Sample records for background genetic susceptibility

  1. Comparison of Genetic Backgrounds of Methicillin-Resistant and Susceptible Staphylococcus aureus Isolates from Portuguese Hospitals and the Community

    Microsoft Academic Search

    M. Aires de Sousa; T. Conceicao; C. Simas; H. de Lencastre

    2005-01-01

    In order to understand the origins of the dominant methicillin-resistant Staphylococcus aureus (MRSA) clones in Portuguese hospitals, we compared the genetic backgrounds of nosocomial MRSA with methicillin- susceptible S. aureus (MSSA) isolates from the same hospitals (n 155) and from the community (n 157) where they were located. Pulsed-field gel electrophoresis, spa typing, multilocus sequence typing, and agr type analysis

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

    PubMed Central

    Pazdro, Robert; Harrison, David E.

    2013-01-01

    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

  3. The evolution of methicillin resistance in Staphylococcus aureus: Similarity of genetic backgrounds in historically early methicillin-susceptible and -resistant isolates and contemporary epidemic clones

    PubMed Central

    Crisóstomo, M. Inês; Westh, Henrik; Tomasz, Alexander; Chung, Marilyn; Oliveira, Duarte C.; de Lencastre, Hermínia

    2001-01-01

    The key genetic component of methicillin resistance, the mecA determinant, is not native to Staphylococcus aureus. Thus, the evolution of methicillin-resistant S. aureus (MRSA) must have begun with the acquisition of the mecA determinant from an unknown heterologous source some time before the first reported appearance of MRSA isolates in clinical specimens in the U.K. and Denmark (in the early 1960s). We compared the genetic backgrounds and phenotypes of a group of methicillin-susceptible S. aureus (MSSA) isolates to the properties of MRSA strains isolated in Denmark and the U.K. during the same time period, and also to the genetic profiles of contemporary epidemic clones of MRSA. All early MRSA isolates resembled a large group of the early MSSA blood isolates in phenotypic and genetic properties, including phage group, antibiotype (resistance to penicillin, streptomycin, and tetracycline), pulsed-field gel electrophoresis pattern, and spaA type and multilocus sequence type, strongly suggesting that the early MSSA examined here represented the progeny of a strain that served as one of the first S. aureus recipients of the methicillin-resistance determinant in Europe. The genetic background of this group of early MSSA isolates was also very similar to that of the widely disseminated contemporary “Iberian clone” of MRSA, suggesting that genetic determinants present in early MSSA and essential for some aspects of the epidemicity and/or virulence of these strains may have been retained by this highly successful contemporary MRSA lineage. PMID:11481426

  4. Genetic susceptibility to endomyocardial fibrosis

    PubMed Central

    Beaton, Andrea; Sable, Craig; Brown, Juliette; Hoffman, Joshua; Mungoma, Michael; Mondo, Charles; Cereb, Nezith; Brown, Colin; Summar, Marshall; Freers, Jurgen; Ferreira, Maria Beatriz; Yacoub, Magdi; Mocumbi, Ana Olga

    2014-01-01

    Background: Endomyocardial fibrosis (EMF) is the most common form of restrictive cardiomyopathy worldwide. It has been linked to poverty and various environmental factors, but—for unknown reasons—only some people who live in similar conditions develop the disease. EMF cases cluster within both families and ethnic groups, suggesting a role for a genetic factor in host susceptibility. The human leukocyte antigen (HLA) system is associated with predisposition to various diseases. This two-center study was designed to investigate variation in the HLA system between EMF patients and unaffected controls. We provide the first genetic investigation of patients with EMF, as well as a comprehensive review of the literature. Methods: HLA class I (HLA-A, -B, -C) and class II (DRB1, DQB1) types were determined in 71 patients with severe EMF and 137 controls from Uganda and Mozambique. Chi Square analysis was used to identify any significant difference in frequency of class I and class II HLA types between cases and controls. Results: Compared to ethnically matched controls, HLA-B*58 occurred more frequently in Mozambique patients with EMF and HLA-A*02:02 occurred more frequently in Ugandan patients with EMF. Conclusions: Ample subjective evidence in the historical literature suggests the importance of a genetically susceptible host in EMF development. In this first formal genetic study, we found HLA alleles associated with cases of EMF in two populations from sub-Saharan Africa, with EMF patients being more likely than controls to have the HLA-B*58 allele in Mozambique (p-0.03) and the HLA-A*02:02 in Uganda (p = 0.005). Further investigations are needed to more fully understand the role of genetics in EMF development. PMID:25780800

  5. Genetic susceptibility to Campylobacter infection

    Microsoft Academic Search

    R. Janssen; Jonge R de; B. Hoebee

    2007-01-01

    Genetic factors partially determine the susceptibility of an individual\\u000ato Campylobacter infection. The genes that are specifically responsible\\u000afor this have not been identified but probably do play a role in gastric\\u000aacid production and in the immune response (specific humoral- and\\u000acell-mediated immunity). Genetic studies in humans could very well\\u000aincrease our understanding of an individual's susceptibility to\\u000aCampylobacter

  6. Genetic Architecture of Intrinsic Antibiotic Susceptibility

    Microsoft Academic Search

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

    2009-01-01

    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

  7. Genetic susceptibility to childhood leukaemia

    PubMed Central

    Chokkalingam, Anand P.; Buffler, Patricia A.

    2008-01-01

    The aetiology of leukaemias among children is believed to be distinct from that of adults, mainly due to the clearer role for early life exposures, including those in utero. However, few risk factors have been established, because of the challenge of studying a disease with relatively low incidence. Identified risk factors, including ionizing radiation, chemotherapeutic agents and specific genetic abnormalities, explain <10% of incidence(1,2). Although the causes for the remaining 90% are unknown, it is possible that genetic susceptibility factors, either alone or in conjunction with environmental factors, may be involved. In this paper, the authors (a) review the evidence surrounding genetic susceptibility factors, with emphasis on the genes' main effects; (b) review some recent developments in the Northern California Childhood Leukaemia Study (NCCLS) as a case study of design and practical considerations in genetic epidemiology research and (c) highlight both challenges and future directions in this exciting research area. PMID:18922824

  8. Genetic susceptibility to radiation

    NASA Astrophysics Data System (ADS)

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

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

  9. Genetic susceptibility to radiation

    NASA Astrophysics Data System (ADS)

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

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

  10. Genetically and medically susceptible workers.

    PubMed

    Mohr, S; Gochfeld, M; Pransky, G

    1999-01-01

    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

  11. Does your gene need a background check? How genetic background

    E-print Network

    Dworkin, Ian

    best to exploit genetic background effects to broaden genetic research programs. What are geneticDoes your gene need a background check? How genetic background impacts the analysis of mutations, USA 2 Department of Biological Sciences, SUNY Oswego, Oswego, NY, USA The premise of genetic analysis

  12. Genetic susceptibility to lead poisoning.

    PubMed Central

    Onalaja, A O; Claudio, L

    2000-01-01

    Major strides have been taken in the regulation of lead intoxication in the general population, but studies using genetic markers of susceptibility to environmental toxicants raise the question of whether genes can make certain individuals more vulnerable to environmental toxins such as lead. At least three polymorphic genes have been identified that potentially can influence the bioaccumulation and toxicokinetics of lead in humans. The first gene to be discussed in this review is the gene coding for delta-aminolevulinic acid dehydratase (ALAD), an enzyme of heme biosynthesis, that exists in two polymorphic forms. The resulting isozymes have been shown to affect the blood and bone lead levels in human populations. The effects of ALAD in lead intoxication have also been studied in laboratory mice that differ in the genetic dose for this enzyme. The second gene reviewed here is the vitamin D receptor (VDR) gene. The VDR is involved in calcium absorption through the gut and into calcium-rich tissues such as bone. Recent findings suggest that VDR polymorphism may influence the accumulation of lead in bone. Finally, the third gene to be discussed here that may influence the absorption of lead is the hemochromatosis gene coding for the HFE protein. The presence of mutations in the HFE gene leads to hemochromatosis in homozygotic individuals. Because of the associations between iron and lead transport, it is possible that polymorphisms in the HFE gene may also influence the absorption of lead, but this has not yet been studied. More studies will be needed to define the role of these genes in lead intoxication. Images Figure 2 Figure 4 PMID:10698721

  13. Awareness of Cancer Susceptibility Genetic Testing

    PubMed Central

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

    2014-01-01

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

  14. Genetic epidemiology of the susceptibility to leprosy.

    PubMed Central

    Shields, E D; Russell, D A; Pericak-Vance, M A

    1987-01-01

    To test the hypothesis that genetic factors are operative in the predisposition to leprosy (Hansen's disease) in humans, a genetic epidemiologic investigation was performed on 269 leprosy kindreds containing 552 affected individuals from an isolated population in Papua New Guinea. The community, and not the family, was the basic social unit. Leprosy, an infectious disease, was not communal but strongly familial within the Karimui. Segregation analysis, to determine whether a major gene for the susceptibility to leprosy was segregating within a single multi-generational kindred, could not differentiate between a Mendelian genetic and a purely environmental hypothesis. The composite kindred data, however, suggest a genetic hypothesis for the non-immunologically induced susceptibility to leprosy per se. Within familial kindreds leprosy invariably emanated from a common ancestral sibship, and risk was associated with the closeness of kin but not with infectivity or severity. PMID:3549780

  15. Genetic susceptibility to autoimmune liver disease.

    PubMed

    Mattner, Jochen

    2011-01-27

    Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are considered as putative autoimmune diseases of the liver. Whereas strong evidence that bacterial infection may trigger PBC exists, the etiologies for PSC and AIH remain unknown. Although there have been significant discoveries of genetic polymorphisms that may underlie the susceptibility to these liver diseases, their associations with environmental triggers and the subsequent implications have been difficult to elucidate. While single nucleotide polymorphisms within the negative costimulatory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) have been suggested as genetic susceptibility factors for all three disorders, we discuss the implications of CTLA-4 susceptibility alleles mainly in the context of PBC, where Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium, has recently been specifically associated with the pathogenesis of this devastating liver disease. Ultimately, the discovery of infectious triggers of PBC may expand the concept of genetic susceptibility in immune-mediated liver diseases from the concept of aberrant immune responses against self-antigens to insufficient and/or inappropriate immunological defense mechanisms allowing microbes to cross natural barriers, establish infection and damage respective target organs. PMID:21307981

  16. Genetic susceptibility to invasive Salmonella disease.

    PubMed

    Gilchrist, James J; MacLennan, Calman A; Hill, Adrian V S

    2015-06-25

    Invasive Salmonella disease, in the form of enteric fever and invasive non-typhoidal Salmonella (iNTS) disease, causes substantial morbidity and mortality in children and adults in the developing world. The study of genetic variations in humans and mice that influence susceptibility of the host to Salmonella infection provides important insights into immunity to Salmonella. In this Review, we discuss data that have helped to elucidate the host genetic determinants of human enteric fever and iNTS disease, alongside data from the mouse model of Salmonella infection. Considered together, these studies provide a detailed picture of the immunobiology of human invasive Salmonella disease. PMID:26109132

  17. Genetic background of supernumerary teeth

    PubMed Central

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

    2015-01-01

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

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

    Microsoft Academic Search

    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

    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

  19. Epidemiology and genetic susceptibility to bladder cancer.

    PubMed

    Wu, Xifeng; Ros, Martine M; Gu, Jian; Kiemeney, Lambertus

    2008-11-01

    The incidence of bladder cancer varies considerably among countries; the highest incidence rates are in Western communities. The variation in occurrence can partly be explained by differences in registration and coding practices of pTa tumours. Factors that modify the occurrence of bladder cancer are smoking and exposure to many kinds of carcinogenic substances in the workplace. Evidence also exists for radiotherapy to the pelvis, infection with Schistosoma haematobium, and certain medications as risk factors for bladder cancer. Despite enormous efforts, other important environmental or lifestyle factors that clearly and consistently increase or decrease the risk of bladder cancer have not been identified. Bladder cancer in first-degree relatives doubles the risk of bladder cancer; this increased risk might be due to high-penetrance susceptibility genes in a small subset of families, but most of this risk is probably caused by common lower-penetrance DNA variants that influence risk through one or more different cancer pathways. In the next 2 years genome-wide association scans will probably yield important new information on such variants. This might also facilitate new studies on lifestyle factors restricted to groups of susceptible people. In the future it will also be necessary to pay more attention to potential risk factors for different types of bladder cancer, more specifically low- vs high-grade cancer. The ultimate goal is to build a risk-prediction model by integrating environmental and genetic factors that can project individualized probabilities of developing bladder cancer. PMID:19035883

  20. Contemplating Genetic Feedback Regarding Lung Cancer Susceptibility

    PubMed Central

    Shepperd, James A.; Novell, Corinne A.; O'Neill, Suzanne C.; Docherty, Sharron L.; Sanderson, Saskia C.; McBride, Colleen M.; Lipkus, Isaac M.

    2013-01-01

    Background and Purpose We examined three theoretical models (self-enhancement theory, consistency theory, and combined model) for understanding how expectations and test result favorability influence smokers' desire for a retest following hypothetical genetic test results. Method College smokers (N = 128) read a brochure describing a biomarker for lung cancer (the GSTM1 gene) then reported whether they thought they had the gene (indicating lower lung cancer risk) or were missing the gene (indicating higher lung cancer risk). Participants then reported whether they would get retested if they received favorable GSTM1 results versus unfavorable GSTM1 results. Results Participants were most likely to want a retest, suggesting rejection of the results, if they expected favorable news yet received unfavorable news. Conclusion The findings supported the combined model such that smokers expressed greatest interest in a retest when they imagined genetic risk feedback that challenges both enhancement and consistency motives. PMID:24222509

  1. 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...

  2. Genetic testing of newborns for type 1 diabetes susceptibility: a prospective cohort study on effects on maternal mental health

    Microsoft Academic Search

    Kaja K Aas; Kristian Tambs; Marit S Kise; Per Magnus; Kjersti S Rønningen

    2010-01-01

    BACKGROUND: Concerns about the general psychological impact of genetic testing have been raised. In the Environmental Triggers of Type 1 Diabetes (MIDIA) study, genetic testing was performed for HLA-conferred type 1 diabetes susceptibility among Norwegian newborns. The present study assessed whether mothers of children who test positively suffer from poorer mental health and well-being after receiving genetic risk information about

  3. Risk Communication in Genetic Testing for Cancer Susceptibility

    Microsoft Academic Search

    Robert T. Croyle; Caryn Lerman

    1999-01-01

    Risk communication is an integral part of genetic counseling and testing for cancer susceptibility. This paper reviews the emerging literature on this topic. Three relevant aspects of risk communication are addressed: communication of indi- vidual risk, communication of the risks inherent in genetic testing, and family communications related to risk. These studies suggest that (a) most individuals with some family

  4. NCI Releases Preliminary Data on Genetic Susceptibility for Prostate Cancer

    Cancer.gov

    The National Cancer Institute (NCI), part of the National Institutes of Health, has released new data from the Cancer Genetic Markers of Susceptibility (CGEMS) study on prostate cancer. This information could help identify genetic factors that influence the disease and will be integral to the discovery and development of new, targeted therapies.

  5. Role of genetic background in induced instability

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

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

  6. Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility

    PubMed Central

    Kuo, Ho-Chang; Huang, Ying-Hsien; Chien, Shu-Chen; Yu, Hong-Ren; Hsieh, Kai-Sheng; Hsu, Yu-Wen; Chang, Wei-Chiao

    2014-01-01

    Background Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. Methods A total of 948 subjects (381 KD and 567 controls) were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Results Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240) and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P?=?0.0002, OR?=?1.61) and G/A/G haplotype (P?=?0.0365, OR?=?1.52) had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. Conclusion CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness. PMID:25148534

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

    Microsoft Academic Search

    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

    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

  8. Genetic background of idiopathic pulmonary fibrosis.

    PubMed

    Santangelo, Simona; Scarlata, Simone; Zito, Anna; Chiurco, Domenica; Pedone, Claudio; Incalzi, Raffaele Antonelli

    2013-05-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive fibrosing interstitial pneumonia. The histological pattern, which displays dense fibrosis with active areas of fibroblastic proliferation, suggests a pathogenetic role of aberrant response to healing of multiple microscopic, repeated alveolar epithelial injuries. Although the exact etiology of the disease is still under investigation, several studies suggest that a combination of genetic and environmental factors may play a causal role. The aim of this review is to describe the genetic background of IPF, reporting the latest advancements made possible by genomic techniques that allow a high-throughput analysis and the identification of target genes implicated in IPF. This information may help to clarify pivotal aspects on prognosis and diagnosis, and may help to identify potential targets for future therapies. PMID:23638821

  9. Genetic Susceptibility and Neurotransmitters in Tourette Syndrome

    PubMed Central

    Paschou, Peristera; Fernandez, Thomas V.; Sharp, Frank; Heiman, Gary A.; Hoekstra, Pieter J.

    2015-01-01

    Family studies have consistently shown that Tourette syndrome (TS) is a familial disorder and twin studies have clearly indicated a genetic contribution in the etiology of TS. Whereas early segregation studies of TS suggested a single-gene autosomal dominant disorder, later studies have pointed to more complex models including additive and multifactorial inheritance and likely interaction with genetic factors. While the exact cellular and molecular base of TS is as yet elusive, neuroanatomical and neurophysiological studies have pointed to the involvement of cortico-striato-thalamocortical circuits and abnormalities in dopamine, glutamate, gamma-aminobutyric acid, and serotonin neurotransmitter systems, with the most consistent evidence being available for involvement of dopamine-related abnormalities, that is, a reduction in tonic extracellular dopamine levels along with hyperresponsive spike-dependent dopamine release, following stimulation. Genetic and gene expression findings are very much supportive of involvement of these neurotransmitter systems. Moreover, intriguingly, genetic work on a two-generation pedigree has opened new research pointing to a role for histamine, a so far rather neglected neurotransmitter, with the potential of the development of new treatment options. Future studies should be aimed at directly linking neurotransmitter-related genetic and gene expression findings to imaging studies (imaging genetics), which enables a better understanding of the pathways and mechanisms through which the dynamic interplay of genes, brain, and environment shapes the TS phenotype. PMID:24295621

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

    SciTech Connect

    Mori, Nobuko; Okumoto, Masaaki; Esaki, Kozaburo [Univ. of Osaka Prefecture (Japan)] [and others] [Univ. of Osaka Prefecture (Japan); and others

    1995-02-10

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

  11. Genetic susceptibility to hypertensive renal disease

    PubMed Central

    Doris, Peter A.

