central

Viruses have exerted a constant and potent selective pressure on human genes throughout evolution. We utilized the marks left by selection on allele frequency to identify viral infection-associated allelic variants. Virus diversity (the number of different viruses in a geographic region) was used to measure virus-driven selective pressure. Results showed an excess of variants correlated with virus diversity in genes involved in immune response and in the biosynthesis of glycan structures functioning as viral receptors; a significantly higher than expected number of variants was also seen in genes encoding proteins that directly interact with viral components. Genome-wide analyses identified 441 variants significantly associated with virus-diversity; these are more frequently located within gene regions than expected, and they map to 139 human genes. Analysis of functional relationships among genes subjected to virus-driven selective pressure identified a complex network enriched in viral products-interacting proteins. The novel approach to the study of infectious disease epidemiology presented herein may represent an alternative to classic genome-wide association studies and provides a large set of candidate susceptibility variants for viral infections. PMID:20174570

Fumagalli, Matteo; Pozzoli, Uberto; Cagliani, Rachele; Comi, Giacomo P.; Bresolin, Nereo

2010-01-01

286

Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer.  

PubMed

Mammalian cytosolic glutathione S-transferases (GSTs; EC 2.5.1.18) form a supergene family consisting of four distinct families, named alpha, mu, pi and theta. In humans one member of the mu class gene family (GSTM1) has been shown to be polymorphic and is only expressed in 55-60% of individuals. Previous studies have shown a possible link with the null phenotype and susceptibility to cancer, in particular to lung cancer. In this study we genotyped individuals with breast, bladder and colorectal cancer. A total of 490 individuals with cancer were studied, and consisted of 97 bladder, 197 breast and 196 colorectal cancers. No significant differences were observed in the frequency of nulled individuals in bladder or breast cancer patients when compared with a control population of 225 individuals. However, a significant excess of nulled individuals were seen in colorectal cancer: 56.1% compared with the control group value of 41.8%. This was shown to be highly significant depending on the site of the tumours and > 70% of individuals with a tumour in the proximal colon were GSTM1 nulled. This is an approximately 2-fold increase in colon cancer risk in these individuals. PMID:8403204

Zhong, S; Wyllie, A H; Barnes, D; Wolf, C R; Spurr, N K

1993-09-01

287

Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity.  

PubMed

Paraoxonase (PON1) is an A-esterase capable of hydrolyzing the active metabolites (oxons) of a number of organophosphorus (OP) insecticides such as parathion, diazinon and chlorpyrifos. PON1 activity is highest in liver and in plasma. Human PON1 displays two polymorphisms in the coding region (Q192R and L55M) and several polymorphisms in the promoter and the 3'-UTR regions. The Q192R polymorphism imparts differential catalytic activity toward some OP substrates, while the polymorphism at position -108 (C/T) is the major contributor of differences in the levels of PON1 expression. Both contribute to determining an individual's PON1 "status". Animal studies have shown that PON1 is an important determinant of OP toxicity. Administration of exogenous PON1 to rats or mice protects them from the toxicity of specific OPs. PON1 knockout mice display a high sensitivity to the toxicity of diazoxon and chlorpyrifos oxon, but not of paraoxon. In vitro catalytic efficiencies of purified PON192 alloforms for hydrolysis of specific oxon substrates accurately predict the degree of in vivo protection afforded by each isoform. Evidence is slowly emerging that a low PON1 status may increase susceptibility to OP toxicity in humans. Low PON1 activity may also contribute to the developmental toxicity and neurotoxicity of OPs, as shown by animal and human studies. PMID:22884923

Costa, Lucio G; Giordano, Gennaro; Cole, Toby B; Marsillach, Judit; Furlong, Clement E

2013-05-10

288

Deciphering the genetic architecture of low-penetrance susceptibility to colorectal cancer  

PubMed Central

Recent genome-wide association studies (GWASs) have identified common variants at 16 autosomal regions influencing the risk of developing colorectal cancer (CRC). To decipher the genetic basis of the association signals at these loci, we performed a meta-analysis of data from five GWASs, totalling 5626 cases and 7817 controls, using imputation to recover un-typed genotypes. To enhance our ability to discover low-frequency risk variants, in addition to using 1000 Genomes Project data as a reference panel, we made use of high-coverage sequencing data on 253 individuals, 199 with early-onset familial CRC. For 13 of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the 16 loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant. PMID:23904454

Whiffin, Nicola; Dobbins, Sara E.; Hosking, Fay J.; Palles, Claire; Tenesa, Albert; Wang, Yufei; Farrington, Susan M.; Jones, Angela M.; Broderick, Peter; Campbell, Harry; Newcomb, Polly A.; Casey, Graham; Conti, David V.; Schumacher, Fred; Gallinger, Steve; Lindor, Noralane M.; Hopper, John; Jenkins, Mark; Dunlop, Malcolm G.; Tomlinson, Ian P.; Houlston, Richard S.

2013-01-01

289

Genetic variants in C-reactive protein and ischemic stroke susceptibility.  

PubMed

Considerable discrepancies in the previously reported associations of the C-reactive protein (CRP) gene variants and ischemic stroke (IS) risk prompted us to perform this meta-analysis. We selected the fixed effects Mantel-Haenszel method to estimate the risk of IS [OR (odds ratio) along with its 95 % CI (confidence interval)] in relation to the CRP variants (-717 A > G, 1444 C > T). Heterogeneity test, influence analysis and publication bias test were appropriately performed using respective methods. We analyzed 1,926 IS patients and 2,678 controls and found the -717 A > G variant was not significantly associated with overall IS risk. Subsequent analysis of the 1444 C > T variant involving 3,278 samples similarly revealed no significant association with IS. There was no substantial heterogeneity or publication bias in this analysis. Our meta-analysis may provide first evidence showing that genetic variants within the CRP locus are unlikely to modulate risk of IS. PMID:24989682

Chen, Bing; Chen, Juan; Huang, Wei

2014-12-01

290

Mitochondrial genetic background in Ghanaian patients with primary open-angle glaucoma  

PubMed Central

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

Hauser, Michael A.; Mohamed, Gamal; Liu, Yutao; Gibson, Jason; Gonzalez, Ana M.; Akafo, Stephen; Allingham, R. Rand

2012-01-01

291

Establishment and Characterization of MRT Cell Lines from Genetically Engineered Mouse Models and the Influence of Genetic Background on Their Development  

PubMed Central

Malignant rhabdoid tumors (MRTs) are rare, aggressive cancers occuring in young children primarily through inactivation of the SNF5(INI1, SMARCB1) tumor suppressor gene. We and others have demonstrated that mice heterozygous for a Snf5 null allele develop MRTs with partial penetrance. We have also shown that Snf5+/? mice that lack expression of the pRb family, due to TgT121 transgene expression, develop MRTs with increased penetrance and decreased latency. Here, we report that altering the genetic background has substantial effects upon MRT development in Snf5+/? and TgT121;Snf5+/? mice, with a mixed F1 background resulting in increased latency and the appearance of brain tumors. We also report the establishment of the first mouse MRT cell lines that recapitulate many features of their human counterparts. Our studies provide further insight into the genetic influences on MRT development as well as provide valuable new cell culture and genetically engineered mouse models for the study of CNS-MRT etiology. PMID:23197309

Kuwahara, Yasumichi; Mora-Blanco, E Lorena; Banine, Fatima; Rogers, Arlin B.; Fletcher, Christopher; Sherman, Larry S.; Roberts, Charles W. M.; Weissman, Bernard E.

2012-01-01

292

Involvement of superoxide dismutase isoenzymes and their genetic variants in progression of and higher susceptibility to vitiligo.  

PubMed

Oxidative stress has been implicated as the initial triggering event in vitiligo pathogenesis leading to melanocyte destruction. Here, we report a significant increase in oxidative stress in vitiligo patients as evidenced by high lipid peroxidation levels suggesting an imbalance in the antioxidant enzyme system as reported in our previous studies. This study examined the role of the enzymatic antioxidant SOD, which converts the pro-oxidant superoxide into H2O2, in vitiligo pathogenesis. The activity of three isoforms of SOD, i.e., SOD1, SOD2, and SOD3, was significantly higher in vitiligo patients. To identify the underlying mechanism for the increase in activities of SOD isoforms, we explored the SOD1, SOD2, and SOD3 genes for their genetic variations and transcript levels. The SOD2 Thr58Ile (rs35289490) and Leu84Phe (rs11575993) polymorphisms were significantly associated with vitiligo patients, and the Val16Ala (rs4880) polymorphism was associated with active vitiligo patients. Interestingly, SOD2 activity was contributed by these polymorphisms along with its increase in transcript levels in patients. SOD3 activity was associated with the Arg213Gly (rs8192291) polymorphism. The SOD3 transcript levels were also increased in patients, which might contribute to the increased SOD3 activity. However, we could not establish the genotype-phenotype correlation for SOD1 as we could not detect any novel or reported SNPs in SOD1. In addition, both transcript and protein levels of SOD1 were unchanged between patients and controls, though SOD1 activity was increased in patients. Activities of SOD isoforms also correlated with progression of the disease as the activity was higher in active cases of vitiligo compared to stable cases. Here, we report that SOD2 and SOD3 polymorphisms may be genetic risk factors for susceptibility and progression of vitiligo and hence the genetic makeup of an individual may form a basis for the effective treatment of the disease. Overall, our results suggest that increased activity of SOD isoforms under the influence of genetic factors may lead to accumulation of H2O2 in cytoplasmic, mitochondrial, and extracellular compartments resulting in oxidative damage to the melanocytes. PMID:24036105

Laddha, Naresh C; Dwivedi, Mitesh; Gani, Amina R; Shajil, E M; Begum, Rasheedunnisa

2013-12-01

293

Genetic Contribution of CISH Promoter Polymorphisms to Susceptibility to Tuberculosis in Chinese Children  

PubMed Central

Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2) domain protein (CISH) gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16–2.74) and 1.86-fold (95% CI, 1.26–2.74) excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C?809451-T?414171-C?622502 haplotype (OR 3.66, 95% CI:2.12–6.32). The G?809451-A?414171-C?622502-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C?809451-T?414171-C?622502-containing counterpart in Hela cell lines (P?=?0.0009). PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis. PMID:24632804

Sun, Lin; Jin, Ya-qiong; Shen, Chen; Qi, Hui; Chu, Ping; Yin, Qing-qin; Li, Jie-qiong; Tian, Jian-ling; Jiao, Wei-wei; Xiao, Jing; Shen, A-dong

2014-01-01

294

Antimicrobial susceptibility and genetic characterisation of oxytetracycline-resistant Edwardsiella tarda isolated from diseased eels.  

PubMed

Edwardsiellosis is one of the most important bacterial diseases in eels. Edwardsiella tarda (E. tarda) isolates (n=94) from diseased eels were screened against the eight most commonly used antimicrobial agents in aquaculture in Taiwan. These isolates were highly susceptible to ampicillin, amoxicillin, florfenicol, oxolinic acid and flumequine. In total, 20 of the 94 (21.3 per cent) isolates tested were resistant to oxytetracycline (OTC). Among the 20 tetracycline-resistant E. tarda isolates, tet(A) was the predominant resistance determinant and was detected in 100 per cent of the isolates, whereas 90 per cent of these isolates carried the tet(M) determinant. The efflux pump inhibitor omeprazole reduced the minimum inhibitory concentrations (MICs) of OTC for these isolates by twofold to eightfold, suggesting that an intact efflux pump, presumably encoded by tet(A), is required for high-level tetracycline resistance. Real-time PCR experiments showed that increased expression levels of tet(A) and tet(R) could contribute to OTC resistance. Southern blot hybridisation also confirmed that the 20 OTC-resistant E. tarda isolates all carried the TetA determinant on a plasmid that is approximately 50 or 70?kb in size, and restriction fragment length polymorphisms (RFLP) showed that the tet(A) gene was located on an 8-10?kb EcoRI fragment in all of these plasmids. The same plasmid type and RFLP patterns were detected across different farms in the same region, but differences in their pulsed-field gel electrophoresis (PFGE) patterns were observed. This suggests a possible role for horizontal spreading and local transmission of the plasmid in the OTC-resistant E. tarda population of eels from two different geographic origins. PMID:24958553

Lo, D Y; Lee, Y J; Wang, J H; Kuo, H C

2014-08-30

295

Genetic Polymorphisms in miRNAs and Susceptibility to Colorectal Cancer.  