    2012-01-01

    Hypertensive renal disease occurs at increased frequency among the relatives of patients with this disease compared with individuals who lack a family history of disease. This suggests a heritable risk in which genetic variation may play a role. These observations have motivated a search for genetic variation contributing to this risk in both experimental animal models and in human populations. Studies of animal models indicate the capacity of natural genetic variants to contribute to disease risk and have produced a few insights into disease mechanism. In its current phase, human population genetic studies have sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome wide association studies (GWAS) have been productive and are a clear technical success; they have also identified narrowly defined loci and genes containing variation contributing to disease risk. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few additional variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining unaccounted heritable risk may be located. At present much consideration is being given to this question and to the challenge of testing hypotheses that lead from the various alternative mechanisms under consideration. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise. PMID:22562581

  12. Comprehensive Assessment and Network Analysis of the Emerging Genetic Susceptibility Landscape of Prostate Cancer

    PubMed Central

    Hicks, Chindo; Miele, Lucio; Koganti, Tejaswi; Vijayakumar, Srinivasan

    2013-01-01

    Background Recent advances in high-throughput genotyping have made possible identification of genetic variants associated with increased risk of developing prostate cancer using genome-wide associations studies (GWAS). However, the broader context in which the identified genetic variants operate is poorly understood. Here we present a comprehensive assessment, network, and pathway analysis of the emerging genetic susceptibility landscape of prostate cancer. Methods We created a comprehensive catalog of genetic variants and associated genes by mining published reports and accompanying websites hosting supplementary data on GWAS. We then performed network and pathway analysis using single nucleotide polymorphism (SNP)-containing genes to identify gene regulatory networks and pathways enriched for genetic variants. Results We identified multiple gene networks and pathways enriched for genetic variants including IGF-1, androgen biosynthesis and androgen signaling pathways, and the molecular mechanisms of cancer. The results provide putative functional bridges between GWAS findings and gene regulatory networks and biological pathways. PMID:24031161

  13. Genetic susceptibility factors for multiple chemical sensitivity revisited

    Microsoft Academic Search

    Nikolaj Drimer Berg; Henrik Berg Rasmussen; Allan Linneberg; Charlotte Brasch-Andersen; Mogens Fenger; Asger Dirksen; Søren Vesterhauge; Thomas Werge; Jesper Elberling

    2010-01-01

    Multiple chemical sensitivity (MCS) is characterised by adverse effects due to exposure to low levels of chemical substances. Various genes, especially genes of importance to the metabolism of xenobiotic compounds, have been associated with MCS, but findings are inconsistent. The purpose of this study was to investigate genetic susceptibility factors for MCS and self-reported chemical sensitivity in a population sample.

  14. Genetic polymorphisms and lung cancer susceptibility: a review

    Microsoft Academic Search

    Chikako Kiyohara; Akiko Otsu; Taro Shirakawa; Sanae Fukuda; Julian M Hopkin

    2002-01-01

    Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Cigarette smoking is an established risk factor for lung cancer although a possible role for genetic susceptibility in the development of lung cancer has been inferred from familial clustering of the disease and segregation analyzes. Everyone may

  15. Host genetic susceptibility, dysbiosis and viral triggers in IBD

    PubMed Central

    Sun, Lulu; Nava, Gerardo M.; Stappenbeck, Thaddeus S.

    2014-01-01

    Purpose of Review Inflammatory bowel disease (IBD) is thought to occur in genetically susceptible individuals. However, environmental factors, potentially including shifts in commensal microbiota, are also required to trigger disease. This review discusses some of the recent discoveries in host susceptibility and interaction with the microbial environment, and pinpoints key areas for advancement in our understanding of IBD pathogenesis. Recent findings Meta-analyses of genome wide association studies have uncovered many new exciting genes associated with susceptibility loci. In addition, improved methods to analyze the commensal microbiota path the way to better define dysbiosis and its potential role in disease. Lastly, identification of viral triggers in experimental systems of IBD suggests a potential role in IBD. Summary Understanding the precise microbial and immune triggers of IBD in a genetic context will hopefully lead to a better understanding of the pathogenesis of this disease and the discovery of novel therapeutic approaches including vaccines for specific viruses. PMID:21483258

  16. Chloroquine Susceptibility and Reversibility in a Plasmodium falciparum Genetic Cross

    PubMed Central

    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

    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

  17. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

    PubMed Central

    2011-01-01

    Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

  18. Update of genetic susceptibility in patients with Kawasaki disease

    PubMed Central

    2015-01-01

    Kawasaki disease (KD) is an acute systemic vasculitis that predominantly affects children, and can result in coronary artery lesions (CAL). A patient with KD who is resistant to treatment with intravenous immunoglobulin (IVIG) has a higher risk of developing CAL. Incomplete KD has increased in prevalence in recent years, and is another risk factor for the development of CAL. Although the pathogenesis of KD remains unclear, there has been increasing evidence for the role of genetic susceptibility to the disease since it was discovered in 1967. We retrospectively reviewed previous genetic research for known susceptibility genes in the pathogenesis of KD, IVIG resistance, and the development of CAL. This review revealed numerous potential susceptibility genes including genetic polymorphisms of ITPKC, CASP3, the transforming growth factor-? signaling pathway, B lymphoid tyrosine kinase, FCGR2A, KCNN2, and other genes, an imbalance of Th17/Treg, and a range of suggested future treatment options. The results of genetic research may improve our understanding of the pathogenesis of KD, and aid in the discovery of new treatment modalities for high-risk patients with KD. PMID:25861330

  19. Human genetic susceptibility and infection with Leishmania peruviana.

    PubMed Central

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

    1995-01-01

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

  20. Genetic diversity among late blight resistant and susceptible potato genotypes

    PubMed Central

    Abou-Taleb, Eid M.; Aboshosha, Sayed M.; El-Sherif, Ebtsam M.; El-Komy, Mahmoud H.

    2010-01-01

    RAPD polymerase chain reaction analysis was used to study the genetic diversity among a wild potato variety Solanum demissum (very resistant to late blight) and six potato cultivars (Hanna, Lady-Olympia, Lady-Rosetta, Spunta, Diamant and Cara) varied in their resistance to Phytophthora infestans. Cluster analysis of six potato genotypes showed that, all tested genotypes were separated into two clusters (1 and 2). Cluster 1, included only the wild potato variety (S. demissum), whereas cluster 2 divided into two groups (G1 and G2). Late blight high resistant cultivars Hanna and Cara were grouped in G1. Group 2 included the moderate resistant cultivar Spunta and the susceptible cultivars Diamant, Lady-Rosetta and Lady-Olympia. The potato cultivars that showed highest genetic similarity to the wild potato variety were the resistant cultivars Hanna and Cara. Lowest genetic similarity was obtained with the susceptible cultivars Lady-Rosetta, Diamant and Lady-Olympia. RAPD primer K17 yielded a band with molecular weight of 936 bp found in all susceptible potato cultivars (Lady-Rosetta, Lady-Olympia and Diamant). On the other hand, band with molecular weight of 765 bp were detected in the wild potato and the resistant cultivars Hanna and Cara. Results of this study suggested that, the RAPD marker technique could be beneficial for revealing the genetic variability of different genotypes of potato varied in their resistibility to late blight. PMID:23961069

  1. Genetic architecture of murine skin inflammation and tumor susceptibility

    PubMed Central

    Quigley, David A.; To, Minh D.; Pérez-Losada, Jesús; Pelorosso, Facundo G.; Mao, Jian-Hua; Nagase, Hiroki; Ginzinger, David G.; Balmain, Allan

    2015-01-01

    Germline polymorphisms in both model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer1,2,3,4. Mice of the Mus spretus species are resistant to tumor development, and crosses between Mus spretus and susceptible Mus musculus strains have been used to map locations of genetic variants that contribute to skin cancer susceptibility4,5,6. We have integrated germline polymorphisms with gene expression in normal skin from a musculus x spretus backcross to generate a network view of the gene expression architecture of mouse skin. Here we demonstrate how this approach identifies expression motifs that contribute to tissue organization and biological functions related to inflammation, hematopoiesis, cell cycle control and tumor susceptibility. Motifs associated with inflammation, epidermal barrier function and proliferation are differentially regulated in backcross mice susceptible or resistant to tumor development. The intestinal stem cell marker Lgr5 is identified as a candidate master regulator of the hair follicle, and the Vitamin D receptor (Vdr) is linked to coordinated control of epidermal barrier function, inflammation, and tumor susceptibility. PMID:19136944

  2. Mitochondrial Genetics & Obesity: Evolutionary Adaptation & Contemporary Disease Susceptibility

    PubMed Central

    Dunham-Snary, Kimberly J.; Ballinger, Scott W.

    2013-01-01

    Obesity is a leading risk factor for a variety of metabolic diseases including cardiovascular disease, diabetes and cancer. Although in its simplest terms, obesity may be thought of as a consequence of excessive caloric intake and sedentary lifestyle, it is also evident that individual propensity for weight gain can vary. The etiology of individual susceptibility to obesity appears to be complex – involving a combination of environmental – genetic interactions. Herein, we suggest that the mitochondrion plays a major role in influencing individual susceptibility to this disease via mitochondrial – nuclear interaction processes, and that environmentally influenced selection events for mitochondrial function that conveyed increased reproductive and survival success during the global establishment of human populations during prehistoric times can influence individual susceptibility to weight gain and obesity. PMID:24075923

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

    E-print Network

    Matuszek, Gregory; Talebizadeh, Zohreh

    2009-09-24

    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 reported in association...

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

    PubMed Central

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

    2008-01-01

    Background Genetic risk for Alzheimer’s disease (AD) may be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the ?4 allele increases the risk of developing late-onset Alzheimer’s disease but is not a definitive predictor of the disease, or by autosomal dominant mutations (e.g., the presenilins), which almost inevitably result in early-onset familial Alzheimer’s disease. The purpose of this study was to compare the psychological impact of using these two different types of genetic information to disclose genetic risk for AD to family members of affected patients. Methods Data were compared from two separate protocols. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study is a randomized, multi-site clinical trial that evaluated the impact of susceptibility testing for Alzheimer’s disease with APOE in 101 adult children of Alzheimer’s disease patients. A separate study, conducted at the University of Washington, assessed the impact of deterministic genetic testing by disclosing presenilin-1, presenilin-2, or TAU genotype to 22 individuals at risk for familial Alzheimer’s disease or frontotemporal dementia. In both protocols, participants received genetic counseling and completed the Impact of Event Scale (IES), a measure of test-specific distress. Scores were analyzed at the time point closest to one year post-disclosure at which IES data were available. The role of genetic test result (positive vs. negative) and type of genetic testing (deterministic vs. susceptibility) in predicting log-transformed IES scores was assessed with linear regression, controlling for age, gender, and time from disclosure. Results Subjects from the REVEAL Study who learned that they were positive for the susceptibility gene APOE ?4+ experienced similar, low levels of test-specific distress compared to those who received positive results of deterministic testing in the University of Washington study (p= 0.78). APOE ?4+ individuals in the susceptibility protocol experienced more test-specific distress than those who tested ?4? in the same study (p= 0.04); however, among those receiving deterministic test disclosure, the subjects who received positive results did not experience significantly higher levels of distress when compared to those who received negative results (p= 0.88). Conclusions The findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and that the majority of participants receiving genotype disclosure do not experience clinically significant distress as indicated by IES scores one year after learning of their test results. PMID:19012865

  5. Genetic Algorithms To provide a background and understanding of basic genetic

    E-print Network

    Qu, Rong

    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

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

    PubMed Central

    Winawer, Melodie R.; Connors, Robert

    2012-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  9. Neutrophils exacerbate tuberculosis infection in genetically susceptible mice.

    PubMed

    Yeremeev, Vladimir; Linge, Irina; Kondratieva, Tatiana; Apt, Alexander

    2015-07-01

    Mice of the I/St inbred strain genetically hyper-susceptible to TB infection and prone to form neutrophil-abundant necrotic lung lesions and relatively resistant mice of the C57BL/6 (B6) strain were infected with 100 CFU of M. tuberculosis H37Rv. To verify the role of neutrophils in TB immunity, we selectively depleted neutrophils from infected mice with highly specific 1A8 anti-Ly6G antibodies at day 2 and 6 post-challenge. Depletion of neutrophils resulted in reduced lung tissue pathology, mycobacterial CFU counts and an increase of the survival time in genetically susceptible I/St, but not in B6 mice. Furthermore, we demonstrated that in vivo neutrophil depletion at the onset of TB infection results in a significant increase in numbers of mycobacteria-specific IFN-?-producing T-cells at the time point when the acquired immunity to mycobacteria is fully developed. These results suggest antagonistic activity of neutrophils and immune T-cells in the course of TB infection and provide further evidence of deleterious rather than protective role of the former. PMID:25935122

  10. Genetic Susceptibility Loci, Pesticide Exposure and Prostate Cancer Risk

    PubMed Central

    Koutros, Stella; Berndt, Sonja I.; Hughes Barry, Kathryn; Andreotti, Gabriella; Hoppin, Jane A.; Sandler, Dale P.; Yeager, Meredith; Burdett, Laurie A.; Yuenger, Jeffrey; Alavanja, Michael C. R.; Beane Freeman, Laura E.

    2013-01-01

    Uncovering SNP (single nucleotide polymorphisms)-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1) SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44–8.15) (P-interaction ?=?0.003). Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41) (P-interaction ?=?0.006). In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer. PMID:23593118

  11. Integrated Laplacian-based phase unwrapping and background phase removal for quantitative susceptibility mapping.

    PubMed

    Li, Wei; Avram, Alexandru V; Wu, Bing; Xiao, Xue; Liu, Chunlei

    2014-02-01

    Quantitative susceptibility mapping (QSM) is a recently developed MRI technique that provides a quantitative measure of tissue magnetic susceptibility. To compute tissue magnetic susceptibilities based on gradient echoes, QSM requires reliable unwrapping of the measured phase images and removal of contributions caused by background susceptibilities. Typically, the two steps are performed separately. Here, we present a method that simultaneously performs phase unwrapping and HARmonic (background) PhasE REmovaL using the LAplacian operator (HARPERELLA). Both numerical simulations and in vivo human brain images show that HARPERELLA effectively removes both phase wraps and background phase, whilst preserving all low spatial frequency components originating from brain tissues. When compared with other QSM phase preprocessing techniques, such as path-based phase unwrapping followed by background phase removal, HARPERELLA preserves the tissue phase signal in gray matter, white matter and cerebrospinal fluid with excellent robustness, providing a convenient and accurate solution for QSM. The proposed algorithm is provided, together with QSM and susceptibility tensor imaging (STI) tools, in a shared software package named 'STI Suite'. PMID:24357120

  12. Integrated Laplacian-based phase unwrapping and background phase removal for quantitative susceptibility mapping

    PubMed Central

    Li, Wei; Avram, Alexandru V.; Wu, Bing; Xiao, Xue; Liu, Chunlei

    2014-01-01

    Quantitative susceptibility mapping (QSM) is a recently developed MRI technique that provides a quantitative measure of tissue magnetic susceptibility. To compute tissue magnetic susceptibilities based on gradient echoes, QSM requires reliable unwrapping of the measured phase images and removal of contributions due to background susceptibilities. Typically, the two steps are performed separately. Here we present a method that simultaneously performs phase unwrapping and HArmonic (background) PhasE REmovaL using the LAplacian operator (HARPERELLA). Both numerical simulations and in vivo human brain images showed that HARPERELLA effectively removes both phase wraps and background phase, while preserving all low spatial frequency components originating from brain tissues. When compared with other QSM phase preprocessing techniques, such as path-based phase unwrapping followed by background phase removal, HARPERELLA preserves the tissue phase signal in gray matter, white matter and cerebrospinal fluid with excellent robustness, providing a convenient and accurate solution for QSM. The proposed algorithm is provided together with QSM and susceptibility tensor imaging (STI) tools in a shared software package named “STI Suite”. PMID:24357120

  13. Genetic Variability in Susceptibility to Occupational Respiratory Sensitization

    PubMed Central

    Yucesoy, Berran; Johnson, Victor J.