PubMed

The associations of SNPs rs11614913, rs2292832, and rs2910164 in miRNAs have been exploded in several independent studies and meta-analyses, but the small sample sizes and incomplete data precluded well-defined roles of the miRNA SNPs in the development of CRC. The aim of this study was to combine all available data to comprehensively assess the unclear association. A meta-analysis of nine studies included 2,209 cancers and 2,803 controls, 2,349 cases and 2,663 controls, and 1,409 cases and 1,115 controls for SNP rs11614913, SNP rs2910164, and SNP rs2292832, respectively. The true effect size was estimated by an odds ratio (OR) and 95 % confidence intervals (CI) with the fixed effects model. For SNP rs11614913, the risk of CRC was more pronounced in the C allele carriers as compared with the T allele carriers among the subjects of Asian decent (CC vs. TT: OR = 1.18, 95 % CI 1.01-1.38, P = 0.734; CC vs. TC + TT: OR = 1.18, 95 % CI 1.02-1.36, P = 0.573; C vs. T: OR = 1.08, 95 % CI 1.00-1.17, P = 0.775). SNP rs2910164 and SNP rs2292832 were not found to be significantly associated with CRC risk. This meta-analysis reveals that SNP rs11614913, but not SNP rs2910164 and SNP rs2292832, may contribute to susceptibility to CRC in an Asian-specific manner. PMID:25213291

Wu, Yu; Hao, Xiaoxiong; Feng, Zili; Liu, Yunsheng

2015-01-01

296

An Integrated Epigenetic and Genetic Analysis of DNA Methyltransferase Genes (DNMTs) in Tumor Resistant and Susceptible Chicken Lines  

PubMed Central

Both epigenetic alterations and genetic variations play essential roles in tumorigenesis. The epigenetic modification of DNA methylation is catalyzed and maintained by the DNA methyltransferases (DNMT3a, DNMT3b and DNMT1). DNA mutations and DNA methylation profiles of DNMTs themselves and their relationships with chicken neoplastic disease resistance and susceptibility are not yet defined. In the present study, we analyzed the complexity of the DNA methylation variations and DNA mutations in the first exon of three DNMTs genes over generations, tissues, and ages among chickens of two highly inbred White Leghorn lines, Marek's disease-resistant line 63 and -susceptible line 72, and six recombinant congenic strains (RCSs). Among them, tissue-specific methylation patterns of DNMT3a were disclosed in spleen, liver, and hypothalamus in lines 63 and 72. The methylation level of DNMT3b on four CpG sites was not significantly different among four tissues of the two lines. However, two line-specific DNA transition mutations, CpG?TpG (Chr20:10203733 and 10203778), were discovered in line 72 compared to the line 63 and RCSs. The methylation contents of DNMT1 in blood cell showed significant epimutations in the first CpG site among the two inbred lines and the six RCSs (P<0.05). Age-specific methylation of DNMT1 was detected in comparisons between 15 month-old and 2 month-old chickens in both lines except in spleen samples from line 72. No DNA mutations were discovered on the studied regions of DNMT1 and DNMT3a among the two lines and the six RCSs. Moreover, we developed a novel method that can effectively test the significance of DNA methylation patterns consisting of continuous CpG sites. Taken together, these results highlight the potential of epigenetic alterations in DNMT1 and DNMT3a, as well as the DNA mutations in DNMT3b, as epigenetic and genetic factors to neoplastic diseases of chickens. PMID:18648519

Yu, Ying; Zhang, Huanmin; Tian, Fei; Zhang, Wensheng; Fang, Hongbin; Song, Jiuzhou

2008-01-01

297

Genomic selection for recovery of original genetic background from hybrids of endangered and common breeds  

PubMed Central

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

Amador, Carmen; Hayes, Ben J; Daetwyler, Hans D

2014-01-01

298

Sardinians Genetic Background Explained by Runs of Homozygosity and Genomic Regions under Positive Selection  

PubMed Central

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

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

299

Genetic diversity and antimicrobial susceptibility of Campylobacter jejuni isolates associated with sheep abortion in the United States and Great Britain.  

PubMed

Campylobacter infection is a leading cause of ovine abortion worldwide. Historically, genetically diverse Campylobacter fetus and Campylobacter jejuni strains have been implicated in such infections, but since 2003 a highly pathogenic, tetracycline-resistant C. jejuni clone (named SA) has become the predominant cause of sheep abortions in the United States. Whether clone SA was present in earlier U.S. abortion isolates (before 2000) and is associated with sheep abortions outside the United States are unknown. Here, we analyzed 54 C. jejuni isolates collected from U.S. sheep abortions at different time periods and compared them with 42 C. jejuni isolates associated with sheep abortion during 2002 to 2008 in Great Britain, using multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and array-based comparative genomic hybridization (CGH). Although clone SA (ST-8) was present in the early U.S. isolates, it was not as tetracycline resistant (19% versus 100%) or predominant (66% versus 91%) as it was in the late U.S isolates. In contrast, C. jejuni isolates from Great Britain were genetically diverse, comprising 19 STs and lacking ST-8. PFGE and CGH analyses of representative strains further confirmed the population structure of the abortion isolates. Notably, the Great Britain isolates were essentially susceptible to most tested antibiotics, including tetracycline, while the late U.S. isolates were universally resistant to this antibiotic, which could be explained by the common use of tetracyclines for control of sheep abortions in the United States but not in Great Britain. These results suggest that the dominance of clone SA in sheep abortions is unique to the United States, and the use of tetracyclines may have facilitated selection of this highly pathogenic clone. PMID:24648552

Wu, Zuowei; Sippy, Rachel; Sahin, Orhan; Plummer, Paul; Vidal, Ana; Newell, Diane; Zhang, Qijing

2014-06-01

300

Genetic Diversity and Antimicrobial Susceptibility of Campylobacter jejuni Isolates Associated with Sheep Abortion in the United States and Great Britain  

PubMed Central

Campylobacter infection is a leading cause of ovine abortion worldwide. Historically, genetically diverse Campylobacter fetus and Campylobacter jejuni strains have been implicated in such infections, but since 2003 a highly pathogenic, tetracycline-resistant C. jejuni clone (named SA) has become the predominant cause of sheep abortions in the United States. Whether clone SA was present in earlier U.S. abortion isolates (before 2000) and is associated with sheep abortions outside the United States are unknown. Here, we analyzed 54 C. jejuni isolates collected from U.S. sheep abortions at different time periods and compared them with 42 C. jejuni isolates associated with sheep abortion during 2002 to 2008 in Great Britain, using multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and array-based comparative genomic hybridization (CGH). Although clone SA (ST-8) was present in the early U.S. isolates, it was not as tetracycline resistant (19% versus 100%) or predominant (66% versus 91%) as it was in the late U.S isolates. In contrast, C. jejuni isolates from Great Britain were genetically diverse, comprising 19 STs and lacking ST-8. PFGE and CGH analyses of representative strains further confirmed the population structure of the abortion isolates. Notably, the Great Britain isolates were essentially susceptible to most tested antibiotics, including tetracycline, while the late U.S. isolates were universally resistant to this antibiotic, which could be explained by the common use of tetracyclines for control of sheep abortions in the United States but not in Great Britain. These results suggest that the dominance of clone SA in sheep abortions is unique to the United States, and the use of tetracyclines may have facilitated selection of this highly pathogenic clone. PMID:24648552

Wu, Zuowei; Sippy, Rachel; Plummer, Paul; Vidal, Ana; Newell, Diane; Zhang, Qijing

2014-01-01

301

Genetic Variant rs401681 at 5p15.33 Modifies Susceptibility to Lung Cancer but Not Esophageal Squamous Cell Carcinoma  

PubMed Central

Background The human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, which have been implicated in carcinogenesis. A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study. However, subsequent replication studies in diverse populations have yielded inconsistent results. In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies. Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC) remains unknown. Methods We genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case–control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC) and 860 healthy individuals. Results Logistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR?=?0.782, 95% CI?=?0.625–0.978, P?=?0.031; CT/TT vs. CC: adjusted OR?=?0.786; 95% CI?=?0.635–0.972, P?=?0.026). Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma. Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR?=?0.910, 95% CI?=?0.734–1.129, P?=?0.392; TT vs. CC: adjusted OR?=?0.897, 95%CI?=?0.624–1.290, P?=?0.558; CT/TT vs. CC: adjusted OR?=?0.908, 95% CI?=?0.740–1.114, P?=?0.355). Conclusions Our findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer. In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese population, and our results suggest that this genetic variant may not be involved in ESCC risk. PMID:24386361

Jiang, Man; Wu, Haijian; Qin, Chengyong

2013-01-01

302

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.  

PubMed

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22?981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.Genes and Immunity advance online publication, 9 October 2014; doi:10.1038/gene.2014.51. PMID:25297839

Crosslin, D R; Carrell, D S; Burt, A; Kim, D S; Underwood, J G; Hanna, D S; Comstock, B A; Baldwin, E; de Andrade, M; Kullo, I J; Tromp, G; Kuivaniemi, H; Borthwick, K M; McCarty, C A; Peissig, P L; Doheny, K F; Pugh, E; Kho, A; Pacheco, J; Hayes, M G; Ritchie, M D; Verma, S S; Armstrong, G; Stallings, S; Denny, J C; Carroll, R J; Crawford, D C; Crane, P K; Mukherjee, S; Bottinger, E; Li, R; Keating, B; Mirel, D B; Carlson, C S; Harley, J B; Larson, E B; Jarvik, G P

2014-10-01

303

Genetic variation in the HLA region is associated with susceptibility to herpes zoster  

PubMed Central

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22?981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10?8). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine. PMID:25297839

Crosslin, D R; Carrell, D S; Burt, A; Kim, D S; Underwood, J G; Hanna, D S; Comstock, B A; Baldwin, E; de Andrade, M; Kullo, I J; Tromp, G; Kuivaniemi, H; Borthwick, K M; McCarty, C A; Peissig, P L; Doheny, K F; Pugh, E; Kho, A; Pacheco, J; Hayes, M G; Ritchie, M D; Verma, S S; Armstrong, G; Stallings, S; Denny, J C; Carroll, R J; Crawford, D C; Crane, P K; Mukherjee, S; Bottinger, E; Li, R; Keating, B; Mirel, D B; Carlson, C S; Harley, J B; Larson, E B; Jarvik, G P

2015-01-01

304

Genetic mapping of quantitative trait loci affecting susceptibility in chicken to develop pulmonary hypertension syndrome.  

PubMed

Pulmonary hypertension syndrome (PHS), also referred to as ascites syndrome, is a growth-related disorder of chickens frequently observed in fast-growing broilers with insufficient pulmonary vascular capacity at low temperature and/or at high altitude. A cross between two genetically different broiler dam lines that originated from the White Plymouth Rock breed was used to produce a three-generation population. This population was used for the detection and localization of quantitative trait loci (QTL) affecting PHS-related traits. Ten full-sib families consisting of 456 G2 birds were typed with 420 microsatellite markers covering 24 autosomal chromosomes. Phenotypic observations were collected on 4202 G3 birds and a full-sib across family regression interval mapping approach was used to identify QTL. There was statistical evidence for QTL on chicken chromosome 2 (GGA2), GGA4 and GGA6. Suggestive QTL were found on chromosomes 5, 8, 10, 27 and 28. The most significant QTL were located on GGA2 for right and total ventricular weight as percentage of body weight (%RV and %TV respectively). A related trait, the ratio of right ventricular weight as percentage to total ventricular weight (RATIO), reached the suggestive threshold on this chromosome. All three QTL effects identified on GGA2 had their maximum test statistic in the region flanked by markers MCW0185 and MCW0245 (335-421 cM). PMID:16293119

Rabie, T S K M; Crooijmans, R P M A; Bovenhuis, H; Vereijken, A L J; Veenendaal, T; van der Poel, J J; Van Arendonk, J A M; Pakdel, A; Groenen, M A M

2005-12-01

305

Transcriptome Profiling of Human Ulcerative Colitis Mucosa Reveals Altered Expression of Pathways Enriched in Genetic Susceptibility Loci  

PubMed Central

Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently-generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate <0.05). The upregulated pathways were dominated by gene sets involved in immune function and signaling, as well as the control of mitosis. We applied pathway analysis to genotype data derived from genome-wide association studies (GWAS) of UC, consisting of 5,584 cases and 11,587 controls assembled from eight European-ancestry cohorts. The upregulated pathways derived from the gene expression data showed a highly significant overlap with pathways derived from the genotype data (33 of 56 gene sets, hypergeometric P?=?1.49×10–19). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process. PMID:24788701

Li, Jin; Zhu, Junfei; Gu, Mengnan; Baldassano, Robert N.; Grant, Struan F. A.; Hakonarson, Hakon

2014-01-01

306

Genetic moderation of interpersonal psychotherapy efficacy for low-income mothers with major depressive disorder: Implications for differential susceptibility.  

PubMed

Genetic moderation of interpersonal psychotherapy (IPT) efficacy for economically disadvantaged women with major depressive disorder was examined. Specifically, we investigated whether genotypic variation in corticotropin releasing hormone receptor 1 (CRHR1) and the linked polymorphic region of the serotonin transporter gene (5-HTTLPR) moderated effects of IPT on depressive symptoms over time. We also tested genotype moderation of IPT mechanisms on social adjustment and perceived stress. Non-treatment-seeking urban women at or below the poverty level with infants were recruited from the community (N = 126; M age = 25.33 years, SD = 4.99; 54.0% African American, 22.2% Caucasian, and 23.8% Hispanic/biracial) and randomized to individual IPT or Enhanced Community Standard groups. The results revealed that changes in depressive symptoms over time depended on both intervention group and genotypes (5-HTTLPR and CRHR1). Moreover, multiple-group path analysis indicated that IPT improved depressive symptoms, increased social adjustment, and decreased perceived stress at posttreatment among women with the 0 copies of the CRHR1 TAT haplotype only. Finally, improved social adjustment at postintervention significantly mediated the effect of IPT on reduced depressive symptoms at 8 months postintervention for women with 0 copies of the TAT haplotype only. Post hoc analyses of 5-HTTLPR were indicative of differential susceptibility, albeit among African American women only. PMID:25640828

Cicchetti, Dante; Toth, Sheree L; Handley, Elizabeth D

2015-02-01

307

Susceptibility of carnivore hosts to strains of canine distemper virus from distinct genetic lineages.  