    2011-01-01

    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

  14. Breast cancer susceptibility: current knowledge and implications for genetic counselling.

    PubMed

    Ripperger, Tim; Gadzicki, Dorothea; Meindl, Alfons; Schlegelberger, Brigitte

    2009-06-01

    Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk. PMID:19092773

  15. Genetic susceptibility testing in smoking-cessation treatment: One-year outcomes of a randomized trial

    Microsoft Academic Search

    Janet Audrain; Neal R. Boyd; Joan Roth; David Main; Neil E. Caporaso; Caryn Lerman

    1997-01-01

    This study evaluated the long-term impact of genetic susceptibility biomarker feedback on smoking behavior change and symptoms of depression in 426 male and female smokers. Smokers were randomized to one of three smoking-cessation interventions: minimal contact quit-smoking counseling (QSC), QSC + exposure biomarker feedback (EBF), and QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer (SBF). The

  16. Genetic background determines metabolic phenotypes in the mouse.

    PubMed

    Champy, Marie-France; Selloum, Mohammed; Zeitler, Valérie; Caradec, Claudia; Jung, Barbara; Rousseau, Stéphane; Pouilly, Laurent; Sorg, Tania; Auwerx, Johan

    2008-05-01

    To evaluate the contribution of genetic background to phenotypic variation, we compared a large range of biochemical and metabolic parameters at different ages of four inbred mice strains, C57BL/6J, 129SvPas, C3HeB/FeJ, and Balb/cByJ. Our results demonstrate that important metabolic, hematologic, and biochemical differences exist between these different inbred strains. Most of these differences are gender independent and are maintained or accentuated throughout life. It is therefore imperative that the genetic background is carefully defined in phenotypic studies. Our results also argue that certain backgrounds are more suited to study a given physiologic phenomenon, as distinct mouse strains have a different propensity to develop particular biochemical, hematologic, and metabolic abnormalities. These genetic differences can furthermore be exploited to identify new genes/proteins that contribute to phenotypic abnormalities. The choice of the genetic background in which to generate and analyze genetically engineered mutant mice is important as it is, together with environmental factors, one of the most important contributors to the variability of phenotypic results. PMID:18392653

  17. Genetic background controls tumor development in PTEN-deficient mice.

    PubMed

    Freeman, Dan; Lesche, Ralf; Kertesz, Nathalie; Wang, Shungyou; Li, Gang; Gao, Jing; Groszer, Matthias; Martinez-Diaz, Hilda; Rozengurt, Nora; Thomas, George; Liu, Xin; Wu, Hong

    2006-07-01

    PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. Germ line mutations of PTEN have been detected in three rare autosomal-dominant disorders. However, identical mutations in the PTEN gene may lead to different symptoms that have traditionally been described as different disorders, such as Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndromes. This lack of genotype-phenotype correlation prompted us to directly test the possible effects of genetic background or modifier genes on PTEN-controlled tumorigenesis using genetically engineered mouse models. In this study, we generated two animal models in which either exon 5 (Pten(Delta5)) or promoter to exon 3 (Pten(-)) of the murine Pten gene were deleted and compared phenotypes associated with individual mutations on two genetic backgrounds. We found that the onset and spectrum of tumor formation depend significantly on the genetic background but less on the type of mutation generated. Our results suggest that PTEN plays a critical role in cancer development, and genetic background may influence the onset, the spectrum, and the progression of tumorigenesis caused by Pten mutation. PMID:16818619

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

    PubMed Central

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

    2012-01-01

    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

  19. Effects of Undergoing Multiplex Genetic Susceptibility Testing on Parent’s Attitudes Towards Testing Their Children

    PubMed Central

    Madeo, Anne C.; Tercyak, Kenneth P.; Tarini, Beth A.; McBride, Colleen M.

    2014-01-01

    Background Parents may pursue common disease risk information about themselves via multiplex genetic susceptibility testing (MGST) for their children. Purpose To prospectively assess whether parents who received MGST disclosed their test results to their child, intended to change the child’s health habits or have the child tested. Methods Eighty parents who opted for free MGST completed an online survey about a child in their household before undergoing MGST and a follow-up telephone survey three months after receiving results. Results Few parents (21%) disclosed results to the child. Undergoing MGST was unrelated to intentions to change the child’s health habits but did increase parental willingness to test the child. Greater willingness to test a child was associated with positive attitudes toward pediatric genetic testing and intentions to change the child’s health habits. Conclusion The experience of receiving MGST had little impact on parents’ perceptions or behaviors related to their minor child. PMID:24338635

  20. Distinct genetic control of autoimmune neuropathy and diabetes in the non-obese diabetic background

    PubMed Central

    Bour-Jordan, Hélène; Thompson, Heather L.; Giampaolo, Jennifer R.; Davini, Dan; Rosenthal, Wendy; Bluestone, Jeffrey A.

    2014-01-01

    The non-obese diabetic (NOD) mouse is susceptible to the development of autoimmune diabetes but also multiple other autoimmune diseases. Over twenty susceptibility loci linked to diabetes have been identified in NOD mice and progress has been made in the definition of candidate genes at many of these loci (termed Idd for insulin-dependent diabetes). The susceptibility to multiple autoimmune diseases in the NOD background is a unique opportunity to examine susceptibility genes that confer a general propensity for autoimmunity versus susceptibility genes that control individual autoimmune diseases. We previously showed that NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) were protected from diabetes but spontaneously developed an autoimmune peripheral neuropathy. Here, we took advantage of multiple NOD mouse strains congenic for Idd loci to test the role of these Idd loci the development of neuropathy and determine if B6 alleles at Idd loci that are protective for diabetes will also be for neuropathy. Thus, we generated NOD-B7-2KO strains congenic at Idd loci and examined the development of neuritis and clinical neuropathy. We found that the NOD-H-2g7 MHC region is necessary for development of neuropathy in NOD-B7-2KO mice. In contrast, other Idd loci that significantly protect from diabetes did not affect neuropathy when considered individually. However, we found potent genetic interactions of some Idd loci that provided almost complete protection from neuritis and clinical neuropathy. In addition, defective immunoregulation by Tregs could supersede protection by some, but not other, Idd loci in a tissue-specific manner in a model where neuropathy and diabetes occurred concomitantly. Thus, our study helps identify Idd loci that control tissue-specific disease or confer general susceptibility to autoimmunity, and brings insight to the Treg-dependence of autoimmune processes influenced by given Idd region in the NOD background. PMID:23850635

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

    PubMed Central

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

    2010-01-01

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

  2. Susceptibility genetic variants associated with early-onset colorectal cancer.

    PubMed

    Giráldez, María Dolores; López-Dóriga, Adriana; Bujanda, Luis; Abulí, Anna; Bessa, Xavier; Fernández-Rozadilla, Ceres; Muñoz, Jenifer; Cuatrecasas, Miriam; Jover, Rodrigo; Xicola, Rosa M; Llor, Xavier; Piqué, Josep M; Carracedo, Angel; Ruiz-Ponte, Clara; Cosme, Angel; Enríquez-Navascués, José María; Moreno, Victor; Andreu, Montserrat; Castells, Antoni; Balaguer, Francesc; Castellví-Bel, Sergi

    2012-03-01

    Colorectal cancer (CRC) is the second most common cancer in Western countries. Hereditary forms only correspond to 5% of CRC burden. Recently, genome-wide association studies have identified common low-penetrant CRC genetic susceptibility loci. Early-onset CRC (CRC<50 years old) is especially suggestive of hereditary predisposition although 85-90% of heritability still remains unidentified. CRC<50 patients (n = 191) were compared with a late-onset CRC group (CRC>65 years old) (n = 1264). CRC susceptibility variants at 8q23.3 (rs16892766), 8q24.21 (rs6983267), 10p14 (rs10795668), 11q23.1 (rs3802842), 15q13.3 (rs4779584), 18q21 (rs4939827), 14q22.2 (rs4444235), 16q22.1 (rs9929218), 19q13.1 (rs10411210) and 20p12.3 (rs961253) were genotyped in all DNA samples. A genotype-phenotype correlation with clinical and pathological characteristics in both groups was performed. Risk allele carriers for rs3802842 [Odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.05, P = 0.0096, dominant model) and rs4779584 (OR = 1.39, 95% CI 1.02-1.9, P = 0.0396, dominant model) were more frequent in the CRC<50 group, whereas homozygotes for rs10795668 risk allele were also more frequent in the early-onset CRC (P = 0.02, codominant model). Regarding early-onset cases, 14q22 (rs4444235), 11q23 (rs3802842) and 20p12 (rs961253) variants were more associated with family history of CRC or tumors of the Lynch syndrome spectrum excluding CRC. In our entire cohort, sum of risk alleles was significantly higher in patients with a CRC family history (OR = 1.40, 95% CI 1.06-1.85, P = 0.01). In conclusion, variants at 10p14 (rs10795668), 11q23.1 (rs3802842) and 15q13.3 (rs4779584) may have a predominant role in predisposition to early-onset CRC. Association of CRC susceptibility variants with some patient's familiar and personal features could be relevant for screening and surveillance strategies in this high-risk group and it should be explored in further studies. PMID:22235025

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

    SciTech Connect

    Galvan, Antonella; Noci, Sara [Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan (Italy); Mancuso, Mariateresa; Pazzaglia, Simonetta; Saran, Anna [ENEA Laboratories, Rome (Italy); Dragani, Tommaso A. [Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan (Italy)], E-mail: tommaso.dragani@istitutotumori.mi.it

    2008-12-01

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

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

    PubMed

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

    2012-12-01

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

  5. News about Genetics and SmokingPriming, Family Smoking History, and News Story Believability on Inferences of Genetic Susceptibility to Tobacco Addiction

    Microsoft Academic Search

    Joseph N. Cappella; Caryn Lerman; Anca Romantan; Lemi Baruh

    2005-01-01

    Print news stories about genetics convey information to the public. This study assesses the effects of priming a belief in genetic susceptibility to smoking addiction on smokers’ inferences about their own susceptibility to smoking addiction, their efficacy to quit smoking, and their intention to get a genetic test for addiction susceptibility. Respondents were 450 young adult smokers surveyed on the

  6. Risk perceptions, worry, and attitudes about genetic testing for breast cancer susceptibility

    Microsoft Academic Search

    Linda D. Cameron; Jeanne Reeve

    2006-01-01

    This study assessed the unique associations of risk perceptions and worry with attitudes about genetic testing for breast cancer susceptibility. Women (general practitioner clinic attenders, university students, and first-degree relatives of breast cancer survivors; N?=?303) read information about genetic testing and completed measures assessing perceived cancer risk, cancer worry, and genetic testing attitudes and beliefs. Worry was associated with greater

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2011-01-01

    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

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

    Microsoft Academic Search

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

    2008-01-01

    Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast

  10. CTLA4 Alanine17 Confers Genetic Susceptibility to Graves' Disease and to Type 1 Diabetes Mellitus

    Microsoft Academic Search

    HORST DONNER; HARALD RAU; PAUL G. WALFISH; JENS BRAUN; THORSTEN SIEGMUND; REINHARD FINKE; JURGEN HERWIG; KLAUS H. USADEL; KLAUS BADENHOOP

    The genetic susceptibility to Graves' disease and type 1 (insulin- dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated

  11. Genetic architecture of susceptibility to PCB126-induced developmental cardiotoxicity in zebrafish.

    PubMed

    Waits, Eric R; Nebert, Daniel W

    2011-08-01

    Variability in risk of developmental defects caused by dioxin-like compounds (DLCs) has been demonstrated within and among several vertebrate species. Beyond our knowledge of the aryl hydrocarbon receptor (AHR) and its role in mediating toxicity for this class of compounds, little else is known concerning precise downstream targets influencing this vulnerability. In the present study, zebrafish with divergent genetic backgrounds were screened for susceptibility to developmental cardiotoxicity caused by the prototypical DLC, 3,3',4,4',5-pentachlorobiphenyl (PCB126); a range up to ?40-fold differences was observed. Differentially sensitive zebrafish were chosen for a genetic cross, and the recombinant generation was used for genome-wide quantitative trait loci (QTL) mapping. Multiple QTLs were identified--several acting alone, one additively, and two others via epistatic interaction. Together, these QTLs account for 24% of the phenotypic variance observed in cardioteratogenicity resulting from PCB126 exposure (logarithm of the odds = 13.55, p = 1.89 × 10?¹?). Candidate genes in these QTL regions include the following: ahr2, bcor, and capn1 (Chr 22); e2f1 and pdyn (Chr 23); ctnnt2, plcg1, eno3, tgm1, and tgm2 (interacting on Chr 23); and vezf1 (Chr 15). These data demonstrate that DLC-induced cardiac teratogenicity is a multifactorial complex trait influenced by gene × gene and gene × environment interactions. The identified QTLs harbor many DLC-responsive genes critical to cardiovascular development and provide insight into the genetic basis of susceptibility to AHR-mediated developmental toxicity. PMID:21613231

  12. Contraselectable streptomycin susceptibility determinant for genetic manipulation and analysis of Helicobacter pylori.

    PubMed

    Dailidiene, Daiva; Dailide, Giedrius; Kersulyte, Dangeruta; Berg, Douglas E

    2006-09-01

    Many Helicobacter pylori genetic studies would benefit from an ability to move DNA sequences easily between strains by transformation and homologous recombination, without needing to leave a conventional drug resistance determinant at the targeted locus. Presented here is a two-gene cassette that can be selected both (i) against, due to a Campylobacter jejuni rpsL gene (dominant streptomycin susceptibility in cells also carrying an rpsL-str(r) allele), and (ii) for, due to an erm gene (erythromycin resistance). This rpsL,erm cassette's utility was assessed by using it to replace four gene loci (mdaB, frxA, fur, and nikR) in four streptomycin-resistant [Str(r)] strain backgrounds (derivatives of 26695, SS1, X47, and G27MA). The resultant 16 strains (phenotypically erythromycin resistant [Erm(r)] and Str(s)) were each transformed with wild-type genomic DNAs, and Str(r) derivatives were selected. The desired Erm(s) Str(r) isolates were obtained at frequencies that ranged from 17 to 96% among Str(r) transformants, with the Erm(s) yield apparently depending on the strain background and genome location of the targeted locus. The ease of isolating unmarked transformants described here should be valuable for many H. pylori molecular genetic and evolutionary analyses. PMID:16957210

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

    PubMed Central

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

    2013-01-01

    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

  14. Genetic susceptibility to post-thymectomy autoimmune diseases in mice

    Microsoft Academic Search

    Akinori Kojima; Richmond T. Prehn

    1981-01-01

    The strain distribution pattern of five different post-thymectomy autoimmune diseases was determined in 21 inbred and two congenic, resistant strains of mice. The results indicated that susceptibility genes outside the H-2 complex may be involved in the development of localized autoimmune diseases in neonatally thymectomized mice. Studies of recombinant inbred strains also showed that susceptibility to gastritis was not associated

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  17. NCI Releases Preliminary Data on Genetic Susceptibility for Prostate Cancer | Office of Cancer Genomics

    Cancer.gov

    The National Cancer Institute (NCI), part of the National Institutes of Health, has released new data from the Cancer Genetic Markers of Susceptibility (CGEMS) study on prostate cancer. This information could help identify genetic factors that influence the disease and will be integral to the discovery and development of new, targeted therapies.

  18. Antimicrobial susceptibility/resistance and genetic characteristics of Neisseria gonorrhoeae isolates from Poland, 2010-2012

    PubMed Central

    2014-01-01

    Background In Poland, gonorrhoea has been a mandatorily reported infection since 1948, however, the reported incidences are likely underestimated. No antimicrobial resistance (AMR) data for Neisseria gonorrhoeae has been internationally reported in nearly four decades, and data concerning genetic characteristics of N. gonorrhoeae are totally lacking. The aims of this study were to investigate the AMR to previously and currently recommended gonorrhoea treatment options, the main genetic resistance determinant (penA) for extended-spectrum cephalosporins (ESCs), and genotypic distribution of N. gonorrhoeae isolates in Poland in 2010-2012. Methods N. gonorrhoeae isolates cultured in 2010 (n?=?28), 2011 (n?=?92) and 2012 (n?=?108) in Warsaw and Bialystok, Poland, were examined using antimicrobial susceptibility testing (Etest), pyrosequencing of penA and N. gonorrhoeae multi-antigen sequence typing (NG-MAST). Results The proportions of N. gonorrhoeae isolates showing resistance were as follows: ciprofloxacin 61%, tetracycline 43%, penicillin G 22%, and azithromycin 8.8%. No isolates resistant to ceftriaxone, cefixime or spectinomycin were found. However, the proportion of isolates with an ESC MIC?=?0.125 mg/L, i.e. at the resistance breakpoint, increased significantly from none in 2010 to 9.3% and 19% in 2012 for ceftriaxone and cefixime, respectively. Furthermore, 3.1% of the isolates showed multidrug resistance, i.e., resistance to ciprofloxacin, penicillin G, azithromycin, and decreased susceptibility to cefixime (MIC?=?0.125 mg/L). Seventy-six isolates (33%) possessed a penA mosaic allele and 14 isolates (6.1%) contained an A501V/T alteration in penicillin-binding protein 2. NG-MAST ST1407 (n?=?58, 25% of isolates) was the most prevalent ST, which significantly increased from 2010 (n?=?0) to 2012 (n?=?46; 43%). Conclusions In Poland, the diversified gonococcal population displayed a high resistance to most antimicrobials internationally previously recommended for gonorrhoea treatment and decreasing susceptibility to the currently recommended ESCs. The decreasing susceptibility to ESCs was mostly due to the introduction of the internationally spread multidrug-resistant NG-MAST ST1407 in 2011. It is essential to promptly revise the gonorrhoea treatment guidelines, improve the gonorrhoea laboratory diagnostics, and implement quality assured surveillance of gonococcal AMR (ideally also treatment failures) in Poland. PMID:24502606

  19. Assessing hypothetical scenario methodology in genetic susceptibility testing analog studies: a quantitative review.

    PubMed

    Persky, Susan; Kaphingst, Kimberly A; Condit, Celeste M; McBride, Colleen M

    2007-11-01

    Hypothetical scenario methodology is commonly employed in the study of genetic susceptibility testing uptake estimation. The methodology, however, has not been rigorously assessed and sizeable gaps exist between estimated and actual uptake for tests that have recently become available. This quantitative review explores the effect of several theoretically based factors on genetic test uptake accuracy among a sample of 38 articles. These factors include verbal immediacy and temporal proximity of test scenarios, method of decision assessment, content of testing detail provided, processing demand required, and study features related to administration and sample. A number of assessed factors influenced uptake accuracy. Among these, temporal proximity of the genetic susceptibility test appeared to be the most consistent. There was also some evidence for effects of verbal immediacy and decision-assessment method on interest in testing. We recommend strategies for increasing accuracy using hypothetical scenario methodology to examine genetic susceptibility test uptake prediction. PMID:18007141

  20. Interleukin-16 gene polymorphisms are considerable host genetic factors for patients' susceptibility to chronic hepatitis B infection.