PubMed

Using the complete haemagglutinin (HA) gene and partial phosphoprotein (P) gene we investigated the genotype of canine distemper virus (CDV) strains recovered from two wildlife species in Mecklenburg-Vorpommern, Germany. Phylogenetic analyses demonstrated significant differences between the strains from raccoons Procyon lotor (family Procyonidae) obtained in 2007 and strains from red foxes Vulpes vulpes (family Canidae) obtained in 2008. The raccoon strains belonged to the CDV European wildlife lineage whereas the red fox strains belonged to the CDV Europe lineage. We combined our genetic sequence data with published data from 138 CDV stains worldwide to investigate the proposed importance of amino acid substitutions in the SLAM binding region of the CDV HA protein at position 530 (G/E to R/D/N) and 549 (Y to H) to the spread of domestic dog-adapted CDV strains to other carnivores. We found no evidence that amino acid 530 was strongly affected by host species. Rather, site 530 was conserved within CDV lineages, regardless of host species. Contrary to expectation, strains from non-dog hosts did not exhibit a bias towards the predicted substitution Y549H. Wild canid hosts were more frequently infected by strains with 549Y, a pattern similar to domestic dogs. Non-canid strains showed no significant bias towards either H or Y at site 549, although there was a trend towards 549H. Significant differences between the prevalence of 549Y and 549H in wild canid strains and non-canid strains suggests a degree of virus adaptation to these categories of host. PMID:22024346

Nikolin, Veljko M; Wibbelt, Gudrun; Michler, Frank-Uwe F; Wolf, Peter; East, Marion L

2012-04-23

308

The Influence of Genetic Background on Conventional Outflow Facility in Mice  

PubMed Central

Purpose. Intraocular pressure (IOP) varies between genetically distinct strains of mice. The purpose was to test the hypothesis that strain-dependent differences in IOP are attributable to differences in conventional outflow facility (C). Methods. The IOP was measured by rebound tonometry in conscious or anesthetized BALB/cJ, C57BL/6J, and CBA/J mice (N = 6–10 per strain). Conventional outflow facility was measured by ex vivo perfusion of enucleated eyes (N = 9–10 per strain). Results. Conscious IOP varied between strains, being highest in CBA/J (14.5 ± 0.9 mm Hg, mean ± SD), intermediate in C57BL/6J (12.3 ± 1.0 mm Hg), and lowest in BALB/cJ (10.6 ± 1.8 mm Hg) mice. Anesthesia reduced IOP and eliminated any detectable differences between strains. Conventional outflow facility also varied between strains, but, in contrast to IOP, C was lowest in CBA/J (0.0113 ± 0.0031 ?L/min/mm Hg) and highest in BALB/cJ (0.0164 ± 0.0059 ?L/min/mm Hg). Like IOP, C was intermediate in C57BL/6J (0.0147 ± 0.0029 ?L/min/mm Hg). There was a strong correlation between conscious IOP and outflow resistance (1/C) from individual eyes across all three strains, revealing that 70% of the variation in IOP was attributable to variation in outflow resistance. Conclusions. Differences in IOP among three genetically distinct murine strains are attributable largely to differences in conventional outflow facility. These results motivate further studies using mice to identify the morphologic and genetic factors that underlie IOP regulation within the conventional outflow pathway. PMID:24235015

Boussommier-Calleja, Alexandra; Overby, Darryl R.

2013-01-01

309

Genetic Factors Affecting Susceptibility to Low Dose & Low Dose-Rate Radiation  

SciTech Connect

Our laboratory has, among other things, developed and used the gamma H2AX focus assay and other chromosomal and cell killing assays to show that differences in this DNA double strand break (dsb) related response can be clearly and distinctly demonstrated for cells which are mildly hyper-radiosensitive such as those associated with A-T heterozygosity. We have found this level of mild hypersensitivity for cells from some 20 to 30 % of apparently normal individuals and from apparently normal parents of Retinoblastoma patients. We found significant differences in gene expression in somatic cells from unaffected parents of Rb patients as compared with normal controls, suggesting that these parents may harbor some as yet unidentified genetic abnormality. In other experiments we sought to determine the extent of differences in normal human cellular reaponses to radiation depending on their irradiation in 2D monolayer vs 3D organized acinar growth conditions. We exmined cell reproductive death, chromosomal aberration induction, and the levels of ?-H2AX foci in cells after single acute gamma-ray doses and immediately after 20 hours of irradiation at a dose rate of 0.0017 Gy/min. We found no significant differences in the dose-responses of these cells under the 2D or 3D growth conditions. While this does not mean such differences cannot occur in other situations, it does mean that they do not generally or necessarily occur. In another series of studies in collaboration with Dr Chuan Li, with supprt from this current grant. We reported a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. In yet another collaboration with Dr, B. Chen with funds from this grant, the relative radiosensitivity to cell killing as well as chromosomal instability of 13 DNA-PKcs site-directed mutant cell lines (defective at phosphorylation sites or kinase activity) were examined after exposure of synchronized G1 cells to 137Cs c rays. DNA-PKcs mutant cells defective in phosphorylation at multiple sites withinthe T2609 cluster or within the PI3K domain displayed extreme radiosensitivity. Cells defective at the S2056 cluster or T2609 single site alone were only mildly radiosensitive, but cells defective at even one site in both the S2056 and T2609 clusters were maximally radiosensitive. Thus a synergism between the capacity for phosphorylation at the S2056 and T2609 clusterswas found to be critical for induction of radiosensitivity.

Bedford, Joel

2014-04-18

310

Symposium 2-1  The autoimmunome: Similarities and differences among genetic susceptibility to common immune-related diseases.  

PubMed

  Autoimmune disorders arise when physiological tolerance to "self" antigens is lost. Although several mechanisms may be involved in this pathogenic process, dysregulation of T-cell and B-cell activation and of pathways leading to inflammation are logical candidates. Susceptibility to autoimmune diseases has been associated with multiple factors including genetics, epigenetics, and the environment. While the modest concordance rate in monozygotic twins suggests that environmental factors are major players in most autoimmune diseases, increased heritability within families and the decrease in risk with the degree of relatedness all argue in favor of genetic factors. With the advent of high-throughput genomics, massive amounts of genetic data are being produced and reported on a monthly basis. Although considerable insight has been gained from each of these individual studies, a detailed comparative analysis will likely identify both unique and common pathways operating in autoimmunity.  More than 40 genome-wide association studies (GWAS) have been published to date in several autoimmune diseases (AID) and hundreds of common variants have been identified that confer risk or protection. While statistical adjustments are essential to refine the list of potential associations with each disease, valuable information can be extracted by the systematic collection of moderately significant variants present in more than one trait. While involvement of the MHC region in chromosome 6p21 is not in question for most AID, the complex genetic architecture of this locus poses a significant analytical challenge. On the other hand, by considering the contribution of non-MHC-related genes, similarities and differences among AID can be readily computed thus gaining insights into possible pathogenic mechanisms. For example, statistically significant excess sharing of non-MHC genes was found between type I diabetes (T1D) and all other AID studied, a result also seen for RA. A smaller but significant degree of sharing was observed for multiple sclerosis (MS), Celiac disease (CeD) and Crohn's disease (CD).   We have developed a bioinformatics tool called iCTNet (integrated Complex Traits networks), that enables downloading and visualization of large volumes of data and the relationships among the different data types, information that is not typically available for the general user. The most recent version of iCNet (scheduled to be released in Spring 2014) includes data from genome-wide association studies, OMIM, protein interactions, tissue expression, drug targets, drug side effects, and miRNA targets among other data types. During my presentation I will describe practical examples of how this tools may facilitate the biological interpretation of large throughput data in human immune-related diseases and how this can help to generate new hypotheses for drug repositioning strategies.   Using this class of approaches the unique genetic landscape for each autoimmune disease can start to be defined. Furthermore, this kind of analysis may set the basis for more targeted and rational therapeutic approaches. PMID:25297131

Baranzini, Sergio E

2014-01-01

311

TNF-? and IFN-? gene variation and genetic susceptibility to type 1 diabetes and its microangiopathic complications  

PubMed Central

Background TNF-? has accelerating role in development of type 1 diabetes. Although an immunosupressor function and leading protecting role in T1DM also has been claimed for this pro-inflammatory cytokine. Over-expression of pro-inflammatory and type 1 cytokines (Th1, like IFN-?) drive insulitis toward the destructive form that leads to type 1 diabetes (T1DM). Among type 1 cytokines only IFN-? has been detectable in the islet ? cells. In deletion studies IFN-? was also the only Th1 cytokine for which its ablation or blockade caused delayed or decreased incidence of T1DM. Methods Functional polymorphisms of TNF-? at position -308*G/A and at position +874*T/A of IFN-? gene were employed as markers and the comparative distribution of derived genotypes/alleles were assessed in 248 British Caucasian T1DM patients and 118 healthy controls. Results There was no significant association between IFN-? gene polymorphism and T1DM or the diabetic complication triad. There was a marginal association between TNF-? –308*G/A polymorphism in nephropaths (vs healthy controls) (p?=?0.06), which its insignificancy may be due to survivor factor. No significant association was evident between the genotype/allele of the applied marker and T1DM or diabetic complication triad. Conclusion Our results are in contrast with previous reports suggesting that these polymorphisms are not related to T1DM. This study also underlines the importance of replication of association studies to confirm the previous interpretation. PMID:24693923

2014-01-01

312

BRIP1 , PALB2 , and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer  

Microsoft Academic Search

Mutations in the recognized breast cancer susceptibility genes BRCA1, BRCA2, TP53, ATM, and CHEK2 account for approximately 20% of hereditary breast cancer. This raises the possibility that mutations in other biologically\\u000a relevant genes may be involved in genetic predisposition to breast cancer. In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of previously being associated

Michelle W. Wong; Cecilia Nordfors; David Mossman; Gordana Pecenpetelovska; Kelly A. Avery-Kiejda; Bente Talseth-Palmer; Nikola A. Bowden; Rodney J. Scott

2011-01-01

313

Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer  

PubMed Central

Background Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT). Methods We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case–control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model. Results One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p?=?0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction?=?0.03). There were no significant interactions after correction for multiple testing. Conclusions We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials. PMID:22726230

2012-01-01

314

Spontaneous lupus-like syndrome in HLA-DQ2 Transgenic Mice with a Mixed Genetic Background  

PubMed Central

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE°DQ2). These AE°DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE°DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE°DQ2 mice also developed significant and progressive hematuria and proteinuria as compared to the AE°DQ6 mice (P<0.05). Histopathology showed immune complex deposits in the glomeruli of AE°DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a “fingerprint” substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE°DQ6 mice. Serum anti-dsDNA IgM and IgG levels were also significantly elevated among AE°DQ2 mice compared to AE°DQ6 mice (P<0.001). In conclusion, AE°DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this SLE-like syndrome in HLA-DQ2 transgenic mice. PMID:20142296

Rashtak, Shadi; Marietta, Eric; Cheng, Shen; Camilleri, Michael; Pittelkow, Mark; David, Chella; Grande, Joseph; Murray, Joseph

2010-01-01

315

Genetic background influences adaptation to cardiac hypertrophy and Ca2+ handling gene expression  

PubMed Central

Genetic variability has a profound effect on the development of cardiac hypertrophy in response to stress. Consequently, using a variety of inbred mouse strains with known genetic profiles may be powerful models for studying the response to cardiovascular stress. To explore this approach we looked at male C57BL/6J and 129/SvJ mice. Hemodynamic analyses of left ventricular pressures (LVPs) indicated significant differences in 129/SvJ and C57BL/6J mice that implied altered Ca2+ handling. Specifically, 129/SvJ mice demonstrated reduced rates of relaxation and insensitivity to dobutamine (Db). We hypothesized that altered expression of genes controlling the influx and efflux of Ca2+ from the sarcoplasmic reticulum (SR) was responsible and investigated the expression of several genes involved in maintaining the intracellular and sarcoluminal Ca2+ concentration using quantitative real-time PCR analyses (qRT-PCR). We observed significant differences in baseline gene expression as well as different responses in expression to isoproterenol (ISO) challenge. In untreated control animals, 129/SvJ mice expressed 1.68× more ryanodine receptor 2(Ryr2) mRNA than C57BL/6J mice but only 0.37× as much calsequestrin 2 (Casq2). After treatment with ISO, sarco(endo)plasmic reticulum Ca2+-ATPase(Serca2) expression was reduced nearly two-fold in 129/SvJ while expression in C57BL/6J was stable. Interestingly, ? (1) adrenergic receptor(Adrb1) expression was lower in 129/SvJ compared to C57BL/6J at baseline and lower in both strains after treatment. Metabolically, the brain isoform of creatine kinase (Ckb) was up-regulated in response to ISO in C57BL/6J but not in 129/SvJ. These data suggest that the two strains of mice regulate Ca2+ homeostasis via different mechanisms and may be useful in developing personalized therapies in human patients. PMID:23508205

Waters, Steve B.; Diak, Douglass M.; Zuckermann, Matthew; Goldspink, Paul H.; Leoni, Lara; Roman, Brian B.

2013-01-01

316

Genetic variation in bacterial kidney disease (BKD) susceptibility in Lake Michigan Chinook Salmon and its progenitor population from the Puget Sound  

USGS Publications Warehouse

Mass mortality events in wild fish due to infectious diseases are troubling, especially given the potential for long-term, population-level consequences. Evolutionary theory predicts that populations with sufficient genetic variation will adapt in response to pathogen pressure. Chinook Salmon Oncorhynchus tshawytscha were introduced into Lake Michigan in the late 1960s from a Washington State hatchery population. In the late 1980s, collapse of the forage base and nutritional stress in Lake Michigan were thought to contribute to die-offs of Chinook Salmon due to bacterial kidney disease (BKD). Previously, we demonstrated that Lake Michigan Chinook Salmon from a Wisconsin hatchery have greater survival following BKD challenge relative to their progenitor population. Here, we evaluated whether the phenotypic divergence of these populations in BKD susceptibility was due to selection rather than genetic drift. Comparison of the overall magnitude of quantitative trait to neutral marker divergence between the populations suggested selection had occurred but a direct test of quantitative trait divergence was not significant, preventing the rejection of the null hypothesis of differentiation through genetic drift. Estimates of phenotypic variation (VP), additive genetic variation (VA) and narrow-sense heritability (h2) were consistently higher in the Wisconsin relative to the Washington population. If selection had acted on the Wisconsin population there was no evidence of a concomitant loss of genetic variation in BKD susceptibility. The Renibacterium salmoninarum exposures were conducted at both 14°C and 9°C; the warmer temperature accelerated time to death in both populations and there was no evidence of phenotypic plasticity or a genotype-by-environment (G × E) interaction. High h2 estimates for BKD susceptibility in the Wisconsin population, combined with a lack of phenotypic plasticity, predicts that future adaptive gains in BKD resistance are still possible and that these adaptive gains would be stable under the temperature range evaluated here.

Purcell, Maureen K.; Hard, Jeffrey J.; Neely, Kathleen G.; Park, Linda K.; Winton, James R.; Elliott, Diane G.

2014-01-01

317

Two genetic variants in FABP1 and susceptibility to non-alcohol fatty liver disease in a Chinese population.  

PubMed

Liver fatty acid-binding protein (FABP1) serves as a key regulator of hepatic lipid metabolism, and polymorphisms within the FABP1 gene have been associated with several metabolic traits. To investigate the association between FABP1 polymorphisms and the risk of non-alcohol fatty liver disease (NAFLD) in a Chinese population, the genotypes and haplotypes of FABP1 (rs2241883 T/C and rs1545224G/A) were determined in 553 patients with NAFLD and 553 healthy controls. The results showed that individuals with at least one copy of the rs2241883 C allele (TC or CC genotype) had an elevated risk for developing NAFLD (odds ratio [OR]=1.32, 95% CI: 1.01-1.71), and individuals with at least one copy of the rs1545224 A allele (GA or AA genotype) also had a significantly increased risk for NAFLD (OR=1.52, 95% CI: 1.14-2.02). Cumulative effect analysis of the two SNPs revealed that individuals with two risk genotypes were at significantly higher risk of NAFLD than those without risk genotype, and a significant trend of increased risk with increasing numbers of risk genotype was observed. Stratification analysis showed that the rs2241883 C allele carriers had higher level of LDL-C and the rs1545224 A allele carriers had higher level of FPG than those without this allele. In addition, haplotype analysis revealed that the one composed of the rs1545224 A and rs2241883 C variants was significantly associated with an increased risk for NAFLD (OR=1.34; 95% CI=1.05-1.40) compared to the GT haplotype. Taken together, the present study suggests that genetic variations within FABP1 influence susceptibility to NAFLD independently or jointly. PMID:22465531

Peng, Xian-E; Wu, Yun-Li; Lu, Qing-Qing; Hu, Zhi-Jian; Lin, Xu

2012-05-25

318

Comparative genomics reveals multiple genetic backgrounds of human pathogenicity in the Trypanosoma brucei complex.  

PubMed

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

Sistrom, Mark; Evans, Benjamin; Bjornson, Robert; Gibson, Wendy; Balmer, Oliver; Mäser, Pascal; Aksoy, Serap; Caccone, Adalgisa

2014-10-01

319

Comparative Genomics Reveals Multiple Genetic Backgrounds of Human Pathogenicity in the Trypanosoma brucei Complex  

PubMed Central

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

Sistrom, Mark; Evans, Benjamin; Bjornson, Robert; Gibson, Wendy; Balmer, Oliver; Mäser, Pascal; Aksoy, Serap; Caccone, Adalgisa

2014-01-01

320

Germline competence of mouse ES and iPS cell lines: Chimera technologies and genetic background  

PubMed Central

In mice, gene targeting by homologous recombination continues to play an essential role in the understanding of functional genomics. This strategy allows precise location of the site of transgene integration and is most commonly used to ablate gene expression (“knock-out”), or to introduce mutant or modified alleles at the locus of interest (“knock-in”). The efficacy of producing live, transgenic mice challenges our understanding of this complex process, and of the factors which influence germline competence of embryonic stem cell lines. Increasingly, evidence indicates that culture conditions and in vitro manipulation can affect the germline-competence of Embryonic Stem cell (ES cell) lines by accumulation of chromosome abnormalities and/or epigenetic alterations of the ES cell genome. The effectiveness of ES cell derivation is greatly strain-dependent and it may also influence the germline transmission capability. Recent technical improvements in the production of germline chimeras have been focused on means of generating ES cells lines with a higher germline potential. There are a number of options for generating chimeras from ES cells (ES chimera mice); however, each method has its advantages and disadvantages. Recent developments in induced pluripotent stem (iPS) cell technology have opened new avenues for generation of animals from genetically modified somatic cells by means of chimera technologies. The aim of this review is to give a brief account of how the factors mentioned above are influencing the germline transmission capacity and the developmental potential of mouse pluripotent stem cell lines. The most recent methods for generating specifically ES and iPS chimera mice, including the advantages and disadvantages of each method are also discussed. PMID:21607104

Carstea, Ana Claudia; Pirity, Melinda K; Dinnyes, Andras

2009-01-01

321

Genetic variability of Spodoptera frugiperda Smith (Lepidoptera: Noctuidae) populations from Latin America is associated with variations in susceptibility to Bacillus thuringiensis cry toxins.  

PubMed

Bacillus thuringiensis strains isolated from Latin American soil samples that showed toxicity against three Spodoptera frugiperda populations from different geographical areas (Mexico, Colombia, and Brazil) were characterized on the basis of their insecticidal activity, crystal morphology, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of parasporal crystals, plasmid profiles, and cry gene content. We found that the different S. frugiperda populations display different susceptibilities to the selected B. thuringiensis strains and also to pure preparations of Cry1B, Cry1C, and Cry1D toxins. Binding assays performed with pure toxin demonstrated that the differences in the toxin binding capacities of these insect populations correlated with the observed differences in susceptibility to the three Cry toxins analyzed. Finally, the genetic variability of the three insect populations was analyzed by random amplification of polymorphic DNA-PCR, which showed significant genetic diversity among the three S. frugiperda populations analyzed. The data presented here show that the genetic variability of S. frugiperda populations should be carefully considered in the development of insect pest control strategies, including the deployment of genetically modified maize in different geographical regions. PMID:16936049

Monnerat, Rose; Martins, Erica; Queiroz, Paulo; Ordúz, Sergio; Jaramillo, Gabriela; Benintende, Graciela; Cozzi, Jorge; Real, M Dolores; Martinez-Ramirez, Amparo; Rausell, Carolina; Cerón, Jairo; Ibarra, Jorge E; Del Rincon-Castro, M Cristina; Espinoza, Ana M; Meza-Basso, Luis; Cabrera, Lizbeth; Sánchez, Jorge; Soberon, Mario; Bravo, Alejandra

2006-11-01

322

Genetic association of KCNJ10 rs1130183 with seizure susceptibility and computational analysis of deleterious non-synonymous SNPs of KCNJ10 gene.  

PubMed

Establishing genetic basis of Idiopathic generalized epilepsies (IGE) is challenging because of their complex inheritance pattern and genetic heterogeneity. Kir4.1 inwardly rectifying channel (KCNJ10) is one of the independent genes reported to be associated with seizure susceptibility. In the current study we have performed a comprehensive in silico analysis of genetic variants in KCNJ10 gene at functional and structural level along with a case-control analysis for the association of rs1130183 (R271C) polymorphism in Indian patients with IGE. Age and sex matched 108 epileptic patients and normal healthy controls were examined. Genotyping of KCNJ10rs1130183 variation was performed using PCR-RFLP method. The risk association was determined by using odds ratio and 95% confidence interval. Functional effects of non-synonymous SNPs (nsSNPs) in KCNJ10 gene were analyzed using SIFT PolyPhen-2, I-Mutant 2.0, PANTHER and FASTSNP. Subsequently, homology modeling of protein three dimensional (3D) structures was performed using Modeller tool (9.10v) and compared the native protein with mutant for assessment of structure and stability. SIFT, PolyPhen-2, I-Mutant 2.0 and PANTHER collectively showed rs1130183, rs1130182 and rs137853073 SNPs inKCNJ10 gene affect protein structure and function. There was a considerable variation in the Root Mean Square Deviation (RMSD) value between the native and mutant structure (1.17?). Association analysis indicate KCNJ10rs1130183 did not contribute to risk of seizure susceptibility in Indian patients with IGE (OR- 0.38; 95%CI, 0.07-2.05) and T allele frequency (0.02%) was in concordance with dbSNP reports. This study identifies potential SNPs that may contribute to seizure susceptibility and further studies with the selected SNPs in larger number of samples and their functional analysis is required for understanding the variants of KCNJ10 with seizure susceptibility. PMID:24378235

Phani, Nagaraja M; Acharya, Shreeshakala; Xavy, Seethu; Bhaskaranand, Nalini; Bhat, Manoj K; Jain, Aditya; Rai, Padmalatha S; Satyamoorthy, Kapaettu; Kapaettu, Satyamoorthy

2014-02-25

323

Maize centromeres expand and adopt a uniform size in the genetic background of oat.  

PubMed

Most existing centromeres may have originated as neocentromeres that activated de novo from noncentromeric regions. However, the evolutionary path from a neocentromere to a mature centromere has been elusive. Here we analyzed the centromeres of nine chromosomes that were transferred from maize into oat as the result of an inter-species cross. Centromere size and location were assayed by chromatin immunoprecipitation for the histone variant CENH3, which is a defining feature of functional centromeres. Two isolates of maize chromosome 3 proved to contain neocentromeres in the sense that they had moved from the original site, whereas the remaining seven centromeres (1, 2, 5, 6, 8, 9, and 10) were retained in the same area in both species. In all cases, the CENH3-binding domains were dramatically expanded to encompass a larger area in the oat background (?3.6 Mb) than the average centromere size in maize (?1.8 Mb). The expansion of maize centromeres appeared to be restricted by the transcription of genes located in regions flanking the original centromeres. These results provide evidence that (1) centromere size is regulated; (2) centromere sizes tend to be uniform within a species regardless of chromosome size or origin of the centromere; and (3) neocentromeres emerge and expand preferentially in gene-poor regions. Our results suggest that centromere size expansion may be a key factor in the survival of neocentric chromosomes in natural populations. PMID:24100079

Wang, Kai; Wu, Yufeng; Zhang, Wenli; Dawe, R Kelly; Jiang, Jiming

2014-01-01

324

Maize centromeres expand and adopt a uniform size in the genetic background of oat  

PubMed Central

Most existing centromeres may have originated as neocentromeres that activated de novo from noncentromeric regions. However, the evolutionary path from a neocentromere to a mature centromere has been elusive. Here we analyzed the centromeres of nine chromosomes that were transferred from maize into oat as the result of an inter-species cross. Centromere size and location were assayed by chromatin immunoprecipitation for the histone variant CENH3, which is a defining feature of functional centromeres. Two isolates of maize chromosome 3 proved to contain neocentromeres in the sense that they had moved from the original site, whereas the remaining seven centromeres (1, 2, 5, 6, 8, 9, and 10) were retained in the same area in both species. In all cases, the CENH3-binding domains were dramatically expanded to encompass a larger area in the oat background (?3.6 Mb) than the average centromere size in maize (?1.8 Mb). The expansion of maize centromeres appeared to be restricted by the transcription of genes located in regions flanking the original centromeres. These results provide evidence that (1) centromere size is regulated; (2) centromere sizes tend to be uniform within a species regardless of chromosome size or origin of the centromere; and (3) neocentromeres emerge and expand preferentially in gene-poor regions. Our results suggest that centromere size expansion may be a key factor in the survival of neocentric chromosomes in natural populations. PMID:24100079

Wang, Kai; Wu, Yufeng; Zhang, Wenli; Dawe, R. Kelly; Jiang, Jiming

2014-01-01

325

Individual Genetic Susceptibility  

SciTech Connect

Risk estimates derived from epidemiological studies of exposed populations, as well as the maximum permissible doses allowed for occupational exposure and exposure of the public to ionizing radiation are all based on the assumption that the human population is uniform in its radiosensitivity, except for a small number of individuals, such as ATM homozygotes who are easily identified by their clinical symptoms. The hypothesis upon which this proposal is based is that the human population is not homogeneous in radiosensitiviry, but that radiosensitive sub-groups exist which are not easy to identify. These individuals would suffer an increased incidence of detrimental radiation effects, and distort the shape of the dose response relationship. The radiosensitivity of these groups depend on the expression levels of specific proteins. The plan was to investigate the effect of 3 relatively rare, high penetrate genes available in mice, namely Atm, mRad9 & Brca1. The purpose of radiation protection is to prevent! deterministic effects of clinical significance and limit stochastic effects to acceptable levels. We plan, therefore to compare with wild type animals the radiosensitivity of mice heterozygous for each of the genes mentioned above, as well as double heterozygotes for pairs of genes, using two biological endpoints: a) Ocular cataracts as an important and relevant deterministic effect, and b) Oncogenic transformation in cultured embryo fibroblasts, as a surrogate for carcinogenesis, the most relevant stochastic effect.

Eric J. Hall

2008-12-08

326

Mitochondrial 12S rRNA A827G mutation is involved in the genetic susceptibility to aminoglycoside ototoxicity  

SciTech Connect

We have analyzed the clinical and molecular characterization of a Chinese family with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluations revealed that only those family members who had a history of exposure to aminoglycoside antibiotics subsequently developed hearing loss, suggesting mitochondrial genome involvement. Sequence analysis of the mitochondrial 12S rRNA and tRNA{sup Ser(UCN)} genes led to the identification of a homoplasmic A827G mutation in all maternal relatives, a mutation that was identified previously in a few sporadic patients and in another Chinese family with non-syndromic deafness. The pathogenicity of the A827G mutation is strongly supported by the occurrence of the same mutation in two independent families and several genetically unrelated subjects. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly conserved in mammals. It is possible that the alteration of the tertiary or quaternary structure of this rRNA by the A827G mutation may lead to mitochondrial dysfunction, thereby playing a role in the pathogenesis of hearing loss and aminoglycoside hypersensitivity. However, incomplete penetrance of hearing impairment indicates that the A827G mutation itself is not sufficient to produce clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Indeed, aminoglycosides may contribute to the phenotypic manifestation of the A827G mutation in this family. In contrast with the congenital or early-onset hearing impairment in another Chinese family carrying the A827G mutation, three patients in this pedigree developed hearing loss only after use of aminoglycosides. This discrepancy likely reflects the difference of genetic backgrounds, either mitochondrial haplotypes or nuclear modifier genes, between two families.

Xing Guangqian [Department of Otolaryngology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Chen Zhibin [Department of Otolaryngology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Wei Qinjun [Department of Biotechnology, Nanjing Medical University, Nanjing 210029 (China); Tian Huiqin [Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, (China); Li Xiaolu [Department of Otolaryngology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Zhou Aidong [Nanjing City School for Deaf Children, Nanjing 210000 (China); Bu Xingkuan [Department of Otolaryngology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Cao Xin [Department of Biotechnology, Nanjing Medical University, Nanjing 210029 (China)]. E-mail: caoxin@njmu.edu.cn

2006-08-11

327

Stress-Induced Activation of the Sympathoadrenal System is Determined by Genetic Background in Rat Models of Tauopathy.  