    PubMed

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

    2014-01-01

    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. PMID:25692036

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

    PubMed Central

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

    2014-01-01

    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. PMID:25692036

  2. Genetic susceptibility to the respiratory effects of air pollution

    Microsoft Academic Search

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

    2009-01-01

    There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative

  3. The Obesity Epidemic: Metabolic Imprinting on Genetically Susceptible Neural Circuits

    Microsoft Academic Search

    Barry E. Levin

    2000-01-01

    The apparent obesity epidemic in the industrialized world is not explained completely by increased food intake or decreased energy expenditure. Once obesity develops in genetically predisposed individuals, their obese body weight is avidly defended against chronic caloric restriction. In animals genetically predisposed toward obesity, there are multiple abnormalities of neural function that prime them to become obese when dietary caloric

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

    PubMed Central

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

    2009-01-01

    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

  5. A Combinatorial Method for Predicting Genetic Susceptibility to Complex Diseases

    E-print Network

    Zelikovsky, Alexander

    's disease and autoimmune disorders for predicting susceptibility to these diseases. The quality.78% for Crohn's disease and 64.99% for autoimmune disorders, respectively. I. INTRODUCTION Recent improvement Mendelian gene [6]. Indeed, some com- plex diseases, such as psychiatric disorders, are character- ized

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

    PubMed Central

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

    2014-01-01

    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

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

    Microsoft Academic Search

    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

    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

  8. Ethnic Background and Genetic Variation in the Evaluation of Cancer Risk: A Systematic Review

    PubMed Central

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

    2014-01-01

    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

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

    PubMed

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

    2015-05-28

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

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

    PubMed Central

    Li, Jun

    2014-01-01

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

  11. Young smokers' views of genetic susceptibility testing for lung cancer risk: minding unintended consequences.

    PubMed

    Docherty, Sharron L; McBride, Colleen M; Sanderson, Saskia C; O'Neill, Suzanne C; Shepperd, James A; Lipkus, Isaac M

    2011-09-01

    Assessment of smokers' responses to individualized feedback of genetic susceptibility has shown little or no influence on smoking cessation outcomes. One explanation is that smokers may be having unintended responses that undermine the feedback's motivational impact (e.g., fatalism or downplaying risk). In preparation for a large randomized trial with college smokers, we conducted a qualitative pilot study to explore smokers' motives for genetic testing and how these motives might influence interpretation of genetic risk feedback.Prior to reviewing informational materials describing a test for the glutathione S-transferase M1 gene, 33 college smokers (18 to 21 years) participated in a 30 minute, semi-structured, open-ended interview regarding their attitudes on health risks, genetic testing in general, genetic testing for lung cancer risk, and informational needs regarding genetics and genetic testing for lung cancer risk.Two central themes emerged from analysis of the interviews: general impressions of genetic testing and perceived value of genetic testing. Prominent in the second theme was the finding that genetic risk feedback may be unsuccessful in motivating quitting a) due to skepticism about genetic tests, b) participants dismissing genetic feedback as personally irrelevant, and c) participants receiving low risk results justifying continued smoking in light of public health messages that "it's never too late to quit". These findings require careful consideration among health professionals looking to genetic risk feedback as a vehicle to motivate disease prevention or behavior change. PMID:21860660

  12. Psychological Interventions and Genetic Testing: Facilitating Informed Decisions About BRCA1\\/2 Cancer Susceptibility

    Microsoft Academic Search

    Yuichi Shoda; Walter Mischel; Suzanne M. Miller; Michael Diefenbach; Mary B. Daly; Paul F. Engstrom

    1998-01-01

    Genetic testing for inherited cancer susceptibility, based on the recently identified. BRCA1 and BRCA2 genes, will soon be available on a large scale. However, at present, genetic test results do not lead to clearly indicated diagnostic or preventive measures, and the nature of the psychological impact of BRCA1\\/2 testing is still largely unknown. This uncertainty, combined with preliminary evidence suggesting

  13. Genetic variation in Eucalyptus globulus for susceptibility to Mycosphaerella nubilosa and its association with tree growth

    Microsoft Academic Search

    A. W. Milgate; B. M. Potts; K. Joyce; C. Mohammed; R. E. Vaillancourt

    2005-01-01

    Mycosphaerella species are fungal leaf pathogens of Eucalyptus globulus, one of the major plantation tree species in temperate regions of the world. We examined the quantitative genetic variation\\u000a in susceptibility to infection by Mycosphaerella nubilosa in a genetically diverse population ofE. globulus families growing in a field trial in north-west Tasmania. Disease incidence and severity were assessed on juvenile foliage

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

    Microsoft Academic Search

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

    2007-01-01

    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

  15. Lay Attitudes toward Genetic Testing for Susceptibility to Inherited Diseases

    Microsoft Academic Search

    John S. Shaw; Kimberly L. Bassi

    2001-01-01

    One of the most important issues facing legal and medical policy makers in the coming years will be whether to employ populationbased testing for genetic markers of inherited diseases. Two hundred and twenty-six randomly selected individuals from Easton, Pennsylvania completed a mail questionnaire that was designed to assess the general public’s attitudes toward many of the personal and societal issues

  16. Empathy Is Moderated by Genetic Background in Mice

    PubMed Central

    Lahvis, Garet P.

    2009-01-01

    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

  17. Genetic and sexual separation between insect resistant and susceptible Barbarea vulgaris plants in Denmark.

    PubMed

    Toneatto, F; Nielsen, J K; Ørgaard, M; Hauser, T P

    2010-08-01

    Co-evolution between herbivores and plants is believed to be one of the processes creating Earth's biodiversity. However, it is difficult to disentangle to what extent diversification is really driven by herbivores or by other historical-geographical processes like allopatric isolation. In the cruciferous plant Barbarea vulgaris, some Danish individuals are resistant to herbivory by flea beetles (Phyllotreta nemorum), whereas others are not. The flea beetles are, in parallel, either resistant or susceptible to the plants defenses. To understand the historical-evolutionary framework of these interactions, we tested how genetically divergent resistant and susceptible plants are, using microsatellite markers. To test whether they are reproductively fully compatible, resistant and susceptible plants were grown intermixed in an outdoor experiment, and the paternity of open-pollinated offspring was determined by analysis of molecular markers. Resistant and susceptible Danish plants were genetically strongly differentiated and produced significantly fewer hybrids than expected from random mating or nearest neighbour mating. Our results suggest that the two types belong to different evolutionary lineages that have been (partly) isolated at some time, during which genetic and reproductive divergence evolved. A parsimonious scenario could be that the two plant types were isolated in different refugia during the previous ice age, from which they migrated into and met in Denmark and possibly neighbouring regions. If so, resistance and susceptibility has for unknown reasons become associated with the different evolutionary lineages. PMID:20670365

  18. Neutrophil Responses to Mycobacterium tuberculosis Infection in Genetically Susceptible and Resistant Mice

    Microsoft Academic Search

    Evgenyi B. Eruslanov; Irina V. Lyadova; Tatiana K. Kondratieva; Konstantin B. Majorov; Ilya V. Scheglov; Marianna O. Orlova; Alexander S. Apt

    2005-01-01

    The role of neutrophils in tuberculosis (TB) resistance and pathology is poorly understood. Neutrophil reactions are meant to target the offending pathogen but may lead to destruction of the host lung tissue, making the defending cells an enemy. Here, we show that mice of the I\\/St strain which are genetically susceptible to TB show an unusually high and prolonged neutrophil

  19. Genetic susceptibility to chronic trichuris muris induced experimental colitis: translation and relevance to human Crohn's disease

    Microsoft Academic Search

    S E Levison; P Fisher; W Newman; J McLaughlin; R KGrencis; J L Pennock

    2011-01-01

    IntroductionUnraveling the genetic architecture of complex traits presents a true challenge. The analysis of experimental models with strict phenotypic documentation and homology to human traits, alongside sensitive scientific methodologies, will facilitate future discoveries. Trichuris muris (T muris) induces chronic colitis in susceptible mouse strains, with previously described clinical, histological, and immunological commonalities to human Crohn's disease (CD). Conversely, resistant mouse

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

    PubMed

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

    2005-06-16

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

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

    PubMed Central

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

    2013-01-01

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

  2. Prevalence, antimicrobial susceptibility, and genetic diversity of Pseudomonas aeruginosa as intestinal colonizer in the community.

    PubMed

    Valenza, Giuseppe; Tuschak, Christian; Nickel, Silke; Krupa, Elzbieta; Lehner-Reindl, Verena; Höller, Christiane

    2015-09-01

    In this study we determined the prevalence of intestinal carriage, the antimicrobial susceptibility rates, and the genetic diversity of Pseudomonas aeruginosa in the community. From July 2010 to December 2011, a total of 2110 nonreplicate fecal samples from individuals living in Bavaria were collected. Samples were screened for P. aeruginosa by a selective medium and antimicrobial susceptibility was determined by disc diffusion technique. Genetic diversity was assessed by multilocus sequence typing (MLST). Intestinal colonization was detected in 31 of 2110 (1.47%) individuals. None of the isolates showed resistance to aztreonam, imipenem, meropenem, ciprofloxacin, amikacin or colistin. Twenty-five isolates could be assigned to 20 different sequence types (STs), whereas the remaining 6 could not be assigned. Interestingly, four isolates belonged to ST253. These data show that intestinal colonization by P. aeruginosa occurs in the community with high genetic diversity and low rates of antimicrobial resistance. PMID:25832457

  3. Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions.

    PubMed

    Monteleone, Palmiero; Maj, Mario

    2008-10-01

    Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are characterized by abnormal eating behaviors often resulting in dramatic physical consequences for the patients. The etiology of eating disorders (EDs) is currently unknown; however, a strong genetic contribution is likely to be involved. To date, the majority of genetic studies have focused on candidate genes, and polymorphic variants of genes coding for substances likely to be involved in the etiopathogenesis of EDs have been assessed for association with AN, BN, BED and/or ED-related phenotypic traits. Results have been generally inconsistent and cannot be considered conclusive because of several methodological flaws and differences, such as small sample sizes, ethnic heterogeneity of studied populations, lack of statistical correction for multiple testing, adoption of different diagnostic criteria and population stratification. Although, at present, no convincing evidence for associations of candidate genes with EDs has been provided, the 5-HT(2A) receptor gene and the BDNF gene seem to be promising candidates for genetic influences on AN, since polymorphic variants of these genes have been found quite consistently, although not specifically, linked to AN restricting subtype in large sample studies. Moreover, pharmacogenetic investigations have suggested a possible role of some gene polymorphisms in predicting the response to treatment with selective serotonin reuptake inhibitors in BN, but results are still preliminary. The heterogeneity of ED phenotypes is believed to represent the most relevant variable responsible for contradictory and not conclusive results. Future studies should focus on more homogeneous subgroups, either relying on specific ED traits or identifying endophenotypes. This will be useful also for prevention and treatment of EDs. PMID:18855537

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

    PubMed Central

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

    2013-01-01

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

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

    DOE PAGESBeta

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

    2015-03-09

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genesmore »involved in cytokines, including TGF?1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGF?1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.« less

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

    NASA Astrophysics Data System (ADS)

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

    2013-03-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2005-03-01

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

  8. Genetic analysis and antimicrobial susceptibility of Francisella noatunensis subsp. orientalis (syn. F. asiatica) isolates from fish.

    PubMed

    Soto, Esteban; Griffin, Matt; Wiles, Judy; Hawke, John P

    2012-01-27

    Francisella noatunensis subsp. orientalis (syn. F. asiatica) (Fno) is an emergent fish pathogen that causes acute to chronic disease in a wide variety of freshwater, brackish and marine fish. Due to the emergent nature of this bacterium, established protocols to measure antimicrobial susceptibility are lacking. In this project we compare three different methods to examine the antimicrobial susceptibility (Etest, broth microdilution and disk diffusion) of 10 different isolates of Fno from two different fish species and four different geographic outbreaks from 2006 to 2010. PCR mediated genomic fingerprinting (rep-PCR) performed on the different isolates confirmed genetic homogeneity amongst the different isolates. The in vitro susceptibility data presented here provides important baseline data for future research monitoring the development of antibiotic resistance among Fno isolates as well as provides invaluable data for the development of potential therapeutics. PMID:21868177

  9. Genetic Testing for TMEM154 Mutations Associated with Lentivirus Susceptibility in Sheep

    PubMed Central

    Petrik, Dustin T.; Simpson, Barry; Kijas, James W.; Clawson, Michael L.; Chitko-McKown, Carol G.; Harhay, Gregory P.; Leymaster, Kreg A.

    2013-01-01

    In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization–time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks. PMID:23408992

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

    PubMed

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

    2014-12-01

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

  11. Cerebral cavernous malformation (CCM) disease: from monogenic forms to genetic susceptibility factors.

    PubMed

    Trapani, E; Retta, S F

    2015-09-01

    Cerebral cavernous malformation (CCM) is a vascular disease of proven genetic origin, which may arise sporadically or can be inherited as autosomal dominant condition with incomplete penetrance and highly variable expressivity. CCM lesions manifest across a range of different phenotypes, including wide interindividual differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH), and may remain asymptomatic during the host's lifetime or result in pathological conditions of various type and severity at any age, with symptoms ranging from relatively minor (but still disabling) headaches through to very severe neurological deficits, seizures, and stroke. Currently, surgical removal of accessible lesions is the only direct therapeutic approach for CCM disease. However, whereas little information is available on the natural history of risk for patients to develop serious complications, such as ICH, prognostic biomarkers remain to be identified in order to ensure timely and optimal clinical decision making. In recent years, it has become clear that the three known CCM genes play an important role in controlling signalling pathways involved in cell responses to oxidative stress, pointing to a novel pathogenic mechanism whereby the function of CCM genes may be relevant in preventing vascular dysfunctions triggered by oxidative stress events. In turn, these novel findings have raised the possibility that genetic susceptibility factors related to differences in sensitivity to oxidative stress, including genetic polymorphisms, may contribute to interindividual differences in CCM disease susceptibility and severity. This review discusses recent progress toward the understanding of molecular mechanisms of pathogenesis and the identification of genetic susceptibility factors that could influence onset, progression and clinical severity of CCM disease, as well as consequent implications for the development of novel, safe and effective therapeutic strategies. PMID:25896717

  12. Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans

    Microsoft Academic Search

    Cody J. Locke; Shelli N. Williams; Erich M. Schwarz; Guy A. Caldwell; Kim A. Caldwell

    2006-01-01

    Epilepsy is estimated to affect 1–2% of the world population, yet remains poorly understood at a molecular level. We have previously established the roundworm Caenorhabditis elegans as a model for investigating genetic susceptibilities to seizure-like convulsions in vivo. Here we investigate the behavioral consequences of decreasing the activity of nematode gene homologs within the LIS1 pathway that are associated with

  13. A Significant Factor in Autism: Methyl Mercury Induced Oxidative Stress in Genetically Susceptible Individuals

    Microsoft Academic Search

    Kerry E. Leslie; Susan M. Koger

    The dramatic increase in prevalence rates of Autism Spectrum Disorders (ASDs) over recent decades likely reflects the influence\\u000a of multiple factors. In the current paper, it is argued ASDs can result from an interaction between genetic susceptibilities\\u000a and environmental exposures. Specifically, we hypothesize that fetal or infantile exposure to methyl mercury containing pollution\\u000a by individuals with biologically inhibited antioxidant functions

  14. 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...

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

    PubMed Central

    2014-01-01

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

  16. Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility

    PubMed Central

    Das, Swapan Kumar; Sharma, Neeraj Kumar

    2014-01-01

    Type 2 diabetes (T2D) is a common metabolic disorder which is caused by multiple genetic perturbations affecting different biological pathways. Identifying genetic factors modulating the susceptibility of this complex heterogeneous metabolic phenotype in different ethnic and racial groups remains challenging. Despite recent success, the functional role of the T2D susceptibility variants implicated by genome-wide association studies (GWAS) remains largely unknown. Genetic dissection of transcript abundance or expression quantitative trait (eQTL) analysis unravels the genomic architecture of regulatory variants. Availability of eQTL information from tissues relevant for glucose homeostasis in humans opens a new avenue to prioritize GWAS-implicated variants that may be involved in triggering a causal chain of events leading to T2D. In this article, we review the progress made in the field of eQTL research and knowledge gained from those studies in understanding transcription regulatory mechanisms in human subjects. We highlight several novel approaches that can integrate eQTL analysis with multiple layers of biological information to identify ethnic-specific causal variants and gene-environment interactions relevant to T2D pathogenesis. Finally, we discuss how the eQTL analysis mediated search for “missing heritability” may lead us to novel biological and molecular mechanisms involved in susceptibility to T2D. PMID:24748924

  17. Model of robust induction of glomerulosclerosis in mice: Importance of genetic background

    Microsoft Academic Search

    Li-Jun Ma; Agnes B. Fogo

    2003-01-01

    Model of robust induction of glomerulosclerosis in mice: Importance of genetic background.BackgroundIncreasing evidence suggests that genetic background plays an important role in the development of progressive glomerulosclerosis. The remnant kidney model (RKM) of progressive renal disease has been used extensively in rats. However, C57BL\\/6 mice are resistant to glomerulosclerosis with RKM induced by either pole amputation or renal artery ligation.

  18. Improved elimination of phase effects from background field inhomogeneities for susceptibility weighted imaging at high magnetic field strengths.

    PubMed

    Rauscher, Alexander; Barth, Markus; Herrmann, Karl-Heinz; Witoszynskyj, Stephan; Deistung, Andreas; Reichenbach, Jüergen R

    2008-10-01

    To enhance susceptibility-related contrast of magnetic resonance images, the phase of susceptibility weighted data needs to be corrected for background inhomogeneities and phase wraps caused by them. Current methods either use homodyne filtering or a combination of phase unwrapping and high pass filtering. The drawback of homodyne filtering is incomplete elimination of phase wraps in areas with steep phase topography produced by background inhomogeneities of the static magnetic field. The disadvantage of phase unwrapping is that it requires subsequent high pass filtering, which introduces artifacts in areas with very steep transitions, such as areas near interfaces between parenchyma and bone or air. A method is proposed that reduces the artifacts associated with high pass filtering without sacrificing the advantages of phase unwrapping. This technique is demonstrated with phantom data at 1.5 T and with human data at 1.5, 3 and 7 T. PMID:18524525

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

    SciTech Connect

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

    1986-03-01

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

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

    EPA Science Inventory

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

  1. Risk of Colorectal Adenomas in Relation to Meat Consumption, Meat Preparation, and Genetic Susceptibility in a Dutch Population

    Microsoft Academic Search

    Edine W. Tiemersma; Dorien W. Voskuil; Annelies Bunschoten; Elbert A. Hogendoorn; Ben J. M. Witteman; Fokko M. Nagengast; HansRuedi Glatt; Frans J. Kok; Ellen Kampman

    2004-01-01

    Objective: We studied the association between meat consumption and colorectal adenomas, and potential influence of genetic susceptibility to heterocyclic aromatic amines (HCAs) formed during meat cooking at high temperatures.