PubMed

Stress may accelerate onset of neurodegenerative diseases in vulnerable subjects and, vice versa, neurodegeneration affects the responsiveness to stressors. We investigated the neuroendocrine response to immobilization stress in normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and transgenic rats of respective WKY and SHR strains overexpressing human truncated tau protein. Plasma levels of epinephrine, norepinephrine, and corticosterone were determined. An immobilization-induced elevation of epinephrine and norepinephrine was significantly reduced in WKY transgenic rats compared to WKY wild-type rats, while no differences were seen between SHR transgenic and SHR wild-type animals. Our data have shown that sympathoadrenal system response to stress strongly depends on both tau protein-induced neurodegeneration and genetic background of experimental animals. PMID:25147110

Lejavova, Katarina; Ondicova, Katarina; Horvathova, Lubica; Hegedusova, Noemi; Cubinkova, Veronika; Vargovic, Peter; Manz, Georg; Filipcik, Peter; Mravec, Boris; Novak, Michal; Kvetnansky, Richard

2015-01-01

328

Genes and personality characteristics: Possible association of the genetic background with intelligence and decision making in 830 Caucasian Greek subjects.  

PubMed

It is well known that intelligence consists of a variety of interactional and cognitive skills and abilities (e.g. tradecraft; critical and divergent thinking; perception of foreign information). Decision making is defined as the conscious choice between given options, relating to a problem. Both genetic background and environment comprise key elements for personality characteristics of the human being. The aim of this study is to determine the frequency distribution of rs324420, rs1800497, rs363050, rs6265, rs1328674 polymorphisms known to be involved in individual personality characteristics, in 830 Greek Subjects. The study is independent from direct clinical measurements (e.g. IQ measurements; physiological tests). The population of the volunteers is described, based on genotype, sex, with the respective gene frequencies, including the Minor Allele Frequency (MAF). A potential influence of the volunteer gender with the above characteristics (based on genotypes and alleles) is examined and finally, volunteers are classified as follows: A volunteer receives + 1, for each genotype/allele, which enhances his intelligence or his decision-making. In contrast, he receives - 1, for each genotype/allele, which relegates the individual characteristic. No statistically significant gender-characteristics correlation is observed. According to their genetic profile, a rate of 92.5%, of the volunteers may be characterized by prudence and temperance of thought, with only a small proportion of them (7.5%) may be classified as genetically spontaneous and adventurous. Regarding intelligence, the study population may lay around average and a little above it, at a rate of 96.3%, while the edges of the scale suggest only a 0.5% of the volunteers, who, although the "smartest", somehow seem to lack prudence. In conclusion, individuals with low cognitive ability may be more prudent than others and vice versa, while the "smartest" ones tend to be more risky, in decision-making. Therefore, intelligence and decision-making may, after all, be less linked to each other than expected. PMID:25606466

Marinos, Georgios; Naziris, Nikolaos; Limnaios, Stefanos A; Drakoulis, Nikolaos

2014-12-01

329

Genes and personality characteristics: Possible association of the genetic background with intelligence and decision making in 830 Caucasian Greek subjects  

PubMed Central

It is well known that intelligence consists of a variety of interactional and cognitive skills and abilities (e.g. tradecraft; critical and divergent thinking; perception of foreign information). Decision making is defined as the conscious choice between given options, relating to a problem. Both genetic background and environment comprise key elements for personality characteristics of the human being. The aim of this study is to determine the frequency distribution of rs324420, rs1800497, rs363050, rs6265, rs1328674 polymorphisms known to be involved in individual personality characteristics, in 830 Greek Subjects. The study is independent from direct clinical measurements (e.g. IQ measurements; physiological tests). The population of the volunteers is described, based on genotype, sex, with the respective gene frequencies, including the Minor Allele Frequency (MAF). A potential influence of the volunteer gender with the above characteristics (based on genotypes and alleles) is examined and finally, volunteers are classified as follows: A volunteer receives + 1, for each genotype/allele, which enhances his intelligence or his decision-making. In contrast, he receives ? 1, for each genotype/allele, which relegates the individual characteristic. No statistically significant gender-characteristics correlation is observed. According to their genetic profile, a rate of 92.5%, of the volunteers may be characterized by prudence and temperance of thought, with only a small proportion of them (7.5%) may be classified as genetically spontaneous and adventurous. Regarding intelligence, the study population may lay around average and a little above it, at a rate of 96.3%, while the edges of the scale suggest only a 0.5% of the volunteers, who, although the “smartest”, somehow seem to lack prudence. In conclusion, individuals with low cognitive ability may be more prudent than others and vice versa, while the “smartest” ones tend to be more risky, in decision-making. Therefore, intelligence and decision-making may, after all, be less linked to each other than expected. PMID:25606466

Marinos, Georgios; Naziris, Nikolaos; Limnaios, Stefanos A.; Drakoulis, Nikolaos

2014-01-01

330

The effects of cocaine self-administration on dendritic spine density in the rat hippocampus are dependent on genetic background.  

PubMed

Chronic exposure to cocaine induces modifications to neurons in the brain regions involved in addiction. Hence, we evaluated cocaine-induced changes in the hippocampal CA1 field in Fischer 344 (F344) and Lewis (LEW) rats, 2 strains that have been widely used to study genetic predisposition to drug addiction, by combining intracellular Lucifer yellow injection with confocal microscopy reconstruction of labeled neurons. Specifically, we examined the effects of cocaine self-administration on the structure, size, and branching complexity of the apical dendrites of CA1 pyramidal neurons. In addition, we quantified spine density in the collaterals of the apical dendritic arbors of these neurons. We found differences between these strains in several morphological parameters. For example, CA1 apical dendrites were more branched and complex in LEW than in F344 rats, while the spine density in the collateral dendrites of the apical dendritic arbors was greater in F344 rats. Interestingly, cocaine self-administration in LEW rats augmented the spine density, an effect that was not observed in the F344 strain. These results reveal significant structural differences in CA1 pyramidal cells between these strains and indicate that cocaine self-administration has a distinct effect on neuron morphology in the hippocampus of rats with different genetic backgrounds. PMID:23966583

Miguéns, Miguel; Kastanauskaite, Asta; Coria, Santiago M; Selvas, Abraham; Ballesteros-Yañez, Inmaculada; DeFelipe, Javier; Ambrosio, Emilio

2015-01-01

331

What the Genetic Background of Individuals with Asthma and Obesity Can Reveal: Is ?2-Adrenergic Receptor Gene Polymorphism Important?  

PubMed Central

The goal of this review was to evaluate the association of ?2-adrenergic receptor (ADRB2) gene polymorphisms with asthma and obesity. Asthma is the most common pediatric inflammatory disorder. The prevalence, severity, and hospitalization index for asthma have increased markedly in the last several decades. Interestingly, asthma is often diagnosed along with obesity. Genetic factors are essential for both conditions, and some of the candidate pleiotropic genes thought to be involved in the development of these diseases are ADRB2, vitamin D receptor (VDR), leptin (LEP), protein kinase C alpha (PRKCA), and tumor necrosis factor alpha (TNF?). The ADRB2 has been studied in multiple populations and more than 80 polymorphisms, mainly single-nucleotide polymorphisms, have been identified. For nonsynonymous Arg16Gly, Gln27Glu, and Thr164Ile, functional effects have been shown. In vivo, these polymorphisms have been evaluated to determine their association with both obesity and asthma, but the results are inconsistent and depend on the population studied or how the disease was defined. Currently, there are only few reports describing the genetic background for the comorbidity of asthma and obesity. PMID:25276484

2014-01-01

332

Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing.  

PubMed

Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron-exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted. PMID:22370629

De Leeneer, K; Van Bockstal, M; De Brouwer, S; Swietek, N; Schietecatte, P; Sabbaghian, N; Van den Ende, J; Willocx, S; Storm, K; Blaumeiser, B; Van Asperen, C J; Wijnen, J T; Leunen, K; Legius, E; Michils, G; Matthijs, G; Blok, M J; Gomez-Garcia, E; De Paepe, A; Tischkowitz, M; Poppe, B; Claes, K

2012-05-01

333

Shared genetic susceptibility to ischemic stroke and coronary artery disease – a genome-wide analysis of common variants  

PubMed Central

Summary Background and Purpose Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each have a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods Genome-wide association data were obtained from the METASTROKE, CARDIoGRAM, and C4D consortia. We first analyzed common variants reaching a nominal threshold of significance (p<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2,167 individuals with the ischemic large artery stroke (LAS) subtype. Results Common variants associated with CAD at p<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, three and five loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (p<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Since these loci had prior evidence for genome-wide significance for CAD we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (pIS=1.62×10-07) and ABO (pIS =2.6×10-4) as well as at HDAC9 (pLAS=2.32×10-12), 9p21 (pLAS =3.70×10-6), RAI1-PEMT-RASD1 (pLAS =2.69×10-5), EDNRA (pLAS =7.29×10-4), and CYP17A1-CNNM2-NT5C2 (pLAS =4.9×10-4). Conclusions Our results demonstrate substantial overlap in the genetic risk of ischemic stroke and particularly the large artery stroke subtype with coronary artery disease. PMID:24262325

Dichgans, Martin; Malik, Rainer; König, Inke R.; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D.; Assimes, Themistocles L.; Levi, Christopher; O?Donnell, Christopher J.; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M.; Hengstenberg, Christian; Seshadri, Sudha; Erdmann, Jeanette; Bis, Joshua C.; Peters, Annette; Boncoraglio, Giorgio B.; März, Winfried; Meschia, James F.; Kathiresan, Sekar; Ikram, M. Arfan; McPherson, Ruth; Stefansson, Kari; Sudlow, Cathie; Reilly, Muredach P.; Thompson, John R.; Sharma, Pankaj; Hopewell, Jemma C.; Chambers, John C.; Watkins, Hugh; Rothwell, Peter M.; Roberts, Robert; Markus, Hugh S.; Samani, Nilesh J.; Farrall, Martin; Schunkert, Heribert

2014-01-01

334

Comparison of the genetic background of different Colombian populations using the SNPforID 52plex identification panel.  

PubMed

Various strategies for analysing SNP markers and genotyping have been published with the goal of obtaining informative profiles from biological samples that contain only small amounts of template and/or degraded DNA. In this study, a multiplex assay of 52 autosomal single-nucleotide polymorphisms (SNPs) was used to analyse 438 individuals from urban populations from different regions of Colombia, as well as a sample of 50 Native American individuals of the Pastos ethnic group from Nariño. To determine if significant differences in these 52 SNPs exist between the distinct regions of Colombia, genetic distance and admixture analyses were performed based on the available data for 17 different Colombian population groups and for population groups from Africa, Europe and America. The results demonstrate significant differences between the populations from the Southwest Andean, Central-West Andean, Central-East Andean, Orinoquian and northern Colombian Pacific Coast regions. Most of the regions exhibited a European and Native American admixture. One exception is the population from the region of Chocó (on the northern Pacific Coast), which exhibits a high proportion of African admixture (54 %). From the observed genetic backgrounds, it is possible to conclude that a single reference database for the entire country would not be suitable for forensic purposes. The allele frequencies and the forensically relevant parameters were calculated for all of the markers in each Colombian region with significant values for the combined matching probability (power of discrimination ?0.99999999999999990) and the combined probability of exclusion (?0.9990) in trios that were obtained from all of the population groups. PMID:23665814

Ibarra, Adriana; Freire-Aradas, Ana; Martínez, Martha; Fondevila, Manuel; Burgos, German; Camacho, Mauricio; Ostos, Henry; Suarez, Zuleyma; Carracedo, Angel; Santos, Sidney; Gusmão, Leonor

2014-01-01

335

Introgression of two chromosome regions for leaf photosynthesis from an indica rice into the genetic background of a japonica rice  

PubMed Central

Increases in rates of individual leaf photosynthesis (P n) are critical for future increases of rice yields. A previous study, using introgression lines derived from a cross between indica cultivar Habataki, with one of the highest recorded values of P n, and the Japanese elite cultivar Koshihikari, identified four QTLs (qCAR4, qCAR5, qCAR8, and qCAR11) that affect P n. The present study examined the combined effect of qCAR4 and qCAR8 on P n in the genetic background of Koshihikari. The pyramided near-isogenic line NIL(qCAR4+qCAR8) showed higher P n than both NIL(qCAR4) and NIL(qCAR8), equivalent to that of Habataki despite being due to only two out of the four QTLs. The high P n of NIL(qCAR4+qCAR8) may be attributable to the high leaf nitrogen content, which may have been inherited from NIL(qCAR4), to the large hydraulic conductance due to the large root surface area from NIL(qCAR4), and to the high hydraulic conductivity from NIL(qCAR8). It might be also attributable to high mesophyll conductance, which may have been inherited from NIL(qCAR4). The induction of mesophyll conductance and the high leaf nitrogen content and high hydraulic conductivity could not be explained in isolation from the Koshihikari background. These results suggest that QTL pyramiding is a useful approach in rice breeding aimed at increasing P n. PMID:24591053

Hirasawa, Tadashi

2014-01-01

336

Emergence of serogroup 15 Streptococcus pneumoniae of diverse genetic backgrounds following the introduction of pneumococcal conjugate vaccines in Hong Kong.  