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

    PubMed Central

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

    2013-01-01

    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

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

    E-print Network

    Cox, Nancy J.

    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

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

    E-print Network

    Reich, David

    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

  5. Genetic Susceptibility to Acute Rheumatic Fever: A Systematic Review and Meta-Analysis of Twin Studies

    Microsoft Academic Search

    Mark E. Engel; Raphaella Stander; Jonathan Vogel; Adebowale A. Adeyemo; Bongani M. Mayosi; Stacey Cherny

    2011-01-01

    BackgroundAcute rheumatic fever is considered to be a heritable condition, but the magnitude of the genetic effect is unknown. The objective of this study was to conduct a systematic review and meta-analysis of twin studies of concordance of acute rheumatic fever in order to derive quantitative estimates of the size of the genetic effect.MethodsWe searched PubMed\\/MEDLINE, ISI Web of Science,

  6. Leveraging Ethnic Group Incidence Variation to Investigate Genetic Susceptibility to Glioma: A Novel Candidate SNP Approach

    PubMed Central

    Jacobs, Daniel I.; Walsh, Kyle M.; Wrensch, Margaret; Wiencke, John; Jenkins, Robert; Houlston, Richard S.; Bondy, Melissa; Simon, Matthias; Sanson, Marc; Gousias, Konstantinos; Schramm, Johannes; Labussière, Marianne; Di Stefano, Anna Luisa; Wichmann, H.-Erich; Müller-Nurasyid, Martina; Schreiber, Stefan; Franke, Andre; Moebus, Susanne; Eisele, Lewin; Dewan, Andrew T.; Dubrow, Robert

    2012-01-01

    Objectives: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans. Methods:? We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets. Results: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing or conducting meta-analysis. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians. Conclusion: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns. PMID:23091480

  7. Responses to Information about Psychosocial Consequences of Genetic Testing for Breast Cancer Susceptibility: Influences of Cancer Worry and Risk Perceptions

    Microsoft Academic Search

    Linda D. Cameron; Michael A. Diefenbach

    2001-01-01

    We assessed the impact of information about psychosocial consequences of genetic testing for breast cancer susceptibility on interest in and beliefs about genetic testing, and whether these effects vary by levels of either cancer worry or perceived cancer risk. Women (N = 180) in an experimental study were randomly assigned to read one of four messages consisting of standard information

  8. AN INVESTIGATION OF SUSCEPTIBILITY TO PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME VIRUS BETWEEN TWO GENETICALLY DIVERSE COMMERCIAL LINES OF PIGS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to determine if host genetics plays a role in susceptibility to the respiratory disease in growing pigs caused by the porcine reproductive and respiratory syndrome virus (PRRSV). Based on a previous study, two genetically diverse commercial lines of pigs that were als...

  9. Fatty acid elongation and Delta9 desaturation: effects of diet and genetic background in cattle 

    E-print Network

    Page, Amy Maurine

    1995-01-01

    FATTY ACID ELONGATION AND A DESATURATIONt EFFECTS OF DIET AND GENETIC BACKGROUND IN CATTLE A Thesis by AMY MAURINE PAGE Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements... for the degree of MASTER OF SCIENCE May 1995 Major Subject: Nutrition FATTY ACID ELONGATION AND A DESATURATION: EFFECTS OF DIET AND GENETIC BACKGROUND IN CATTLE A Thesis by AMY MAURINE PAGE Submitted to the Office of Graduate Studies of Texas ARM...

  10. Genetic background of HSH in three Polish families and a patient with an X;9 translocation

    Microsoft Academic Search

    Reetta Jalkanen; Ewa Pronicka; Henna Tyynismaa; Andre Hanauer; Roxanne Walder; Tiina Alitalo

    2006-01-01

    Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disease, characterised by neurological symptoms, such as tetany, muscle spasms and seizures, due to hypocalcemia. It has been suggested that HSH is genetically heterogeneous, but only one causative gene, TRPM6, on chromosome 9 has so far been isolated. We have now studied the genetic background of HSH in four Polish patients

  11. Genetic variants in interleukin genes and susceptibility to IgA nephropathy: a meta-analysis.

    PubMed

    Liu, Da-Jun; Liu, Ying; Ran, Li-Mei; Li, De-Tian

    2014-06-01

    Many existing studies have demonstrated that genetic variants in interleukin (IL) genes might have an impact on an individual's susceptibility to IgA nephropathy (IgAN); but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between IL genetic variants and IgAN risk. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and China BioMedicine (CBM) and China National Knowledge Infrastructure (CNKI) databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Seven case-control studies were included with a total of 1135 IgAN patients and 1603 healthy controls. Our meta-analysis results revealed that genetic variants in IL-1 and IL-1RN genes were associated with an increased risk of IgAN. However, similar associations were not observed in IL-6, IL-10, and IL-22R genes. Subgroup analysis by ethnicity suggested that there were significant associations between IL genetic variants and an increased risk of IgAN among both Asian and Caucasian populations. Meta-regression analyses showed that gene types may be a major source of heterogeneity. No publication bias was detected in this meta-analysis. The present meta-analysis suggests that IL genetic variants may contribute to the risk of IgAN, especially in IL-1 and IL-1RN genes. PMID:24592969

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

    PubMed

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

    2014-12-01

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

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

    PubMed Central

    Fishbein, Lauren; Nathanson, Katherine L.

    2012-01-01

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

  14. Mouse Models of Type 1 and Type 2 Diabetes Derived from the Same Closed Colony: Genetic Susceptibility Shared Between Two Types of Diabetes

    Microsoft Academic Search

    Hiroshi Ikegami; Tomomi Fujisawa; Toshio Ogihara

    Except for rare subtypes of diabetes, both type 1 and type 2 diabetes are multifactorial diseases in which genetic factors consisting of multiple susceptibility genes and environmen- tal factors contribute to the disease development. Due to complex interaction among multiple susceptibility genes and between genetic and environmental factors, genetic analysis of multifactorial diseases is difficult in humans. Inbred animal models,

  15. Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from India, Pakistan and Bhutan in 2007–2011

    PubMed Central

    2013-01-01

    Background Knowledge on antimicrobial drug resistance and genetic characteristics of Neisseria gonorrhoeae isolates circulating in India, Pakistan, and Bhutan is sorely lacking. In this paper, we describe the prevalence of antimicrobial resistance and molecular characteristics of N. gonorrhoeae isolates from India, Pakistan, and Bhutan in 2007–2011. Methods Antimicrobial susceptibility and ?-lactamase production were tested for 65 N. gonorrhoeae isolates from India (n=40), Pakistan (n=18) and Bhutan (n=7) using Etest methodology (eight antimicrobials) and nitrocefin solution, respectively. Resistance determinants, i.e. penA, mtrR, porB1b, gyrA, and parC, were sequenced. N. gonorrhoeae multiantigen sequence typing (NG-MAST) was performed for molecular epidemiology. Results The highest resistance level was observed for ciprofloxacin (94%), followed by penicillin G (68%), erythromycin (62%), tetracycline (55%), and azithromycin (7.7%). All the isolates were susceptible to ceftriaxone, cefixime, and spectinomycin. Thirty-four (52%) of the isolates were producing ?-lactamase. No penA mosaic alleles or A501-altered alleles of penicillin-binding protein 2 were identified. Forty-nine NG-MAST STs were identified, of which 42 STs have not been previously described worldwide. Conclusions Based on this study, ceftriaxone, cefixime, and spectinomycin can be used as an empirical first-line therapy for gonorrhoea in India, Pakistan, and Bhutan, whereas ciprofloxacin, penicillin G, tetracycline, erythromycin, and azithromycin should not be. It is imperative to strengthen the laboratory infrastructure in this region, as well as to expand the phenotypic and genetic surveillance of antimicrobial resistance, emergence of new resistance, particularly, to extended-spectrum cephalosporins, and molecular epidemiology. PMID:23347339

  16. Causes and Consequences of Genetic Background Effects Illuminated by Integrative Genomic Analysis

    PubMed Central

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

    2014-01-01

    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 scallopedE3 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

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

    PubMed Central

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

    2008-01-01

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

  18. 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...

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

    PubMed Central

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

    2011-01-01

    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 alleles on different strain backgrounds, we produced the reciprocal congenic strains B6.CBACa-Cdh23Ahl+and CBACa.B6-Cdh23ahl and tested 15-30 mice from each for hearing loss progression. ABR thresholds for 8 kHz, 16 kHz, and 32 kHz pure-tone stimuli were measured at 3, 6, 9, 12, 15 and 18 months of age and compared with age-matched mice of the C57BL/6J and CBA/CaJ parental strains. Mice of the C57BL/6N strain, which is the source of embryonic stem cells for the large International Knockout Mouse Consortium, were also tested for comparisons with C57BL/6J mice. Mice of the C57BL/6J and C57BL/6N strains exhibited identical hearing loss profiles: their 32 kHz ABR thresholds were significantly higher than those of CBA/CaJ and congenic strain mice by 6 months of age, and their 16 kHz thresholds were significantly higher by 12 months. Thresholds of the CBA/CaJ, the B6.CBACa-Cdh23Ahl+, and the CBACa.B6-Cdh23ahl strain mice differed little from one another and only slightly increased throughout the 18-month test period. Hearing loss, which corresponded well with cochlear hair cell loss, was most profound in the C57BL/6J and C57BL/6NJ strains. These results indicate that the CBA/CaJ-derived Cdh23Ahl+ allele dramatically lessens hearing loss and hair cell death in an otherwise C57BL/6J genetic background, but that the C57BL/6J-derived Cdh23ahl allele has little effect on hearing loss in an otherwise CBA/CaJ background. We conclude that although Cdh23ahl homozygosity is necessary, it is not by itself sufficient to account for the accelerated hearing loss of C57BL/6J mice. PMID:22138310

  20. The Adiponectin variants contribute to the genetic background of type 2 diabetes in Turkish population.

    PubMed

    Arikoglu, Hilal; Ozdemir, Hulya; Kaya, Dudu Erkoc; Ipekci, Suleyman Hilmi; Arslan, Ahmet; Kayis, Seyit Ali; Gonen, Mustafa Sait

    2014-01-15

    Adiponectin, an adipose tissue specific protein encoded by the Adiponectin gene, modulates insulin sensitivity and plays an important role in regulating energy homeostasis. Many studies have shown that single nucleotide polymorphisms (SNPs) in the Adiponectin gene are associated with low plasma Adiponectin levels, insulin resistance and an increased risk of type 2 diabetes mellitus. The aim of the present study was to evaluate the contribution of the Adiponectin gene polymorphisms in genetic background of type 2 diabetes in a Turkish population. In total, 169 unrelated and non-obese diabetic patients and 119 age- and BMI-matched nondiabetic individuals with no family history of diabetes were enrolled in this study. We detected a significant association between type 2 diabetes and two SNPs: SNP ?11391G N A, which is located in the promoter region of the Adiponectin gene, and SNP +276G N T, which is found in intron 2 of the gene (P b 0.05). The silence SNP G15G (+45TN G) in exon 1 and SNP+349ANG in intron 2 also showed a weak association with type 2 diabetes (P=0.06 and P=0.07, respectively),while SNPs?3971ANG in intron 1 and Y111H, R112C and H241P in exon 3 showed no association (P N 0.05). In conclusion, these findings suggest that Adiponectin gene polymorphisms might be effective on susceptibility for type 2 diabetes development which emerged from the interactions between multiple genes, variants and environmental factors. PMID:24404592

  1. The Adiponectin Variants Contribute to the Genetic Background of Type 2 Diabetes in Turkish Population.

    PubMed

    Arikoglu, Hilal; Ozdemir, Hulya; Kaya, Dudu Erkoc; Ipekci, Suleyman Hilmi; Arslan, Ahmet; Kayis, Seyit Ali; Gonen, Mustafa Sait

    2013-10-26

    Adiponectin, an adipose tissue specific protein encoded by the Adiponectin gene, modulates insulin sensitivity and plays an important role in regulating energy homeostasis. Many studies have shown that single nucleotide polymorphisms (SNPs) in the Adiponectin gene are associated with low plasma adiponectin levels, insulin resistance and an increased risk of type 2 diabetes mellitus. The aim of the present study was to evaluate the contribution of the Adiponectin gene polymorphisms in genetic background of type 2 diabetes in a Turkish population. In total, 169 unrelated and non-obese diabetic patients and 119 age- and BMI-matched non-diabetic individuals with no family history of diabetes were enrolled in this study. We detected a significant association between type 2 diabetes and two SNPs: SNP -11391G>A, which is located in the promoter region of the Adiponectin gene, and SNP +276G>T, which is found in intron 2 of the gene (P<0.05). The silence SNP G15G (+45T>G) in exon 1 and SNP +349A>G in intron 2 also showed a weak association with type 2 diabetes (P=0.06 and P=0.07, respectively), while SNPs -3971A>G in intron 1 and Y111H, R112C and H241P in exon 3 showed no association (P>0.05). In conclusion, these findings suggest that Adiponectin gene polymorphisms might be effective on susceptibility for type 2 diabetes development which emerged from the interactions between multiple genes, variants and environmental factors. PMID:24513330

  2. Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders.

    PubMed

    Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong; Faustman, Elaine M

    2010-10-01

    To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. PMID:20706997

  3. The genetic basis for susceptibility to Rift Valley fever disease in MBT/Pas mice.

    PubMed

    Tokuda, S; Do Valle, T Z; Batista, L; Simon-Chazottes, D; Guillemot, L; Bouloy, M; Flamand, M; Montagutelli, X; Panthier, J-J

    2015-04-01

    The large variation in individual response to infection with Rift Valley fever virus (RVFV) suggests that host genetic determinants play a role in determining virus-induced disease outcomes. These genetic factors are still unknown. The systemic inoculation of mice with RVFV reproduces major pathological features of severe human disease, notably the hepatitis and encephalitis. A genome scan performed on 546 (BALB/c × MBT) F2 progeny identified three quantitative trait loci (QTLs), denoted Rvfs-1 to Rvfs-3, that were associated with disease susceptibility in MBT/Pas mice. Non-parametric interval-mapping revealed one significant and two suggestive linkages with survival time on chromosomes 2 (Rvfs-1), 5 (Rvfs-3) and 11 (Rvfs-2) with respective logarithm of odds (LOD) scores of 4.58, 2.95 and 2.99. The two-part model, combining survival time and survival/death, identified one significant linkage to Rvfs-2 and one suggestive linkage to Rvfs-1 with respective LOD scores of 5.12 and 4.55. Under a multiple model, with additive effects and sex as a covariate, the three QTLs explained 8.3% of the phenotypic variance. Sex had the strongest influence on susceptibility. The contribution of Rvfs-1, Rvfs-2 and Rvfs-3 to survival time of RVFV-infected mice was further confirmed in congenic mice. PMID:25569261

  4. Differential genetic susceptibility to child risk at birth in predicting observed maternal behavior.

    PubMed

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

    2011-01-01

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

  5. Identification of a Shared Genetic Susceptibility Locus for Coronary Heart Disease and Periodontitis

    PubMed Central

    Schaefer, Arne S.; Richter, Gesa M.; Groessner-Schreiber, Birte; Noack, Barbara; Nothnagel, Michael; Mokhtari, Nour-Eddine El; Loos, Bruno G.; Jepsen, Søren; Schreiber, Stefan

    2009-01-01

    Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD) and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33–2.94; P?=?6.9×10?4) for generalized aggressive periodontitis, and 1.72 (1.06–2.76; P?=?2.6×10?2) for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases. PMID:19214202

  6. A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection

    PubMed Central

    Ciencewicki, Jonathan M.; Wang, Xuting; Marzec, Jacqui; Serra, M. Elina; Bell, Douglas A.; Polack, Fernando P.; Kleeberger, Steven R.

    2014-01-01

    Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract infection during childhood and causes severe symptoms in some patients, which may cause hospitalization and death. Mechanisms for differential responses to RSV are unknown. Our objective was to develop an in vitro model of RSV infection to evaluate interindividual variation in response to RSV and identify susceptibility genes. Populations of human-derived HapMap lymphoblastoid cell lines (LCLs) were infected with RSV. Compared with controls, RSV-G mRNA expression varied from ?1- to 400-fold between LCLs. Basal expression of a number of gene transcripts, including myxovirus (influenza virus) resistance 1 (MX1), significantly correlated with RSV-G expression in HapMap LCLs. Individuals in a case-control population of RSV-infected children who were homozygous (n=94) or heterozygous (n=172) for the predicted deleterious A allele in a missense G/A SNP in MX1 had significantly greater risk for developing severe RSV disease relative to those with the major allele (n=108) (?2=5.305, P=0.021; OR: 1.750, 95% CI: 1.110, 2.758, P=0.021). We conclude that genetically diverse human LCLs enable identification of susceptibility genes (e.g., MX1) for RSV disease severity in children, providing insight for disease risk.—Ciencewicki, J. M., Wang, X., Marzec, J., Serra, M. E., Bell, D. A., Polack, F. P., Kleeberger, S. R. A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection. PMID:24421397

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

    Microsoft Academic Search

    Christopher G. Bell; Sarah Finer; Cecilia M. Lindgren; Gareth A. Wilson; Vardhman K. Rakyan; Andrew E. Teschendorff; Pelin Akan; Elia Stupka; Thomas A. Down; Inga Prokopenko; Ian M. Morison; Jonathan Mill; Ruth Pidsley; Panos Deloukas; Timothy M. Frayling; Andrew T. Hattersley; Mark I. McCarthy; Stephan Beck; Graham A. Hitman; Thorkild I. A. Sorensen

    2010-01-01

    Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci.

  8. Modifying Behavioral Phenotypes in Fmr1 KO Mice: Genetic Background Differences Reveal Autistic-Like Responses

    PubMed Central

    Spencer, Corinne M.; Alekseyenko, Olga; Hamilton, Shannon M.; Thomas, Alexia M.; Serysheva, Ekaterina; Yuva-Paylor, Lisa A.; Paylor, Richard

    2010-01-01

    Scientific Abstract Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in humans. In addition to cognitive impairment, patients may exhibit hyperactivity, attention deficits, social difficulties and anxiety, and autistic-like behaviors. The degree to which patients display these behaviors varies considerably and is influenced by family history, suggesting that genetic modifiers play a role in the expression of behaviors in FXS. Several studies have examined behavior in a mouse model of FXS in which the Fmr1 gene has been ablated. Most of those studies were done in Fmr1 knockout mice on a pure C57BL/6 or FVB strain background. To gain a better understanding of the effects of genetic background on behaviors resulting from the loss of Fmr1 gene expression, we generated F1 hybrid lines from female Fmr1 heterozygous mice on a pure C57BL/6J background bred with male Fmr1 wild-type mice of various background strains (A/J, DBA/2J, FVB/NJ, 129S1/SvImJ and CD-1). Male Fmr1 knockout and wild-type littermates from each line were examined in an extensive behavioral test battery. Results clearly indicate that multiple behavioral responses are dependent on genetic background, including autistic-like traits that are present on limited genetic backgrounds. This approach has allowed us to identify improved models for different behavioral symptoms present in FXS including autistic-like traits. PMID:21268289

  9. Susceptibility of the QCD Vacuum to CP-Odd Electromagnetic Background Fields

    NASA Astrophysics Data System (ADS)

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

    2013-02-01

    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?·B?. 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.

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

    PubMed Central

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

    2013-01-01

    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

  11. [Host genetic factors associated with susceptibility to HIV infection and progression of infection].

    PubMed

    Zwoli?ska, Katarzyna

    2009-01-01

    HIV infection causes progressive immune system deficiency, the development of AIDS and eventual death. Genetic factors play a very important role in the susceptibility to HIV infection and disease progression. Estimation of their effects is realized by comparing different patients groups. Four group of HIV-infected patients are taken into account: RP - rapid progressors, SP - slow progressors, LTNP - long term non-progressors and EU - exposed but uninfected. Genetic factors influencing the course of disease can be divided in groups, for example genes coding proteins connected with viral entry into cells (chemokine receptors, chemokines, lectins receptors), proteins engaged in the innate response to viral infections (cytokines, MBL, cyclophilin A, TRIM-5 alpha, APOBEC3G), human leukocyte antigens (HLAs) and killer cell immunoglobulin-like receptors (KIRs). It is suggested that some sequences of human endogenous retroviruses (HERV) and microRNA (miRNA) can also interact with the course of HIV infection. Knowledge of the roles of genetic determinants in HIV infection is very important and useful for their cognitive significance as well as in the prognosis of AIDS progression and the selection of specific therapies for individual patients. It is also a basis for the development of new antiviral drugs and vaccines. PMID:19252466

  12. Lifespan modulation in mice and the confounding effects of genetic background.

    PubMed

    Mulvey, Lorna; Sinclair, Amy; Selman, Colin

    2014-09-20

    We are currently in the midst of a revolution in ageing research, with several dietary, genetic and pharmacological interventions now known to modulate ageing in model organisms. Excitingly, these interventions also appear to have beneficial effects on late-life health. For example, dietary restriction (DR) has been shown to slow the incidence of age-associated cardiovascular disease, metabolic disease, cancer and brain ageing in non-human primates and has been shown to improve a range of health indices in humans. While the idea that DR's ability to extend lifespan is often thought of as being universal, studies in a range of organisms, including yeast, mice and monkeys, suggest that this may not actually be the case. The precise reasons underlying these differential effects of DR on lifespan are currently unclear, but genetic background may be an important factor in how an individual responds to DR. Similarly, recent findings also suggest that the responsiveness of mice to specific genetic or pharmacological interventions that modulate ageing may again be influenced by genetic background. Consequently, while there is a clear driver to develop interventions to improve late-life health and vitality, understanding precisely how these act in response to particular genotypes is critical if we are to translate these findings to humans. We will consider of the role of genetic background in the efficacy of various lifespan interventions and discuss potential routes of utilising genetic heterogeneity to further understand how particular interventions modulate lifespan and healthspan. PMID:25269675

  13. Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus

    Microsoft Academic Search

    Gisela Orozco; Steve Eyre; Anne Hinks; John Bowes; Ann W Morgan; Anthony G Wilson; Paul Wordsworth; Sophia Steer; Lynne Hocking; Wendy Thomson; Jane Worthington; Anne Barton

    2011-01-01

    BackgroundEvidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases.ObjectiveTo investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls.Methods3962 patients with RA and 9275 controls were included in the study.

  14. Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution but No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits

    PubMed Central

    Kristiansson, Kati; Perola, Markus; Tikkanen, Emmi; Kettunen, Johannes; Surakka, Ida; Havulinna, Aki S.; Stan?áková, Alena; Barnes, Chris; Widen, Elisabeth; Kajantie, Eero; Eriksson, Johan G.; Viikari, Jorma; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T.; Hartikainen, Anna-Liisa; Ruokonen, Aimo; Pouta, Anneli; Jula, Antti; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mika; Männistö, Satu; Jousilahti, Pekka; Bonnycastle, Lori L.; Järvelin, Marjo-Riitta; Kuusisto, Johanna; Collins, Francis S.; Laakso, Markku; Hurles, Matthew E.; Palotie, Aarno; Peltonen, Leena; Ripatti, Samuli; Salomaa, Veikko

    2012-01-01

    Background Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in four Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and NMR-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis and built a genetic risk score for MetS. Methods and Results A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all four study samples (P=7.23×10?9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 associated with various VLDL, TG, and HDL metabolites (P=0.024-1.88×10?5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these associated with lipid phenotypes and none with two or more uncorrelated MetS components. A genetic risk score, calculated as the number of alleles in loci associated with individual MetS traits, was strongly associated with MetS status. Conclusions Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits such as hypertension and glucose intolerance. PMID:22399527

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

    Microsoft Academic Search

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

    2006-01-01

    \\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

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

    PubMed Central

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

    2011-01-01

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

  17. Genetic susceptibility to dental caries differs between the sexes: a family-based study.

    PubMed

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

    2015-01-01

    Many of the factors affecting susceptibility to dental caries are likely influenced by genetics. In fact, genetics accounts for up to 65% of inter-individual variation in dental caries experience. Sex differences in dental caries experience 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. PMID:25612913

  18. Survey of plasmid-associated genetic markers in enterobacteriaceae with reduced susceptibilities to cephalosporins.

    PubMed

    Preston, Karen E; Graffunder, Eileen M; Evans, Ann M; Venezia, Richard A

    2003-07-01

    Clinical isolates of Enterobacteriaceae with reduced susceptibilities to cephalosporins were collected from 1993 to 2000. The organisms were screened for the extended-spectrum beta-lactamase (ESBL) phenotype, and plasmid extracts were screened for genetic markers by hybridization. A bla(TEM) probe was derived from pUC19; other probes were derived from pACM1, the plasmid responsible for the first known appearance of an ESBL in our institution. These probes included bla(SHV), int, aac(3)-Ia, dfrA1, IS6100, tetA, IncM markers, and Anon 13, a marker for the Klebsiella pneumoniae chromosomal sequences that flank bla(SHV-5). There were 42 hybridization patterns among 237 isolates. Patterns designated pACM1-like occurred in 44% of the isolates (eight species) and were always associated with the clavulanic acid (CA)-susceptible ESBL phenotype. The TEM marker was not predictive of the ESBL phenotype. Mapping indicated the presence of an SHV marker and up to 7.5 kb of its flanking chromosomal sequences in three non-IncM plasmids obtained in transformation experiments. We theorize that this DNA segment spread to other plasmids from pACM1-like sources. CA insensitivity became more frequent with time and was usually associated with either the TEM marker or the absence of both bla markers. One plasmid-encoded enzyme with characteristics of an AmpC beta-lactamase was observed in a transformant lacking both TEM and SHV markers. Although SHV type ESBLs were a continuing source of reduced susceptibility to cephalosporins in our institution, organisms with different resistance mechanisms were added to the hospital microflora in later years. These changes might be related, in part, to ESBL control strategies implemented in 1995. PMID:12821465

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

    PubMed Central

    2013-01-01

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

  20. Functional BCL-2 regulatory genetic variants contribute to susceptibility of esophageal squamous cell carcinoma

    PubMed Central

    Pan, Wenting; Yang, Jinyun; Wei, Jinyu; Chen, Hongwei; Ge, Yunxia; Zhang, Jingfeng; Wang, Zhiqiong; Zhou, Changchun; Yuan, Qipeng; Zhou, Liqing; Yang, Ming

    2015-01-01

    B-cell lymphoma-2 (BCL-2) prevents apoptosis and its overexpression could promote cancer cell survival. Multiple functional BCL-2 genetic polymorphisms, such as rs2279115, rs1801018 and rs1564483, have been identified previously and might be involved in cancer development through deregulating BCL-2 expression. Therefore, we examined associations between these three polymorphisms and esophageal squamous cell carcinoma (ESCC) susceptibility as well as its biological function in vivo. Genotypes were determined in two independent case-control sets consisted of 1588 ESCC patients and 1600 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. The impact of the rs2279115 polymorphism on BCL-2 expression was detected using esophagus tissues. Our results demonstrated that the BCL-2 rs2279115 AA genotype was significantly associated with decreased ESCC risk compared with the CC genotype (OR?=?0.72, 95% CI?=?0.57–0.90, P?=?0.005), especially in nonsmokers (OR?=?0.42, 95% CI?=?0.29–0.59, P?=?0.001) or nondrinkers (OR?=?0.44, 95% CI?=?0.32–0.62, P?=?0.002). Genotype-phenotype correlation studies demonstrated that subjects with the rs2279115 CA and AA genotypes had a statistically significant decrease of BCL-2 mRNA expression compared to the CC genotype in both normal and cancerous esophagus tissues. Our results indicate that the BCL-2 rs2279115 polymorphism contributes to ESCC susceptibility in Chinese populations. PMID:26132559

  1. E-selectin genetic variation as a susceptibility factor for ischemic stroke.

    PubMed

    Haidari, Mehran; Hajilooi, Mehrdad; Rafiei, Ali Reza; Rezaii, Ali Akbar; Hoseinipanah, Seyed Mohamad

    2009-01-01

    The polymorphism of the E-selectin gene has been implicated in the pathogenesis of atherosclerosis. We sought to explore whether the allelic variants relate to ischemic stroke. We conducted a case-control study of 359 cases of ischemic stroke and 353 community controls. Participants were evaluated for known cerebrovascular risk factors, and the E-selectin S128R and L554F genotypes were established using the polymerase chain reaction (PCR) method. The frequency of minor allele (R) and heterozygous (RS) genotype of E-selectin S128R polymorphism was significantly higher in the stroke patients than in the controls. Evaluation of genetic variation for E-selectin L554F polymorphisms revealed that the frequency of minor allele (F) and its heterozygous genotype (LF) is almost 4 times higher in the stroke patients than the controls (16.7 vs. 4.3 and 33.4 vs. 8.5, respectively). Multivariable logistic regression analysis after adjustment for age, sex and conventional vascular risk factors demonstrated that alleles R of S128R and F of L554F polymorphisms are independent risk factors for ischemic stroke. The combination of 2 minor alleles of E-selectin genes appeared to be the strongest susceptibility factor for ischemic stroke (adjusted OR: 5.89, 95% CI: 2.84-12.21, p = 0.0001). Our study demonstrates that the E-selectin S128R and L554F polymorphisms are associated with susceptibility to ischemic stroke. PMID:19420919

  2. Inflammation and susceptibility to neurodegeneration: the use of unbiased genetics to decipher critical regulatory pathways.

    PubMed

    Piehl, F; Olsson, T

    2009-02-01

    Neurodegeneration and signs of immune activation, with T cell infiltration, major histocompatibility complex class II expression and glial activation, occur in many neurological diseases. Although particular qualities of the inflammatory response have been proposed to be of importance, still very little is known about the exact factors that determine susceptibility to neurodegeneration. Mechanistic studies have yielded conflicting results, where inflammation is suggested both to attenuate and aggravate loss of nerve cells depending on the circumstances. In this context experimental genetic dissection in relevant rodent models such as experimental autoimmune encephalomyelitis and mechanical nerve injury can be a valuable tool to identify important genes/molecules/pathways. We here review emerging evidence using this approach that indicates different pathways related both to adaptive and local innate immune responses, which determine strain-specific susceptibility to neuroimmune inflammation and neurodegeneration. Exact positioning of genes in these types of complex traits will be important for the understanding of pathogenetic mechanisms and to direct the focus of functional studies using classical experimental tools. Ultimately, a better knowledge about the interplay between the nervous system and the local and systemic immune system can define new ways of intervention in neurodegenerative processes. PMID:18805461

  3. A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection.

    PubMed

    Ciencewicki, Jonathan M; Wang, Xuting; Marzec, Jacqui; Serra, M Elina; Bell, Douglas A; Polack, Fernando P; Kleeberger, Steven R

    2014-04-01

    Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract infection during childhood and causes severe symptoms in some patients, which may cause hospitalization and death. Mechanisms for differential responses to RSV are unknown. Our objective was to develop an in vitro model of RSV infection to evaluate interindividual variation in response to RSV and identify susceptibility genes. Populations of human-derived HapMap lymphoblastoid cell lines (LCLs) were infected with RSV. Compared with controls, RSV-G mRNA expression varied from ~1- to 400-fold between LCLs. Basal expression of a number of gene transcripts, including myxovirus (influenza virus) resistance 1 (MX1), significantly correlated with RSV-G expression in HapMap LCLs. Individuals in a case-control population of RSV-infected children who were homozygous (n=94) or heterozygous (n=172) for the predicted deleterious A allele in a missense G/A SNP in MX1 had significantly greater risk for developing severe RSV disease relative to those with the major allele (n=108) (?(2)=5.305, P=0.021; OR: 1.750, 95% CI: 1.110, 2.758, P=0.021). We conclude that genetically diverse human LCLs enable identification of susceptibility genes (e.g., MX1) for RSV disease severity in children, providing insight for disease risk. PMID:24421397

  4. Genetic susceptibility to neural tube defect pregnancy varies with offspring phenotype.

    PubMed

    Relton, C L; Wilding, C S; Jonas, P A; Lynch, S A; Tawn, E J; Burn, J

    2003-11-01

    Neural tube defects (NTDs) have a well-established genetic basis, although no single genetic factor has been identified as a major risk factor in NTD susceptibility. A large number of association studies have been conducted to investigate the possibility that NTD susceptibility is linked to polymorphic variation in genes involved in early embryonic development or in the absorption or metabolism of folate, a nutrient that has been clearly associated with a reduction in the risk of NTD pregnancy. A study of three candidate gene polymorphisms at loci implicated in folate absorption and metabolism has been conducted on a population of 211 mothers of a heterogeneous mix of NTD phenotypes: 59% spina bifida aperta (SBA), 20.3% spina bifida occulta (SBO), 17% anencephaly, and 3.7% other NTD. Allele and genotype frequencies were stratified according to offspring NTD phenotype, and variation in the level of NTD risk was associated with different phenotypes. All the three variants (MTHFR 677C > T, GCPII 1561C > T, and RFC-1 80G > A) were shown to significantly influence the risk of anencephalic pregnancy. In addition, the MTHFR 677C > T variant conferred a modest protective effect in SBO mothers and the total NTD mother group, but not in SBA mothers. The RFC-1 80G > A variant elevated the risk of SBO and anencephalic pregnancy. The findings of this study suggest that NTD phenotypic heterogeneity may help explain the mixed findings of previous association studies and that different polymorphisms may hold differing degrees of significance for the various NTD phenotypes. PMID:14616766

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

    PubMed Central

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

    2015-01-01

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

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

    SciTech Connect

    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

    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.

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

    E-print Network

    Paris-Sud XI, Université de

    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

  8. Genetic susceptibility to environmental toxicants: the interface between human and experimental studies in the development of new toxicological concepts

    Microsoft Academic Search

    Ricarda Thier; Klaus Golka; Thomas Brüning; Yon Ko; Hermann M. Bolt

    2002-01-01

    The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological

  9. Genetic Susceptibility for Lung Cancer: Interactions with Gender and Smoking History and Impact on Early Detection Policies

    Microsoft Academic Search

    Olga Y. Gorlova; Christopher Amos; Claudia Henschke; Lei Lei; Margaret Spitz; Qingyi Wei; Xifeng Wu; Marek Kimmel

    2003-01-01

    Objectives: To identify a subgroup of former, current and never smokers (males and females) at high risk for developing lung cancer, based on their genetic susceptibility profiles, to estimate their lifetime probabilities of the disease, and to assess the potential mortality reduction that could be achieved by screening the high-risk group. Methods: Case-control data (764 cases and 677 matched controls),

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

    EPA Science Inventory

    Genetic Background but not Metallothionein Phenotype Dictates Sensitivity to Cadmium-Induced Testicular Injury in Mice Jie Liu1,2, Chris Corton3, David J. Dix4, Yaping Liu1, Michael P. Waalkes2 and Curtis D. Klaassen1 ABSTRACT Parenteral administrati...

  11. COMPARISON OF TRANSCRIPT PROFILES IN WILD-TYPE AND 02 MAIZE ENDOSPERM IN DIFFERENT GENETIC BACKGROUNDS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations in the Opaque2 (O2) gene of maize (Zea mays L.) improve the nutritional value of maize by reducing the level of zeins in the kernel. The phenotype of o2 grain is controlled by many modifier genes and is, therefore, strongly dependent on genetic background. We propose two hypotheses to expl...

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

    PubMed Central

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

    2015-01-01

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

  13. Genetic variants in the IL1A gene region contribute to intestinal-type gastric carcinoma susceptibility in European populations.