PubMed

Serogroup 15 pneumococcal isolates from nasopharyngeal carriage of hospitalized children admitted to a teaching hospital in Hong Kong from April 2009 to September 2013 were characterized by pulse-field gel electrophoresis (PFGE), multilocus sequence typing, and antimicrobial non-susceptibility testing. The overall proportion of serogroup 15 isolates in the pre-PCV7 and post-PCV13 periods rose from 5.7% to 20.0%. The increase in trend for serotype 15B/C was statistically significant among children presented with pneumonia; bronchiolitis; upper respiratory tract infection; and febrile, non-respiratory diseases and for serotype 15A/F, among children with bronchiolitis and febrile, non-respiratory diseases. The predominant PFGE cluster of serotype 15B/C belonged to sequence type (ST) 199. Replacement of this more susceptible cluster (Ery and Tet non-susceptibilities of 32.2% and 25.4%) with the non-susceptible cluster, ST8859 (Ery and Tet non-susceptibilities of 91.7% and 87.5%) was noted. ST63 was the predominant serotype 15A cluster (Ery and Tet non-susceptibilities of 97.4% and 92.3%). Serogroup 15 subtypes have emerged in the post-PCV13 era, and these non-susceptible clusters warrant closer monitoring as candidates for incorporation to future pneumococcal vaccines. PMID:25445117

Liyanapathirana, Veranja; Nelson, E Anthony S; Ang, Irene; Subramanian, Reema; Ma, Helen; Ip, Margaret

2015-01-01

337

A specific superoxide dismutase mutation is on the same genetic background in sporadic and familial cases of amyotrophic lateral sclerosis  

SciTech Connect

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons, causing progressive muscular atrophy, weakness, and death from respiratory failure, often within 2-3 years. Although most cases are sporadic, some 5%-10% are inherited as autosomal dominants with age-dependent penetrance. An ALS locus has been mapped to chromosome 21q, and causative mutations identified in the Cu/Zn superoxide dismutase (SOD1) gene. A majority of SOD1 mutations have been found in cases with a clear family history of ALS. However, we and others have also described SOD1 mutations in patients where the disease appears to be sporadic. This is especially true for the missense mutation in codon 113 of the SOD1 gene, which substitutes threonine for isoleucine (I113T). One explanation for this finding is that this codon is a mutational hot spot with sporadic cases representing new mutations. Another is that the inherited nature of the cases is disguised by the reduced penetrance of this specific mutation. We have now shown that each of six unrelated cases of I113T mutation that we have collected in the Scottish population occurs on the same genetic background. Association analysis of multiple flanking loci on chromosome 21q supports the conclusion of a founder effect, with the original mutational event occurring {ge}10 generations ago. 12 refs., 1 fig., 1 tab.

Hayward, C.; Brock, D.J.H. [Univ. of Edinburgh (United Kingdom); Swingler, R.J. [Dundee Royal Infirmary (United Kingdom)] [and others

1996-11-01

338

Genetic variation in susceptibility of lodgepole pine to western gall rust in the inland northwest. Forest Service research note  

SciTech Connect

Infection of a provenance-family test of lodgepole pine by western gall rust was 70 percent at age 11 years. The test provided data for determining geographic and elevation patterns of variation for infection, plus data to assess levels of variation among families. Susceptibility was highest in the western portion of the populations included in the test and decreased easterly. Susceptibility also increased slightly with elevation to about 1,300 m trailing off 1,830 m. Family heritability was 0.57. This information can be incorporated into breeding programs.

Hoff, R.J.; Minggao, S.

1994-02-01

339

Genetics of experimental lupus nephritis: non-H-2 factors determine susceptibility for renal involvement in murine chronic graft-versus-host disease.  

PubMed Central

Chronic graft-versus-host disease (GvHD) was induced in (C57BL/10 x DBA/2)F1 and (B10.S x DBA/2)F1 hybrids by injection of DBA/2 lymphocytes. All of the animals developed GvHD. Renal disease and proteinuria occurred in all of the (C57BL/10 x DBA/2)F1 hybrids, but only in 54% of the (B10.S x DBA/2)F1. The type of renal lesion was similar in all diseased animals of both strains, i.e., immune complex glomerulonephritis (ICGN) with deposition of antibodies and complement in glomeruli. To find out whether H-2 haplotype or other factors, such as non-H-2 linked genes, determine the susceptibility for renal involvement in GvHD, we produced (B10 x B10.S)F1 x DBA/2 mice, determined their H-2 genotype serologically, and separated them into H-2b/d and H-2s/d groups. These two groups did not differ with respect to susceptibility to renal disease in the course of GvHD, which indicates that H-2 is not the decisive genetic factor. We conclude that factors not linked with H-2 exert a major influence on susceptibility to GvHD-related renal disease in these mice. PMID:2758697

Bruijn, J A; Van Elven, E H; Corver, W E; Oudshoorn-Snoek, M; Fleuren, G J

1989-01-01

340

Genetics  

NSDL National Science Digital Library

This online tutorial from the TheTech Museum of Innovation focuses on genetics. The interactive topics will initially introduce the user to the DNA, chromosomes, and the make up of human genes. Further topics will examine forensic science, the history of forensics, fingerprinting, and cloning background research and community response to cloning. Finally, the resource provides connections to gallery exhibits, science labs, and a design challenge that engages the learner to write a persuasive letter to a group or organization responsible for cloning or DNA decision making. Copyright 2005 International Technology Education Association

The Tech Museum of Innovation

2004-01-01

341

Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: Complement component C1q and Prnp polymorphisms  

USGS Publications Warehouse

The genetic basis of susceptibility to chronic wasting disease (CWD) in free-ranging cervids is of great interest. Association studies of disease susceptibility in free-ranging populations, however, face considerable challenges including: the need for large sample sizes when disease is rare, animals of unknown pedigree create a risk of spurious results due to population admixture, and the inability to control disease exposure or dose. We used an innovative matched case-control design and conditional logistic regression to evaluate associations between polymorphisms of complement C1q and prion protein (Prnp) genes and CWD infection in white-tailed deer from the CWD endemic area in south-central Wisconsin. To reduce problems due to admixture or disease-risk confounding, we used neutral genetic (microsatellite) data to identify closely related CWD-positive (n = 68) and CWD-negative (n = 91) female deer to serve as matched cases and controls. Cases and controls were also matched on factors (sex, location, age) previously demonstrated to affect CWD infection risk. For Prnp, deer with at least one Serine (S) at amino acid 96 were significantly less likely to be CWD-positive relative to deer homozygous for Glycine (G). This is the first characterization of genes associated with the complement system in white-tailed deer. No tests for association between any C1q polymorphism and CWD infection were significant at p < 0.05. After controlling for Prnp, we found weak support for an elevated risk of CWD infection in deer with at least one Glycine (G) at amino acid 56 of the C1qC gene. While we documented numerous amino acid polymorphisms in C1q genes none appear to be strongly associated with CWD susceptibility. ?? 2009 Elsevier B.V.

Blanchong, J.A.; Heisey, D.M.; Scribner, K.T.; Libants, S.V.; Johnson, C.; Aiken, J.M.; Langenberg, J.A.; Samuel, M.D.

2009-01-01

342

ALTERED SENSITIVITY OF THE MOUSE FETUS TO IMPAIRED PROSTATIC BUD FORMATION BY DIOXIN: INFLUENCE OF GENETIC BACKGROUND AND NULL EXPRESSION OF TGF-ALFA AND EGF  

EPA Science Inventory

Altered sensitivity of the mouse fetus to impaired prostatic bud formation by dioxin: Influence of genetic background and null expression of TGF and EGF. Rasmussen, N.T., Lin T-M., Fenton, S.E., Abbott, B.D. and R.E. Peterson. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)...

343

Mapping the Major Susceptibility Loci for Familial Graves' and Hashimoto's Diseases: Evidence for Genetic Heterogeneity and Gene Interactions  

Microsoft Academic Search

The autoimmune thyroid diseases (AITDs), comprising Graves' disease (GD) and Hashimoto's thyroiditis (HT), appear to develop as a result of a complex interaction between predisposing genes and environmental triggers. The goals of the present study were to iden- tify the susceptibility loci for GD and HT and to study the relation- ships between them. We performed a whole genome linkage

YARON TOMER; GIUSEPPE BARBESINO; DAVID A. GREENBERG; ERLINDA CONCEPCION; TERRY F. DAVIES

2010-01-01

344

Drug susceptibility and genetic evaluation of Plasmodium falciparum isolates obtained in four distinct geographical regions of Kenya.  

PubMed

The drug resistance profiles of Plasmodium falciparum isolated from four regions in Kenya were analyzed for drug resistance profiles. We observed variability in resistance to a broad range of antimalarial drugs across Kenya as determined from in vitro drug susceptibility screening and genotyping analysis. PMID:15328137

Mbaisi, Abigael; Liyala, Pamela; Eyase, Fredrick; Achilla, Rachel; Akala, Hosea; Wangui, Julia; Mwangi, Josphat; Osuna, Finnley; Alam, Uzma; Smoak, Bonnie L; Davis, Jon M; Kyle, Dennis E; Coldren, Rodney L; Mason, Carl; Waters, Norman C

2004-09-01

345

Modulation of microRNAs in two genetically disparate chicken lines showing different susceptibility levels of necrotic enteritis  

Technology Transfer Automated Retrieval System (TEKTRAN)

MicroRNAs (miRNA) play a critical role in post-transcriptional regulation by influencing the 3'-UTR of target genes. Using two inbred White Leghorn chicken lines, line 6.3 and line 7.2 showing Marek’s disease-resistant and -susceptible phenotypes, respectively, we used small RNA high-throughput sequ...

346

Who seeks genetic susceptibility testing for Alzheimer???s disease? Findings from a multisite, randomized clinical trial  

Microsoft Academic Search

Purpose: Alzheimer's disease, for which one form of the apolipoprotein E (APOE) genotype is a risk factor, provides a paradigm in which to examine response to susceptibility testing for common, complex diseases. This study's main purposes were to estimate interest in such testing and to examine demographic predictors of study participation. Methods: In this 3-site, randomized clinical trial (RCT), the

J. Scott Roberts; Melissa Barber; Tamsen M. Brown; L. Adrienne Cupples; Lindsay A. Farrer; Susan A. LaRusse; Stephen G. Post; Kimberly A. Quaid; Lisa D. Ravdin; Norman R. Relkin; A. Dessa Sadovnick; Peter J. Whitehouse; John L. Woodard; Robert C. Green

2004-01-01

347

Impact of the Genetic Background on the Composition of the Chicken Plasma MiRNome in Response to a Stress  

PubMed Central

Circulating extra-cellular microRNAs (miRNAs) have emerged as promising minimally invasive markers in human medicine. We evaluated miRNAs isolated from total plasma as biomarker candidates of a response to an abiotic stress (feed deprivation) in a livestock species. Two chicken lines selected for high (R+) and low (R?) residual feed intake were chosen as an experimental model because of their extreme divergence in feed intake and energy metabolism. Adult R+ and R? cocks were sampled after 16 hours of feed deprivation and again four hours after re-feeding. More than 292 million sequence reads were generated by small RNA-seq of total plasma RNA. A total of 649 mature miRNAs were identified; after quality filtering, 148 miRNAs were retained for further analyses. We identified 23 and 19 differentially abundant miRNAs between feeding conditions and between lines respectively, with only two miRNAs identified in both comparisons. We validated a panel of six differentially abundant miRNAs by RT-qPCR on a larger number of plasma samples and checked their response to feed deprivation in liver. Finally, we evaluated the conservation and tissue distribution of differentially abundant miRNAs in plasma across a variety of red jungle fowl tissues. We show that the chicken plasma miRNome reacts promptly to the alteration of the animal physiological condition driven by a feed deprivation stress. The plasma content of stress-responsive miRNAs is strongly influenced by the genetic background, with differences reflecting the phenotypic divergence acquired through long-term selection, as evidenced by the profiles of conserved miRNAs with a regulatory role in energy metabolism (gga-miR-204, gga-miR-let-7f-5p and gga-miR-122-5p). These results reinforce the emerging view in human medicine that even small genetic differences can have a considerable impact on the resolution of biomarker studies, and provide support for the emerging interest in miRNAs as potential novel and minimally invasive biomarkers for livestock species. PMID:25473826

Dhorne-Pollet, Sophie; Rau, Andrea; Cooksey, Amanda; Giuffra, Elisabetta

2014-01-01

348

Genetic Variants and Increased Expression of Parascaris equorum P-glycoprotein-11 in Populations with Decreased Ivermectin Susceptibility  

PubMed Central

Macrocyclic lactones (MLs) represent the major drug class for control of parasitic infections in humans and animals. However, recently reports of treatment failures became more frequent. In addition to human and ruminant parasitic nematodes this also is the case for the horse-nematode Parascaris equorum. Nevertheless, to date the molecular basis of ML resistance is still not understood. Unspecific resistance mechanisms involving transporters such as P-glycoproteins (Pgps) are expected to contribute to ML resistance in nematodes. Here, complete sequences of two P. equorum Pgps were cloned and identified as orthologs of Caenorhabditis elegans Ppg-11 and an unnamed Caenorhabditis briggsae Pgp designated as Pgp-16 using phylogenetic analysis. Quantitative real-time PCR was used to compare expression between tissues. Significantly higher PeqPgp-11 expression was found in the gut for both genders, whereas for PeqPgp-16 the body wall was identified as predominant expression site. Furthermore, Pgps were analyzed regarding their participation in resistance development. Using SeqDoC analyses, Pgp-sequences of P. equorum populations with different ML susceptibility were compared. This approach revealed three single nucleotide polymorphisms (SNPs) causing missense mutations in the PeqPgp-11 sequence which correlated with decreased ML susceptibility. However, no resistance associated differences in mRNA expression levels were detected between embryonated eggs of these populations. In contrast, comparison of two pre-adult groups with different ivermectin (IVM) susceptibility revealed the presence of the three SNPs and in addition statistically significant PeqPgp-11 overexpression in the group of worms with reduced susceptibility. These results indicate that Pgp-11 might be involved in IVM resistance in P. equorum as it shows increased expression in an IVM exposed life-cycle stage of an IVM resistant population as well as occurrence of putatively resistance associated SNPs in populations with reduced IVM susceptibility. These SNPs are promising diagnostic candidates for detection of ML resistance with potential also for other parasitic nematode species. PMID:23637871

Janssen, I. Jana I.; Krücken, Jürgen; Demeler, Janina; Basiaga, Marta; Korna?, S?awomir; von Samson-Himmelstjerna, Georg

2013-01-01

349

Identification of low penetrance alleles for lung cancer: The GEnetic Lung CAncer Predisposition Study (GELCAPS)  

E-print Network

Abstract Background Part of the inherited risk to lung cancer is likely to include common, low risk alleles. The identification of this class of susceptibility is contingent on association-based analyses. We established GEnetic Lung CAncer...