    PubMed

    Durães, Cecília; Muñoz, Xavier; Bonet, Catalina; García, Nadia; Venceslá, Adoración; Carneiro, Fátima; Peleteiro, Bárbara; Lunet, Nuno; Barros, Henrique; Lindkvist, Björn; Boutron-Ruault, Marie-Christine; Bueno-de-Mesquita, H Bas; Rizzato, Cosmeri; Trichopoulou, Antonia; Weiderpass, Elisabete; Naccarati, Allessio; Travis, Ruth C; Tjønneland, Anne; Gurrea, Aurelio Barricarte; Johansson, Mattias; Riboli, Elio; Figueiredo, Céu; González, Carlos Alberto; Capellà, Gabriel; Machado, José Carlos; Sala, Núria

    2014-09-15

    The most studied genetic susceptibility factors involved in gastric carcinoma (GC) risk are polymorphisms in the inflammation-linked genes interleukin 1 (IL1) B and IL1RN. Despite the evidence pointing to the IL1 region, definite functional variants reproducible across populations of different genetic background have not been discovered so far. A high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to identify haplotype tagSNPs. Eighty-seven SNPs were genotyped in a Portuguese case-control study (358 cases, 1,485 controls) for the discovery analysis. A replication study, including a subset of those tagSNPs (43), was performed in an independent analysis (EPIC-EurGast) containing individuals from 10 European countries (365 cases, 1284 controls). Single SNP and haplotype block associations were determined for GC overall and anatomopathological subtypes. The most robust association was observed for SNP rs17042407, 16Kb upstream of the IL1A gene. Although several other SNP associations were observed, only the inverse association of rs17042407 allele C with GC of the intestinal type was observed in both studies, retaining significance after multiple testing correction (p?=?0.0042) in the combined analysis. The haplotype analysis of the IL1A LD block in the combined dataset revealed the association between a common haplotype carrying the rs17042407 variant and GC, particularly of the intestinal type (p?=?3.1 × 10(-5) ) and non cardia localisation (p?=?4.6 × 10(-3) ). These results confirm the association of IL1 gene variants with GC and reveal a novel SNP and haplotypes in the IL1A region associated with intestinal type GC in European populations. PMID:24615437

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

    PubMed Central

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

    2003-01-01

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

  15. APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors

    PubMed Central

    De Martino, Lucia; Capalbo, Donatella; Improda, Nicola; D’Elia, Federica; Di Mase, Raffaella; D’Assante, Roberta; D’Acunzo, Ida; Pignata, Claudio; Salerno, Mariacarolina

    2013-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named Autoimmune regulator gene (AIRE) which results in a failure of T-cell tolerance. Central tolerance takes place within the thymus and represents the mechanism by which potentially auto-reactive T-cells are eliminated through the negative selection process. The expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) in the thymus is a key process in the central tolerance and is driven by the protein encoded by AIRE gene, the transcription factor autoimmune regulator (AIRE). A failure in this process caused by AIRE mutations is thought to be responsible of the systemic autoimmune reactions of APECED. APECED is characterized by several autoimmune endocrine and non-endocrine manifestations and the phenotype is often complex. Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression even between siblings with the same genotype, thus implying that additional mechanisms, other than the failure of Aire function, are involved in the pathogenesis of the disease. Unraveling open issues of the molecular basis of APECED, will help improve diagnosis, management, and therapeutical strategies of this complex disease. PMID:24167503

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

    PubMed Central

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

    1999-01-01

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

  17. Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese.

    PubMed

    Bi, Rui; Zhang, Wen; Yu, Dandan; Li, Xiao; Wang, Hui-Zhen; Hu, Qiu-Xiang; Zhang, Chen; Lu, Weihong; Ni, Jianliang; Fang, Yiru; Li, Tao; Yao, Yong-Gang

    2015-03-01

    Mitochondrial dysfunction has been widely reported in psychiatric and neurodegenerative diseases. We aimed to investigate the association between matrilineal structures of Han Chinese populations and Alzheimer's disease (AD) by a 2-stage case-control study: A total of 341 AD patients and 435 normal individuals from Southwest China were analyzed for mitochondrial DNA sequence variations and were classified into respective haplogroups. A total of 371 AD patients and 470 normal individuals from East China, as validation samples, were genotyped for the variants defining the risk haplogroup. Haplogroup B5 had a significantly higher frequency in AD patients (7.33%) than in control subjects (3.68%) from Southwest China, and we found a similar pattern of higher frequency of B5 in patients in the case-control sample from East China. In the combined population, association of haplogroup B5 with AD risk was strengthened (p = 0.02; odds ratio = 1.74; 95% confidence interval = 1.10-2.76). In lymphoblastoid cell lines belonging to haplogroup B5a, we observed significantly increased reactive oxygen species and decreased mitochondrial mass. Hela cells with stable expression of the MT-ATP6 gene with B5-defining variant m.8584G>A also showed a significantly decreased mitochondrial function. Taken together, our results indicated that haplogroup B5 conferred genetic susceptibility to AD in Han Chinese, and this effect was most likely mediated by ancient variant m.8584G>A. The predisposing effect of B5 to AD is consistent with the ancestral-susceptibility model of complex diseases. PMID:25457022

  18. Genetic mapping of quantitative trait loci affecting susceptibility to Marek's disease virus induced tumors in F2 intercross chickens.

    PubMed Central

    Vallejo, R L; Bacon, L D; Liu, H C; Witter, R L; Groenen, M A; Hillel, J; Cheng, H H

    1998-01-01

    Marek's disease (MD) is a lymphoproliferative disease caused by the MD virus (MDV), which costs the poultry industry nearly $1 billion annually. To identify quantitative trait loci (QTL) affecting MD susceptibility, the inbred lines 6(3) (MD resistant) and 7(2) (MD susceptible) were mated to create more than 300 F2 chickens. The F2 chickens were challenged with MDV JM strain, moderately virulent) at 1 wk of age and assessed for MD susceptibility. The QTL analysis was divided into three stages. In stage 1, 65 DNA markers selected from the chicken genetic maps were typed on the 40 most MD-susceptible and the 40 most MD-resistant F2 chickens, and 21 markers residing near suggestive QTL were revealed by analysis of variance (ANOVA). In stage 2, the suggestive markers plus available flanking markers were typed on 272 F2 chickens, and three suggestive QTL were identified by ANOVA. In stage 3, using the interval mapping program Map Manager and permutation tests, two significant and two suggestive MD QTL were identified on four chromosomal subregions. Three to five loci collected explained between 11 and 23% of the phenotypic MD variation, or 32-68% of the genetic variance. This study constitutes the first report in the domestic chicken on the mapping of non-major histocompatibility complex QTL affecting MD susceptibility. PMID:9475745

  19. Genetic heterogeneity in pbp genes among clinically isolated group B Streptococci with reduced penicillin susceptibility.

    PubMed

    Nagano, Noriyuki; Nagano, Yukiko; Kimura, Kouji; Tamai, Kiyoko; Yanagisawa, Hideji; Arakawa, Yoshichika

    2008-12-01

    The recent emergence of group B streptococcal isolates exhibiting increased penicillin MICs at the Funabashi Municipal Medical Center and other hospitals in Japan prompted a comparative analysis of the penicillin-binding proteins (PBPs) from those strains with the PBPs from penicillin-susceptible strains comprising four neonatal invasive strains isolated from 1976 to 1988 and two recent isolates. The PBP sequences of the penicillin-susceptible strains were highly conserved, irrespective of their isolation date. Of six strains with reduced susceptibility to penicillin (penicillin MICs, 0.25 to 0.5 mug/ml), strains R1, R2, R5, and R6 shared a unique set of five amino acid substitutions, including V405A adjacent to the (402)SSN(404) motif in PBP 2X and one in PBP 2B. The remaining two strains, R3 and R4, shared several substitutions, including Q557E adjacent to the (552)KSG(554) motif in PBP 2X, in addition to the substitutions in PBP 2B, which are commonly found among penicillin-insusceptible strains. Strains R7 and R8, which had a penicillin MIC of 1 mug/ml, shared a unique set of eight amino acid substitutions (two in PBP 2X; two in PBP 2B, including G613R adjacent to the (614)KTG(616) motif; three in PBP 1A; and one in PBP 2A), and the Q557E substitution in PBP 2X was common to R3 and R4. The binding of Bocillin FL was reduced or not detected in some PBPs, including PBP 2X of penicillin-insusceptible strains, but no significant reduction in the level of pbp2x transcription was found in such strains. The results of phylogenetic comparative analyses imply the absence of epidemic penicillin-insusceptible strains, and several genetic lineages of penicillin-insusceptible strains have been independently emerging through the accumulation of mutations in their pbp genes, especially in pbp2x. PMID:18809936

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

    PubMed

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

    2015-07-01

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

  1. Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions.

    PubMed

    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, José I; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G; Truong, Thérèse; Cordina-Duverger, Emilie; Menegaux, Florence; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W; Ekici, Arif B; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J; Makalic, Enes; Schmidt, Daniel F; Southey, Melissa C; Cox, Angela; Simard, Jacques; Giles, Graham G; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D P; Garcia-Closas, Montserrat; Schmidt, Marjanka K; Hall, Per; Easton, Douglas F; Chang-Claude, Jenny

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) 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

  2. Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent

    PubMed Central

    Taioli, Emanuela; Flores-Obando, Rafael E.; Agalliu, Ilir; Blanchet, Pascal; Bunker, Clareann H.; Ferrell, Robert E.; Jackson, Maria; Kidd, La Creis R.; Kolb, Suzanne; Lavender, Nicol A.; McFarlane-Anderson, Norma; Morrison, Seian S.; Multigner, Luc; Ostrande, Elaine A.; Park, Jong Y.; Patrick, Alan L.; Rebbeck, Timothy R.; Romana, Marc; Stanford, Janet L.; Ukoli, Flora; VanCleave, Tiva T.; Zeigler-Johnson, Charnita M.; Mutetwa, Batsirai; Ragin, Camille

    2011-01-01

    Prostate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case–control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African-Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83–0.97 and OR 0.88, 95% CI: 0.82–0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01–1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46–0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene–environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent. PMID:21705483

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2009-01-01

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

  5. Improving strategies for detecting genetic patterns of disease susceptibility in association studies.

    PubMed

    Calle, M L; Urrea, V; Vellalta, G; Malats, N; Steen, K V

    2008-12-30

    The analysis of gene interactions and epistatic patterns of susceptibility is especially important for investigating complex diseases such as cancer characterized by the joint action of several genes. This work is motivated by a case-control study of bladder cancer, aimed at evaluating the role of both genetic and environmental factors in bladder carcinogenesis. In particular, the analysis of the inflammation pathway is of interest, for which information on a total of 282 SNPs in 108 genes involved in the inflammatory response is available. Detecting and interpreting interactions with such a large number of polymorphisms is a great challenge from both the statistical and the computational perspectives. In this paper we propose a two-stage strategy for identifying relevant interactions: (1) the use of a synergy measure among interacting genes and (2) the use of the model-based multifactor dimensionality reduction method (MB-MDR), a model-based version of the MDR method, which allows adjustment for confounders. PMID:18837071

  6. The Population Structure of Acinetobacter baumannii: Expanding Multiresistant Clones from an Ancestral Susceptible Genetic Pool

    PubMed Central

    Diancourt, Laure; Passet, Virginie; Nemec, Alexandr; Dijkshoorn, Lenie; Brisse, Sylvain

    2010-01-01

    Outbreaks of hospital infections caused by multidrug resistant Acinetobacter baumannii strains are of increasing concern worldwide. Although it has been reported that particular outbreak strains are geographically widespread, little is known about the diversity and phylogenetic relatedness of A. baumannii clonal groups. Sequencing of internal portions of seven housekeeping genes (total 2,976 nt) was performed in 154 A. baumannii strains covering the breadth of known diversity and including representatives of previously recognized international clones, and in 19 representatives of other Acinetobacter species. Restricted amounts of diversity and a star-like phylogeny reveal that A. baumannii is a genetically compact species that suffered a severe bottleneck in the recent past, possibly linked to a restricted ecological niche. A. baumannii is neatly demarcated from its closest relative (genomic species 13TU) and other Acinetobacter species. Multilocus sequence typing analysis demonstrated that the previously recognized international clones I to III correspond to three clonal complexes, each made of a central, predominant genotype and few single locus variants, a hallmark of recent clonal expansion. Whereas antimicrobial resistance was almost universal among isolates of these and a novel international clone (ST15), isolates of the other genotypes were mostly susceptible. This dichotomy indicates that antimicrobial resistance is a major selective advantage that drives the ongoing rapid clonal expansion of these highly problematic agents of nosocomial infections. PMID:20383326

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

    PubMed

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

    2011-06-01

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

  8. Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients.

    PubMed

    Council, M Laurin; Gardner, Jennifer M; Helms, Cynthia; Liu, Ying; Cornelius, Lynn A; Bowcock, Anne M

    2009-05-01

    The risks of developing malignant melanoma (MM) include ultraviolet irradiation and genetic factors. To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 4, melanocortin 1 receptor (MC1R) and tyrosinase (TYR)] were resequenced in 109-135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R'R' variants known or predicted to alter its function (P = 0.002), particularly the R160W variant (P = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer. PMID:19320745

  9. Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies.

    PubMed

    Wang, Tao; Jia, Weiping; Hu, Cheng

    2015-06-01

    Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed. PMID:25556696

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

    Microsoft Academic Search

    DANIEL DYKHUIZEN; DANIEL L. HARTL

    1980-01-01

    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

  11. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility

    Microsoft Academic Search

    Jason H. Moore; Joshua C. Gilbert; Chia-Ti Tsai; Fu-Tien Chiang; Todd Holden; Nate Barney; Bill C. White

    2006-01-01

    Detecting, characterizing, and interpreting gene–gene interactions or epistasis in studies of human disease susceptibility is both a mathematical and a computational challenge. To address this problem, we have previously developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension (i.e. constructive induction) thus permitting interactions to be detected in relatively small sample sizes. In

  12. Birth Order and Narcolepsy Risk Among Genetically Susceptible Individuals: a Population-based Case-control Study

    PubMed Central

    Watson, Nathaniel F.; Ton, Thanh G.N.; Koepsell, Thomas D.; Longstreth, W.T.

    2011-01-01

    Background Birth order may play a role in autoimmune diseases and early childhood infections, both factors implicated in the etiology of narcolepsy. We investigated the association between birth order and narcolepsy risk in a population-based case-control study in which all study subjects were HLA-DQB1*0602 positive. Methods Subjects were 18-50 years old, residents of King County, Washington, and positive for HLA-DQB1*0602. Birth order was obtained from administered interviews. We used logistic regression to generate odds ratios adjusted for income and African American race. Results Analyses included 67 cases (mean age 34.3 [SD=9.1], 70.2% female) and 95 controls (mean age 35.1 [SD=8.8], 58.1% female). Associations for birth order were as follows: First born (cases 38.8% vs. controls 50.2%, OR=1.0; Reference), second born (cases 29.9% vs. controls 32.9%, OR=1.6; 95% CI 0.7, 3.7), third born or higher (cases 31.3% vs. controls 16.8%, OR=2.5; 95% CI 1.0, 6.0). A linear trend was significant (p<0.05). Sibling number, sibling gender, having children, and number of children did not differ significantly between narcolepsy cases and controls. Conclusions Narcolepsy risk was significantly associated with higher birth order in this population-based study of genetically susceptible individuals. This finding supports an environmental influence on narcolepsy risk through an autoimmune mechanism, early childhood infections, or both. PMID:22281000

  13. Association of Matrix Metalloproteinase 9 C-1562T Polymorphism with Genetic Susceptibility to Myocardial Infarction: A Meta-Analysis

    PubMed Central

    Juan, Zhang; Wei-Guo, Zhang; Heng-Liang, Song; Da-Guo, Wan

    2015-01-01

    Background Myocardial infarction (MI) is the major cause of death by disease in the world. Many studies have identified the associations between matrix metalloproteinase 9 (MMP9) C-1562T polymorphisms and MI. However, the results remain inconclusive. To clarify the role of MMP9 C-1562T polymorphism in MI risk, we conducted a systematic review and large-scale meta-analysis. Methods Studies published between January 2005 and March 2014 were obtained from the electronic databases PubMed, Medline, and Embase. The odds ratios (ORs) with 95% CIs were calculated for comparisons of the alleles and genotypes in the overall population and in ethnicity subgroups to measure the strength of genetic associations. Results A total of 7 related studies, including 3952 MI cases and 4977 healthy control subjects were included in our meta-analysis. Our results show a statistically significant association between T allele and MI in the overall population (OR = 1.23; 95% CI, 1.02–1.48; P = 0.03). The risk of MI was also significantly higher in patients carrying the T allele (TC + TT genotypes) than in those with the CC genotype (P < 0.05). In stratified analysis by ethnicity, we found the T allele was strongly associated with MI in white populations, whereas in Asian populations there appeared no significant association. Conclusions Our data show that the MMP9 C-1562T polymorphism is a risk factor associated with increased MI susceptibility in the total population and white populations, although no significant association was observed in Asians populations. Further studies with larger sample sizes and assessing gene–gene and gene–environment interactions are required.

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

    PubMed Central

    2013-01-01

    Background RNA interference (RNAi) is a powerful tool to study gene function in organisms that are not amenable to classical forward genetics. Hence, together with the ease of comprehensively identifying genes by new generation sequencing, RNAi is expanding the scope of animal species and questions that can be addressed in terms of gene function. In the case of genetic mutants, the genetic background of the strains used is known to influence the phenotype while this has not been described for RNAi experiments. Results Here we show in the red flour beetle Tribolium castaneum that RNAi against Tc-importin ?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

  15. Characterizing Genetic Risk at Known Prostate Cancer Susceptibility Loci in African Americans

    PubMed Central

    Haiman, Christopher A.; Chen, Gary K.; Blot, William J.; Strom, Sara S.; Berndt, Sonja I.; Kittles, Rick A.; Rybicki, Benjamin A.; Isaacs, William B.; Ingles, Sue A.; Stanford, Janet L.; Diver, W. Ryan; Witte, John S.; Chanock, Stephen J.; Kolb, Suzanne; Signorello, Lisa B.; Yamamura, Yuko; Neslund-Dudas, Christine; Thun, Michael J.; Murphy, Adam; Casey, Graham; Sheng, Xin; Wan, Peggy; Pooler, Loreall C.; Monroe, Kristine R.; Waters, Kevin M.; Le Marchand, Loic; Kolonel, Laurence N.; Stram, Daniel O.; Henderson, Brian E.