Eisen, Tim; Matakidou, Athena; Consortium, Gelcaps; Houlston, Richard

2008-08-20

350

Segregation of a Latent High Adiposity Phenotype in Families with a History of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants with Large Effects in Diabetes-Related Obesity  

PubMed Central

Background We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH?) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+. Methods Normoglycaemic participants were categorised either FH+ (?1 1st degree relative with T2DM, 50F/30M, age 45±14 (SD) yr) or FH? (71F/51M, age 43±14 yr). Log-transformed anthropometric measurements (height, hip and waist circumferences) and lean, bone and fat mass (Dual Energy X-ray Absorptiometry) data were analysed by rotated Factor Analysis. The age- and gender-adjusted distributions of indices of adiposity in FH+ were assessed by fits to a bimodal model and by relative risk ratios (RR, FH+/FH?) and interpreted in a purely genetic model of FH effects. Results The two orthogonal factors extracted, interpretable as Frame and Adiposity accounted for 80% of the variance in the input data. FH+ was associated with significantly higher Adiposity scores (p<0.01) without affecting Frame scores. Adiposity scores in FH+ conformed to a bimodal normal distribution, consistent with dominant expression of major susceptibility genes with 59% (95% CI 40%, 74%) of individuals under the higher mode. Calculated risk allele frequencies were 0.09 (0.02, 0.23) in FH?, 0.36 (0.22, 0.48) in FH+ and 0.62 (0.36, 0.88) in unobserved T2DM-affected family members. Conclusions The segregation of Adiposity in T2DM-affected families is consistent with dominant expression of rare risk variants with major effects, which are expressed in over half of FH+ and which can account for most T2DM-associated obesity in our population. The calculated risk allele frequency in FH? suggests that rare genetic variants could also account for a substantial fraction of the prevalent obesity in this society. PMID:23950934

Jenkins, Arthur B.; Batterham, Marijka; Samocha-Bonet, Dorit; Tonks, Katherine; Greenfield, Jerry R.; Campbell, Lesley V.

2013-01-01

351

Mass General researchers find that cultured circulating tumor cells reveal genetic profile, potential drug susceptibility of breast cancer cells  

Cancer.gov

Circulating tumor cells captured with a microchip-based device developed at the Massachusetts General Hospital Center for Engineering in Medicine and the MGH Cancer Center can be cultured to establish cell lines for genetic analysis and drug testing.

352

Preservation of Eumelanin Hair Pigmentation in Proopiomelanocortin-Deficient Mice on a Nonagouti (a/a) Genetic Background  

PubMed Central

The original strain of proopiomelanocortin (POMC)-deficient mice (Pomc?/? ) was generated by homologous recombination in 129X1/SvJ (Aw/Aw)-derived embryonic stem cells using a targeting construct that deleted exon 3, encoding all the known functional POMC-derived peptides including ?MSH, from the Pomc gene. Although these Pomc?/? mice exhibited adrenal hypoplasia and obesity similar to the syndrome of POMC deficiency in children, their agouti coat color was only subtly altered. To further investigate the mechanism of hair pigmentation in the absence of POMC peptides, we studied wild-type (Pomc+/+), heterozygous (Pomc+/?), and homozygous (Pomc?/?) mice on a nonagouti (a/a) 129;B6 hybrid genetic background. All three genotypes had similar black fur pigmentation with yellow hairs behind the ears, around the nipples, and in the perianal area characteristic of inbred C57BL/6 mice. Histologic and electron paramagnetic resonance spectrometry examination demonstrated that hair follicles in back skin of Pomc?/? mice developed with normal structure and eumelanin pigmentation; corresponding molecular analyses, however, excluded local production of ?MSH and ACTH because neither Pomc nor putative Pomc pseudogene mRNAs were detected in the skin. Thus, 129;B6 Pomc null mutant mice produce abundant eumelanin hair pigmentation despite their congenital absence of melanocortin ligands. These results suggest that either the mouse melanocortin receptor 1 has sufficient basal activity to trigger and sustain eumelanogenesis in vivo or that redundant nonmelanocortin pathway(s) compensate for the melanocortin deficiency. Whereas the latter implies feedback control of melanogenesis, it is also possible that the two mechanisms operate jointly in hair follicles. PMID:15564334

Slominski, Andrzej; Plonka, Przemyslaw M.; Pisarchik, Alexander; Smart, James L.; Tolle, Virginie; Wortsman, Jacobo; Low, Malcolm J.

2005-01-01

353

Immune responses of mice with different genetic backgrounds to improved multiepitope, multitarget malaria vaccine candidate antigen FALVAC-1A.  

PubMed

FALVAC-1A is a second-generation multitarget, multiepitope synthetic candidate vaccine against Plasmodium falciparum, incorporating elements designed to yield a stable and immunogenic molecule. Characteristics of the immunogenicity of FALVAC-1A were evaluated in congenic (H-2(b), H-2(k), and H-2(d)) and outbred strains of mice. The influences of four adjuvants (aluminum phosphate, QS-21, Montanide ISA-720, and copolymer CRL-1005) on different aspects of the immune response were also assessed. FALVAC-1A generated strong antibody responses in all mouse strains. The highest mean enzyme-linked immunosorbent assay (ELISA) antibody concentrations against FALVAC-1A were observed in the outbred ICR mice, followed by B10.BR, B10.D2, and C57BL/6 mice, though this order varied for the different adjuvants, with no statistical differences between mouse strains. In all mouse strains, the highest anti-FALVAC-1A antibody titers in ELISAs were induced by FALVAC-1A in copolymer and ISA-720 formulations, followed by QS-21 and AlPO4. These antibodies were of all four subclasses, though immunoglobulin G1 (IgG1) predominated, with the exception of FALVAC-1A with the QS-21 adjuvant, which induced predominantly IgG2c responses. Both sporozoites and blood stages of P. falciparum were recognized by anti-FALVAC-1A sera in the immunofluorescence assay. In addition to antibody, cellular immune responses were detected; these responses were studied by examining spleen cells producing gamma interferon and interleukin-4 in enzyme-linked immunospot assays. In summary, FALVAC-1A was found to be highly immunogenic and elicited functionally relevant antibodies that can recognize sporozoites and blood-stage parasites in diverse genetic backgrounds. PMID:18784343

Kaba, S A; Price, A; Zhou, Z; Sundaram, V; Schnake, P; Goldman, I F; Lal, A A; Udhayakumar, V; Todd, C W

2008-11-01

354

Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis  

Microsoft Academic Search

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate

Ping-I Lin; Eden R. Martin; Carrie A. Browning-Large; Donald E. Schmechel; Kathleen A. Welsh-Bohmer; P. Murali Doraiswamy; John R. Gilbert; Jonathan L. Haines; Margaret A. Pericak-Vance

2006-01-01

355

Considerations for Designing a Prototype Genetic Test for Use in Translational Research  

Microsoft Academic Search

Background: Translational research is needed to explore how people will respond to personal genetic susceptibility information related to common health conditions. Maximizing the rigor of this research will require that genetic test results be returned to study participants. Currently, there is no established method that guides the selection of genetic variants to be used in research with these objectives. Methods

C. H. Wade; C. M. McBride; S. L. R. Kardia; L. C. Brody

2010-01-01

356

Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study  

Microsoft Academic Search

BACKGROUND: Approximately 5-10% of persons infected with M. tuberculosis develop tuberculosis, but the factors associated with disease progression are incompletely understood. Both linkage and association studies have identified human genetic variants associated with susceptibility to pulmonary tuberculosis, but few genetic studies have evaluated extrapulmonary disease. Because extrapulmonary and pulmonary tuberculosis likely have different underlying pathophysiology, identification of genetic mutations associated

Noffisat O Oki; Alison A Motsinger-Reif; Paulo RZ Antas; Shawn Levy; Steven M Holland; Timothy R Sterling

2011-01-01

357

Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1  

PubMed Central

It has been suggested that a genetic factor(s) or a familial predisposition may contribute to the clinical manifestations of disc herniation; moreover, no genetic linkage between spinal disc herniation and spastic paraplegia has ever been described. A family with consanguineous parents and four of eight sibs affected by multiple disc herniations and spastic paraplegia was clinically and genetically analysed. Surgery caused partial improvement in all of them. After the exclusion of type II collagen and vitamin D receptor genes and the recessive loci for HSPs, a genome wide search was performed with about 500 fluorescent markers. Positive lod score values were obtained for chromosome 6q22.31-q24.1, with evidence of three homozygous intervals. The maximum multipoint lod score of 3.28 was obtained in only one interval, between markers D6S1699 and D6S314. On the whole, a susceptibility locus for disc herniation and autosomal recessive spastic paraplegia was found on chromosome 6q23.3-q24.1. This is the first time that disc herniation and the associated neurological syndrome has been linked to a human chromosomal region. PMID:12070243

Zortea, M; Vettori, A; Trevisan, C; Bellini, S; Vazza, G; Armani, M; Simonati, A; Mostacciuolo, M

2002-01-01

358

Genetic and pharmacological modulation of giant depolarizing potentials in the neonatal hippocampus associates with increased seizure susceptibility  

PubMed Central

The expression of Na+–K+–2Cl? cotransporter (NKCC1) is responsible for high intracellular Cl? resulting in the excitatory action of GABAA receptor activation in the developing brain. Giant depolarizing potentials (GDPs) are spontaneous network oscillations that involve GABAA receptors and are thought to be important in establishing neuronal circuit wiring. Earlier work established that seizure susceptibility in the GABAA?2R43Q epilepsy mouse is impacted by developmental consequences of impaired GABAA receptor function. We investigated the potential mechanism of the developmental influence by recording GDPs in the CA3 pyramidal neurons from brain slices of the neonatal GABAA?2R43Q mouse. Interestingly, the number of GPDs was significantly lower in slices from mutant mouse compared with wild-type control, suggesting an involvement in setting seizure susceptibility. To test this idea we blocked NKCC1 with bumetanide in neonatal mice and reduced the number of GDPs to a level similar to that seen in the mutant mice. We found that neonatal treatment with bumetanide resulted in a similar level of susceptibility to thermally induced seizures as described for the GABAA?2R43Q mouse. These results provide evidence that a human GABAA receptor epilepsy mutation exerts a developmental influence by modulating the number of GDPs. It also draws attention to the potential risk of early treatment with bumetanide. PMID:23006485

Vargas, Ernesto; Petrou, Steven; Reid, Christopher A

2013-01-01

359

Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder  

Microsoft Academic Search

Background: Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1–3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided

Maria Karayiorgou; Christina Sobin; Maude L. Blundell; Brandi L. Galke; Lubomira Malinova; Pablo Goldberg; Jurg Ott; Joseph A. Gogos

1999-01-01

360

The Moroccan Genetic Disease Database (MGDD): a database for DNA variations related to inherited disorders and disease susceptibility.  

PubMed

National and ethnic mutation databases provide comprehensive information about genetic variations reported in a population or an ethnic group. In this paper, we present the Moroccan Genetic Disease Database (MGDD), a catalogue of genetic data related to diseases identified in the Moroccan population. We used the PubMed, Web of Science and Google Scholar databases to identify available articles published until April 2013. The Database is designed and implemented on a three-tier model using Mysql relational database and the PHP programming language. To date, the database contains 425 mutations and 208 polymorphisms found in 301 genes and 259 diseases. Most Mendelian diseases in the Moroccan population follow autosomal recessive mode of inheritance (74.17%) and affect endocrine, nutritional and metabolic physiology. The MGDD database provides reference information for researchers, clinicians and health professionals through a user-friendly Web interface. Its content should be useful to improve researches in human molecular genetics, disease diagnoses and design of association studies. MGDD can be publicly accessed at http://mgdd.pasteur.ma. PMID:23860041

Charoute, Hicham; Nahili, Halima; Abidi, Omar; Gabi, Khalid; Rouba, Hassan; Fakiri, Malika; Barakat, Abdelhamid

2014-03-01

361

Am. J. Hum. Genet. 73:000000, 2003 Search for Haplotype Interactions That Influence Susceptibility to Type 1  

E-print Network

diabetes, such as human leukocyte antigen (HLA), has been established unequivocally, al- though is accumulating. Both processes contribute to the deterioration of b cells in the islets of Langerhans by The American Society of Human Genetics. All rights reserved. 0002-9297/2003/7306-00XX$15.00 lotype interactions

Liang, Faming

362

Copyright 2000 by the Genetics Society of America Bacillus thuringiensis (Bt) Toxin Susceptibility and Isolation of Resistance Mutants  

E-print Network

Copyright © 2000 by the Genetics Society of America Bacillus thuringiensis (Bt) Toxin produced by Bacillus thuringiensis (Bt) are the most widely used natural insecticides in agriculture cascade related to pore formationlus thuringiensis (Bt) are the most widely used biolog- ically produced

Aroian, Raffi V.

363

Association detection between genetic variants in the microRNA binding sites of toll-like receptors signaling pathway genes and bladder cancer susceptibility  

PubMed Central

Bladder cancer (BCa) is the second most common urological malignancy, and the incidence of BCa has dramatically increased recently. Various toll-like receptors (TLRs) signaling pathway proteins were proven to be associated with BCa susceptibility. However, the effect of genetic variants in TLRs signaling pathway genes on risk of BCa has not been elucidated clearly. Previous studies mainly focused on the coding region of target genes, while in this study, polymorphisms in the non-coding region, microRNA (miRNA) binding sites were investigated as potential targets. We used bioinformatics approach to screen 100 BCa related TLRs signaling pathway genes. Candidate polymorphisms were select in this region and 8 polymorphisms were confirmed. Rs72552316, located at the 3’UTR of the TLR7 gene, exhibited significant association with risk of BCa, indicating a strong relationship with decreased risk of BCa (P ? 0.0001). Furthermore, no association was detected between all the polymorphisms and recurrence-free survival time of overall study population or non-muscle invasive BCa subgroups. In conclusion, rs72552316 in the miRNA binding sites of TLR7 might contribute to BCa susceptibility, and this finding provided new targets for high BCa risk population screening. PMID:25550860

Cheng, Sihang; Liu, Jiaming; Zhang, Yonggang; Lin, Yifei; Liu, Qinyu; Li, Hong; Huang, Jin; Zhang, Peng

2014-01-01

364

Genetic susceptibility to sickness absence is similar among women and men: findings from a Swedish twin cohort.  

PubMed

Previous studies of risk factors for sickness absence (SA) focus primarily on psychosocial and work environmental exposures. The aim of this study was to investigate the relative contribution of genetic influences on SA among women and men. The population-based study sample of Swedish twins (34,547) included 13,743 twin pairs of known zygosity, 3,495 monozygotic, 5,073 same-sexed dizygotic, and 5,175 opposite sexed. The point prevalence of long-term SA (?15 days) in each zygosity and sex group was calculated. The risk of SA was estimated as an odds ratio (OR) with 95% confidence intervals (CI) where the odds for twins on SA to have a co-twin on SA was compared to the OR for SA in twins whose co-twin were not sickness absent. Intrapair correlations and probandwise concordance rates were calculated and standard biometrical genetic model-fitting methods were used to estimate the heritability of SA. The prevalence of SA was 8.8% (women 10.7%; men 6.5%). Intrapair similarity was higher among monozygotic than dizygotic twin pairs. The best-fitting model showed no sex differences in genetic effects or variance components contributing to SA. The heritability estimate was 36% (95% CI: 35-40%). Results suggest genetic contribution to the variation of SA and that environmental factors have an important role, for women and men. As SA seem to be influenced by genetic factors, future studies of associations between risk factors and SA should consider this potentially confounding effect. PMID:22931554

Svedberg, Pia; Ropponen, Annina; Alexanderson, Kristina; Lichtenstein, Paul; Narusyte, Jurgita

2012-10-01

365

Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions.  

PubMed

At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the "missing heritability." PMID:25077817

Barrett, Jennifer H; Taylor, John C; Bright, Chloe; Harland, Mark; Dunning, Alison M; Akslen, Lars A; Andresen, Per A; Avril, Marie-Françoise; Azizi, Esther; Bianchi Scarrà, Giovanna; Brossard, Myriam; Brown, Kevin M; D?bniak, Tadeusz; Elder, David E; Friedman, Eitan; Ghiorzo, Paola; Gillanders, Elizabeth M; Gruis, Nelleke A; Hansson, Johan; Helsing, Per; Ho?evar, Marko; Höiom, Veronica; Ingvar, Christian; Landi, Maria Teresa; Lang, Julie; Lathrop, G Mark; Lubi?ski, Jan; Mackie, Rona M; Molven, Anders; Novakovi?, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; van der Stoep, Nienke; van Doorn, Remco; van Workum, Wilbert; Goldstein, Alisa M; Kanetsky, Peter A; Pharoah, Paul D P; Demenais, Florence; Hayward, Nicholas K; Newton Bishop, Julia A; Bishop, D Timothy; Iles, Mark M

2015-03-15

366

Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle.  

PubMed

Treacher Collins syndrome (TCS) is a craniofacial disorder that results from mutations in TCOF1, which encodes the nucleolar protein Treacle. The severity of the clinical features exhibits wide variation and includes hypoplasia of the mandible and maxilla, abnormalities of the external ears and middle ear ossicles, and cleft palate. To determine the in vivo function of Treacle, we previously generated Tcof1 heterozygous mice on a mixed C57BL/6 and 129 background. These mice exhibited a lethal phenotype, which included abnormal development of the maxilla, absence of the eyes and nasal passages, and neural tube defects. Here, we show that placing the mutation onto different genetic backgrounds has a major effect on the penetrance and severity of the craniofacial and other defects. The offspring exhibit markedly variable strain-dependent phenotypes that range from extremely severe and lethal in a mixed CBA/Ca and 129 background, to apparently normal and viable in a mixed BALB/c and 129 background. In the former case, in addition to a profoundly severe craniofacial phenotype, CBA-derived heterozygous mice also exhibited delayed ossification of the long bones, rib fusions, and digit anomalies. The results of our studies indicate that factors in the different genetic backgrounds contribute extensively to the Tcof1 phenotype. PMID:15042714

Dixon, Jill; Dixon, Michael James

2004-04-01

367

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study  

Microsoft Academic Search

ABSTRACT: INTRODUCTION: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS: We evaluated two-way interactions between each of age at

Roger Milne; Mia Gaudet; Amanda Spurdle; Peter Fasching; Fergus Couch; Javier Benítez; José Ignacio Arias Pérez; M Pilar Zamora; Núria Malats; Isabel dos Santos Silva; Lorna Gibson; Olivia Fletcher; Nichola Johnson; Hoda Anton-Culver; Argyrios Ziogas; Jonine Figueroa; Louise Brinton; Mark Sherman; Jolanta Lissowska; John Hopper; Gillian Dite; Carmel Apicella; Melissa Southey; Alice Sigurdson; Martha Linet; Sara Schonfeld; D Michal Freedman; Arto Mannermaa; Veli-Matti Kosma; Vesa Kataja; Päivi Auvinen; Irene Andrulis; Gord Glendon; Julia Knight; Nayana Weerasooriya; Angela Cox; Malcolm Reed; Simon Cross; Alison Dunning; Shahana Ahmed; Mitul Shah; Hiltrud Brauch; Yon-Dschun Ko; Thomas Brüning; Diether Lambrechts; Joke Reumers; Ann Smeets; Shan Wang-Gohrke; Per Hall; Kamila Czene; Jianjun Liu; Astrid Irwanto; Georgia Chenevix-Trench; Helene Holland; Graham Giles; Laura Baglietto; Gianluca Severi; Stig Bojensen; Børge Nordestgaard; Henrik Flyger; Esther John; Dee West; Alice Whittemore; Celine Vachon; Janet Olson; Zachary Fredericksen; Matthew Kosel; Rebecca Hein; Alina Vrieling; Dieter Flesch-Janys; Judith Heinz; Matthias Beckmann; Katharina Heusinger; Arif Ekici; Lothar Haeberle; Manjeet Humphreys; Jonathan Morrison; Doug Easton; Paul Pharoah; Montserrat García-Closas; Ellen Goode; Jenny Chang-Claude

2010-01-01

368

Effects of Cu/Zn Superoxide Dismutase (sod1) Genotype and Genetic Background on Growth, Reproduction and Defense in Biomphalaria glabrata  

PubMed Central

Resistance of the snail Biomphalaria glabrata to the trematode Schistosoma mansoni is correlated with allelic variation at copper-zinc superoxide dismutase (sod1). We tested whether there is a fitness cost associated with carrying the most resistant allele in three outbred laboratory populations of snails. These three populations were derived from the same base population, but differed in average resistance. Under controlled laboratory conditions we found no cost of carrying the most resistant allele in terms of fecundity, and a possible advantage in terms of growth and mortality. These results suggest that it might be possible to drive resistant alleles of sod1 into natural populations of the snail vector for the purpose of controlling transmission of S. mansoni. However, we did observe a strong effect of genetic background on the association between sod1 genotype and resistance. sod1 genotype explained substantial variance in resistance among individuals in the most resistant genetic background, but had little effect in the least resistant genetic background. Thus, epistatic interactions with other loci may be as important a consideration as costs of resistance in the use of sod1 for vector manipulation. PMID:22724037

Bonner, Kaitlin M.; Bayne, Christopher J.; Larson, Maureen K.; Blouin, Michael S.

2012-01-01

369

Genetic mapping of quantitative trait loci affecting susceptibility in chicken to develop the Pulmonary Hypertension Syndrome (PHS)  

Microsoft Academic Search

Pulmonary hypertension syndrome (PHS), also referred to as ascites syndrome, is a growth-related disorder of chickens frequently observed in fast-growing broilers with insufficient pulmonary vascular capacity at low temperature and\\/or at high altitude. A cross between two genetically different broiler dam lines that originated from the White Plymouth Rock breed was used to produce a three-generation population. This population was

T. S. K. M. Rabie; R. P. M. A. Crooijmans; H. Bovenhuis; A. L. J. Vereijken; A. Veenendaal; Poel van der J. J; Arendonk van J. A. M; A. Pakdel; M. A. M. Groenen

2005-01-01

370

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption  

PubMed Central

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ?2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10?8 to P = 4 × 10?9). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior. PMID:21471458

Schumann, Gunter; Coin, Lachlan J.; Lourdusamy, Anbarasu; Charoen, Pimphen; Berger, Karen H.; Stacey, David; Desrivières, Sylvane; Aliev, Fazil A.; Khan, Anokhi A.; Amin, Najaf; Aulchenko, Yurii S.; Bakalkin, Georgy; Bakker, Stephan J.; Balkau, Beverley; Beulens, Joline W.; Bilbao, Ainhoa; de Boer, Rudolf A.; Beury, Delphine; Bots, Michiel L.; Breetvelt, Elemi J.; Cauchi, Stéphane; Cavalcanti-Proença, Christine; Chambers, John C.; Clarke, Toni-Kim; Dahmen, Norbert; de Geus, Eco J.; Dick, Danielle; Ducci, Francesca; Easton, Alanna; Edenberg, Howard J.; Esko, Tõnu; Fernández-Medarde, Alberto; Foroud, Tatiana; Freimer, Nelson B.; Girault, Jean-Antoine; Grobbee, Diederick E.; Guarrera, Simonetta; Gudbjartsson, Daniel F.; Hartikainen, Anna-Liisa; Heath, Andrew C.; Hesselbrock, Victor; Hofman, Albert; Hottenga, Jouke-Jan; Isohanni, Matti K.; Kaprio, Jaakko; Khaw, Kay-Tee; Kuehnel, Brigitte; Laitinen, Jaana; Lobbens, Stéphane; Luan, Jian'an; Mangino, Massimo; Maroteaux, Matthieu; Matullo, Giuseppe; McCarthy, Mark I.; Mueller, Christian; Navis, Gerjan; Numans, Mattijs E.; Núñez, Alejandro; Nyholt, Dale R.; Onland-Moret, Charlotte N.; Oostra, Ben A.; O'Reilly, Paul F.; Palkovits, Miklos; Penninx, Brenda W.; Polidoro, Silvia; Pouta, Anneli; Prokopenko, Inga; Ricceri, Fulvio; Santos, Eugenio; Smit, Johannes H.; Soranzo, Nicole; Song, Kijoung; Sovio, Ulla; Stumvoll, Michael; Surakk, Ida; Thorgeirsson, Thorgeir E.; Thorsteinsdottir, Unnur; Troakes, Claire; Tyrfingsson, Thorarinn; Tönjes, Anke; Uiterwaal, Cuno S.; Uitterlinden, Andre G.; van der Harst, Pim; van der Schouw, Yvonne T.; Staehlin, Oliver; Vogelzangs, Nicole; Vollenweider, Peter; Waeber, Gerard; Wareham, Nicholas J.; Waterworth, Dawn M.; Whitfield, John B.; Wichmann, Erich H.; Willemsen, Gonneke; Witteman, Jacqueline C.; Yuan, Xin; Zhai, Guangju; Zhao, Jing H.; Zhang, Weihua; Martin, Nicholas G.; Metspalu, Andres; Doering, Angela; Scott, James; Spector, Tim D.; Loos, Ruth J.; Boomsma, Dorret I.; Mooser, Vincent; Peltonen, Leena; Stefansson, Kari; van Duijn, Cornelia M.; Vineis, Paolo; Sommer, Wolfgang H.; Kooner, Jaspal S.; Spanagel, Rainer; Heberlein, Ulrike A.; Jarvelin, Marjo-Riitta; Elliott, Paul

2011-01-01

371

Picosecond-resolved FRET on non-amplified DNA for identifying individuals genetically susceptible to type-1 diabetes  

NASA Astrophysics Data System (ADS)

By tens-of-picosecond resolved fluorescence detection we study Förster resonance energy transfer between a donor and a black-hole-quencher bound at the 5'- and 3'-positions of an oligonucleotide probe matching the highly polymorphic region between codons 51 and 58 of the human leukocyte antigen DQB1 0201 allele, conferring susceptibility to type-1 diabetes. The probe is annealed with non-amplified genomic DNAs carrying either the 0201 sequence or other DQB1 allelic variants. We detect the longest-lived donor fluorescence in the case of hybridization with the 0201 allele and definitely faster and distinct decays for the other allelic variants, some of which are single-nucleotide polymorphic.

Nardo, Luca; Tosi, Giovanna; Bondani, Maria; Accolla, Roberto; Andreoni, Alessandra

2012-06-01

372

Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease  

PubMed Central

Abnormalities in the development of enteric neural crest-derived progenitors (ENPs) that generate the enteric nervous system (ENS) can lead to aganglionosis in a variable portion of the distal gastrointestinal tract. Cumulative evidence suggests that variation of aganglionosis is due to gene interactions that modulate the ability of ENPs to populate the intestine; however, the developmental processes underlying this effect are unknown. We hypothesized that differences in enteric ganglion deficits could be attributable to the effects of genetic background on early developmental processes, including migration, proliferation, or lineage divergence. Developmental processes were investigated in congenic Sox10Dom mice, an established Hirschsprung disease (HSCR) model, on distinct inbred backgrounds, C57BL/6J (B6) and C3HeB/FeJ (C3Fe). Immuno-staining on whole-mount fetal gut tissue and dissociated cell suspensions was used to assess migration and proliferation. Flow cytometry utilizing the cell surface markers p75 and HNK-1 was used to isolate live ENPs for analysis of developmental potential. Frequency of ENPs was reduced in Sox10Dom embryos relative to wi