    2011-01-01

    GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p?0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p?6×10?4) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR?=?1.17) over the alleles reported in the original GWAS (OR?=?1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry. PMID:21637779

  16. Impact of Intercellular Adhesion Molecule-1 Genetic Polymorphisms on Coronary Artery Disease Susceptibility in Taiwanese Subjects

    PubMed Central

    Chou, Chi-Hung; Ueng, Kwo-Chang; Liu, Yu-Fan; Wu, Chih-Hsien; Yang, Shun-Fa; Wang, Po-Hui

    2015-01-01

    The principal pathogenesis of coronary artery disease (CAD) is coronary artery atherosclerosis, a chronic inflammatory disease of the vessel walls of the coronary artery. Intercellular adhesion molecule-1 (ICAM-1) displays an important role in the development of the inflammation reaction and atherosclerosis. Few studies report the association of ICAM-1 genetic polymorphisms with CAD in Taiwanese subjects. Therefore, we conducted a study to associate the single nucleotide polymorphisms (SNPs) of ICAM-1, rs5491, rs5498, rs281432 and rs3093030 with CAD. Five hundred and twenty-five male and female subjects, who received elective coronary angiography in Taiwan Chung Shan Medical University Hospital, were recruited to determine four ICAM-1 SNPs by real time-polymerase chain reaction and genotyping. The relationships among ICAM-1 SNPs, haplotypes, demographic and characteristics and CAD were analyzed. This study showed that rs281432 (C8823G) was the only ICAM-1 SNP which affect the development of CAD. Multivariate analysis revealed that ICAM-1 SNP rs281432 CC/CG [p=0.016; odds ratio (OR): 2.56, 95% confidence interval (CI): 1.19-5.56], male gender (p=0.018; OR: 1.66, 95% CI: 1.09-2.51), aspirin use in the past 7 days (p=0.001; OR: 2.05, 95% CI: 1.33-3.14), hypertension (p<0.001; OR: 2.15, 95% CI: 1.42-3.25), serum cardiac troponin I elevation (p<0.001; OR: 2.14, 95% CI: 1.47-3.24) and severe angina in recent 24 hours (p=0.001; OR: 1.97, 95% CI: 1.31- 2.95) increase the risk of CAD. In conclusion, ICAM-1 SNP rs281432 is an independent factor to predict the development of CAD. ICAM-1 SNP rs281432 homozygotic mutant GG can reduce the susceptibility to the CAD in Taiwanese subjects. PMID:26078712

  17. Genetic susceptibility to chronic otitis media with effusion: candidate gene SNPs

    PubMed Central

    MacArthur, Carol J.; Wilmot, Beth; Wang, Linda; Schuller, Michael; Lighthall, Jessyka; Trune, Dennis

    2014-01-01

    Objective The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag-single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion. Study Design A 1:1 case/control design of 100 cases and 100 controls was used. The study was limited to the chronic otitis media with effusion phenotype to increase the population homogeneity. Methods A panel of 192 tag-SNPs was selected. Saliva for DNA extraction was collected from 100 chronic otitis media with effusion cases and 100 controls. After quality control, 100 case and 79 control samples were available for hybridization. Genomic DNA from each subject was hybridized to the single nucleotide polymorphism probes, and genotypes were generated. Quality control across all samples and SNPs reduced the final SNPs used for analysis to 170. Each single nucleotide polymorphism was then analyzed for statistical association with chronic otitis media with effusion. Results Eight single nucleotide polymorphisms from 4 genes had an unadjusted p-value of <0.05 for association with the chronic otitis media with effusion phenotype (TLR4, MUC5B, SMAD2, SMAD4); five of these polymorphisms were in the TLR4 gene. Conclusion While these results need to be replicated in a novel population, the presence of 5 single nucleotide polymorphisms in the TLR4 gene having association with chronic otitis media with effusion in our study population lends evidence for the possible role of this gene in the susceptibility to otitis media. PMID:23929584

  18. GSTT1 genetic polymorphism and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis.

    PubMed

    Xu, Ling-Yun; Cao, Lan-Fang

    2014-02-01

    Glutathione S-transferase T1 (GSTT1) genetic polymorphism has been considered as a risk factor for developing malignant diseases including acute lymphoblastic leukemia; however, the results from previous studies are inconsistent. We performed a meta-analysis of 16 published studies to investigate the association between GSTT1 null variant and risk of acute lymphoblastic leukemia in childhood. Between-study heterogeneity was assessed using the I (2) statistic method. Odds ratios (ORs) with corresponding 95 % confidence intervals (95 %CI) were pooled to assess the association. Those 16 studies were from 14 publications and included a total of 2,424 cases and 3,447 controls. Meta-analysis of a total of 16 studies showed that GSTT1 null variant was significantly associated with risk of childhood acute lymphoblastic leukemia (fixed-effect OR = 1.22, 95 %CI 1.07-1.39, P = 0.003, I (2)?= 35 %). Subgroup analysis showed that GSTT1 null variant was significantly associated with risk of childhood acute lymphoblastic leukemia in Asians (fixed-effect OR = 1.47, 95 %CI 1.16-1.85, P = 0.001, I (2)?= 0 %). However, there was no obvious association in both Caucasians (random-effect OR = 1.07, 95 %CI 0.83-1.38, P = 0.59, I (2)?= 53 %) and Africans (random-effect OR = 0.99, 95 %CI 0.31-3.10, P = 0.98, I (2)?= 72 %). Therefore, the GSTT1 null variant is significantly associated with susceptibility to childhood acute lymphoblastic leukemia in Asians. PMID:24282086

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

    Microsoft Academic Search

    Julie A. Blanchong; Dennis M. Heisey; Kim T. Scribner; Scot V. Libants; Chad Johnson; Judd M. Aiken; Julia A. Langenberg; Michael D. Samuel

    2009-01-01

    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

  20. Further evidence supporting a genetic background for Paget's disease of bone in Spain.

    PubMed

    Morales-Piga, A; Bachiller-Corral, J; Villaverde-Hueso, A; Alonso-Ferreira, V; Posada de la Paz, M; López-Abente, G

    2012-01-01

    The aim of this paper is to investigate heritable factors that might be related to the recognised genetic susceptibility for developing Paget's disease of bone (PD). This was a hospital-based, case-control study of a systematically selected group of PD patients and a group of controls drawn from the same health setting. In these populations we assessed surname pattern, parental consanguinity and constitutional physical traits. In a separate case-control analysis, genetically-based features and pathological traits of interest for genetic inference in 43 demonstrated familial cases were then compared to those in 24 sporadic cases. Results showed coincidence of three or four surnames (Odds Ratio [OR] = 5.6; 95% CI = 1.7-18.5), degree of parental consanguinity (OR = 4.1; 95% CI = 2.1-1.8), and green or blue eye colour (OR = 1.5; 95% CI = 1.1-2.1) were significantly associated with PD. Comparison of proven familial and sporadic PD cases showed that the former had a stronger association with Monckeberg-type vascular calcifications (32% vs. 4%; p = 0.02), percentage of skeleton affected (13.1 vs. 9.0), and green and blue eye colour (82% vs. 25%; p = 0.006), with Monckeberg-type vascular calcifications being the main variable of interest (OR = 30.9; 95% CI = 12.75-347.00) in the multivariate analysis. In conclusion, heritable factors are crucial in the pathogenesis of PD and, in line with other data sources, might account for the ethnic predisposition observed in different countries. PMID:23350154

  1. Persistence of transmitted HIV-1 drug resistance mutations associated with fitness costs and viral genetic backgrounds.

    PubMed

    Yang, Wan-Lin; Kouyos, Roger D; Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Scherrer, Alexandra U; Shilaih, Mohaned; Hinkley, Trevor; Petropoulos, Christos; Bonhoeffer, Sebastian; Günthard, Huldrych F

    2015-03-01

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

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

    PubMed Central

    2014-01-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS) including 26,488 cases and 83,964 controls of European, East Asian, South Asian, and Mexican and Mexican American ancestry. We observed significant excess in directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven novel T2D susceptibility loci. Furthermore, we observed considerable improvements in fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterisation of complex trait loci, and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. PMID:24509480

  3. Linkage and expression analysis to elucidate the genetic background of muscle structure and meat quality in the pig

    Microsoft Academic Search

    KLAUS WIMMERS; NGUYEN TRONG NGU; EDUARD MURANI; KARL SCHELLANDER; SIRILUCK PONSUKSILI

    2006-01-01

    Genome scans are the most general approaches to identify genomic regions exhibiting quantitative trait loci, QTL, without prior hypothesis of the physiology and genetic control of a trait. Function-oriented expression analyses are a complementary approach to derive hypotheses of the physiologic and genetic background of phenotypic variation. The proportion of muscle fibre types and their size affect body composition traits,

  4. 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

    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

    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

  5. 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 Central

    Jackson, Samuel J.; Tanner, Carolyn; Ross, Ruth A.; Michael, Gregory J.; Selwood, David L.; Giovannoni, Gavin; Baker, David

    2013-01-01

    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 (Cnr2tm1Zim) 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 (Cnr2Dgen) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2tm1Zim 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

  6. 1998 Oxford University Press 13931398Human Molecular Genetics, 1998, Vol. 7, No. 9 Genome-wide search for asthma susceptibility loci in

    E-print Network

    Abney, Mark

    -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

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

    PubMed Central

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

    2014-01-01

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

  8. Unifying genetic canalization, genetic constraint, and genotype-by-environment interaction: QTL by genomic background by environment interaction of flowering time in Boechera stricta.

    PubMed

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

    2014-10-01

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

  9. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996.

    PubMed

    1996-05-01

    As the leading organization of physicians who treat people with cancer, the American Society of Clinical Oncology (ASCO) recognizes that cancer specialists must be fully informed of the range of issues involved in genetic testing for cancer risk. The newly discovered and still developing ability to identify individuals at highest risk for cancer holds the promise of improved prevention and early detection of cancers. It also poses potential medical, psychological, and other personal risks that must be addressed in the context of informed consent for genetic testing. ASCO firmly believes that any physician who offers genetic testing should be aware of, and able to communicate, the benefits and limits of current testing procedures, and the range of prevention and treatment options available to patients and their families. For these reasons, ASCO endorses the following principles: ASCO affirms the role of clinical oncologists in documenting a family history of cancer in their patients, providing counseling regarding familial cancer risk and options for prevention and early detection, and recognizing those families for which genetic testing may serve as an aid in counseling. To the greatest extent possible, genetic testing for cancer susceptibility should be performed in the setting of long-term outcome studies. ASCO endorses the formulation and implementation of a national cooperative study/registry with appropriate confidentiality to define the clinical significance of mutations in known cancer susceptibility genes. ASCO is committed to providing educational opportunities for physicians concerning methods of quantitative cancer risk assessment, genetic testing, and pre- and post-test genetic counseling so that oncologists may more responsibly integrate genetic counseling and testing into the practice of clinical and preventive oncology. Oncologists must assure that informed consent has been given by the patient as an integral part of the process of genetic predisposition testing, whether such testing is offered on a clinical or research basis. ASCO recommends that cancer predisposition testing be offered only when: 1) the person has a strong family history of cancer or very early age of onset of disease; 2) the test can be adequately interpreted; and 3) the results will influence the medical management of the patient or family member. As clinical testing becomes more widely available, the Society encourages oncologists to utilize laboratories committed to the validation of testing methodologies, and to facilitate families' participation in long-term outcome studies. ASCO recommends that oncologists include in pre- and post-test counseling discussion of possible risks and benefits of cancer early detection and prevention modalities, which have presumed but unproven efficacy for individuals at the highest hereditary risk for cancer. ASCO endorses efforts to strengthen regulatory authority over laboratories that provide cancer predisposition tests that will be utilized to inform clinical decisions. These regulatory requirements should include appropriate oversight of the products used in genetic testing, interlaboratory comparisons of reference samples, as well as quality control mechanisms. ASCO endorses all efforts including legislation to prohibit discrimination by insurance companies or employers based on an individual's inherited susceptibility to cancer. All individuals at hereditary risk for cancer should have access to appropriate genetic testing and associated medical care, which should be covered by public and private third-party payers. ASCO endorses continued support of patient-oriented research to analyze the psychological impact of genetic testing of at-risk populations. PMID:8622094

  10. The value of animal models in predicting genetic susceptibility to complex diseases such as rheumatoid arthritis

    Microsoft Academic Search

    Emma Ahlqvist; Malin Hultqvist; Rikard Holmdahl

    2009-01-01

    For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our

  11. Multiple effects of genetic background on variegated transgene expression in mice.

    PubMed

    Opsahl, Margaret L; McClenaghan, Margaret; Springbett, Anthea; Reid, Sarah; Lathe, Richard; Colman, Alan; Whitelaw, C Bruce A

    2002-03-01

    BLG/7 transgenic mice express an ovine beta-lactoglobulin transgene during lactation. Unusually, transgene expression levels in milk differ between siblings. This variable expression is due to variegated transgene expression in the mammary gland and is reminiscent of position-effect variegation. The BLG/7 line was created and maintained on a mixed CBA x C57BL/6 background. We have investigated the effect on transgene expression of backcrossing for 13 generations into these backgrounds. Variable transgene expression was observed in all populations examined, confirming that it is an inherent property of the transgene array at its site of integration. There were also strain-specific effects on transgene expression that appear to be independent of the inherent variegation. The transgene, compared to endogenous milk protein genes, is specifically susceptible to inbreeding depression. Outcrossing restored transgene expression levels to that of the parental population; thus suppression was not inherited. Finally, no generation-dependent decrease in mean expression levels was observed in the parental population. Thus, although the BLG/7 transgene is expressed in a variegated manner, there was no generation-associated accumulated silencing of transgene expression. PMID:11901126

  12. Genetic Determinants Involved in the Susceptibility of Pseudomonas aeruginosa to ?-Lactam Antibiotics?

    PubMed Central

    Alvarez-Ortega, Carolina; Wiegand, Irith; Olivares, Jorge; Hancock, Robert E. W.; Martínez, José Luis

    2010-01-01

    The resistome of P. aeruginosa for three ?-lactam antibiotics, namely, ceftazidime, imipenem, and meropenem, was deciphered by screening a comprehensive PA14 mutant library for mutants with increased or reduced susceptibility to these antimicrobials. Confirmation of the phenotypes of all selected mutants was performed by Etest. Of the total of 78 confirmed mutants, 41 demonstrated a reduced susceptibility phenotype and 37 a supersusceptibility (i.e., altered intrinsic resistance) phenotype, with 6 mutants demonstrating a mixed phenotype, depending on the antibiotic. Only three mutants demonstrated reduced (PA0908) or increased (glnK and ftsK) susceptibility to all three antibiotics. Overall, the mutant profiles of susceptibility suggested distinct mechanisms of action and resistance for the three antibiotics despite their similar structures. More detailed analysis indicated important roles for novel and known ?-lactamase regulatory genes, for genes with likely involvement in barrier function, and for a range of regulators of alginate biosynthesis. PMID:20679510

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

    PubMed Central

    2012-01-01

    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

  14. Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from Vietnam, 2011

    PubMed Central

    2013-01-01

    Background Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern worldwide. In Vietnam, knowledge regarding N. gonorrhoeae prevalence and AMR is limited, and data concerning genetic characteristics of N. gonorrhoeae is totally lacking. Herein, we investigated the phenotypic AMR (previous, current and possible future treatment options), genetic resistance determinants for extended-spectrum cephalosporins (ESCs), and genotypic distribution of N. gonorrhoeae isolated in 2011 in Hanoi, Vietnam. Methods N. gonorrhoeae isolates from Hanoi, Vietnam isolated in 2011 (n?=?108) were examined using antibiograms (Etest for 10 antimicrobials), Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST), and sequencing of ESC resistance determinants (penA, mtrR and penB). Results The levels of in vitro resistance were as follows: ciprofloxacin 98%, tetracycline 82%, penicillin G 48%, azithromycin 11%, ceftriaxone 5%, cefixime 1%, and spectinomycin 0%. The MICs of gentamicin (0.023-6?mg/L), ertapenem (0.002-0.125?mg/L) and solithromycin (<0.016-0.25?mg/L) were relatively low. No penA mosaic alleles were found, however, 78% of the isolates contained an alteration of amino acid A501 (A501V (44%) and A501T (34%)) in the encoded penicillin-binding protein 2. A single nucleotide (A) deletion in the inverted repeat of the promoter region of the mtrR gene and amino acid alterations in MtrR was observed in 91% and 94% of the isolates, respectively. penB resistance determinants were detected in 87% of the isolates. Seventy-five different NG-MAST STs were identified, of which 59 STs have not been previously described. Conclusions In Vietnam, the highly diversified gonococcal population displayed high in vitro resistance to antimicrobials previously recommended for gonorrhoea treatment (with exception of spectinomycin), but resistance also to the currently recommended ESCs were found. Nevertheless, the MICs of three potential future treatment options were low. It is essential to strengthen the diagnostics, case reporting, and epidemiologic surveillance of gonorrhoea in Vietnam. Furthermore, the surveillance of gonococcal AMR and gonorrhoea treatment failures is imperative to reinforce. Research regarding novel antimicrobial treatment strategies (e.g., combination therapy) and new antimicrobials is crucial for future treatment of gonorrhoea. PMID:23351067

  15. Do the mutations of C1GALT1C1 gene play important roles in the genetic susceptibility to Chinese IgA nephropathy?

    PubMed Central

    Li, Gui-Sen; Nie, Guang-Jun; Zhang, Hong; LV, Ji-Cheng; Shen, Yan; Wang, Hai-Yan

    2009-01-01

    Background The deficiency of ?1,3 galactose in hinge region of IgA1 molecule played a pivotal role in pathogenesis of IgA nephropathy (IgAN). Cosmc, encoded by C1GALT1C1 gene, was indispensable to ?1,3 galactosylation of IgA1. We designed a serial study to investigate the relationship between the mutations of C1GALT1C1 gene and the genetic susceptibility to IgAN. Methods Nine hundred and thirty-eight subjects, including 661 patients with IgAN and 277 healthy controls were enrolled in the study. Firstly, single nucleotide polymorphisms (SNPs) in the promoter region of C1GALT1C1 gene were screened. Then the c.-347-190G>A was analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) for further case-control association analysis. Secondly the somatic mutations of DNAs from peripheral blood B lymphocytes were detected in 15 patients and 7 normal controls. Results No significant association was observed between the different alleles or genotypes of c.-347-190G>A and IgAN. The patients with different genotypes of C1GALT1C1 gene did not significantly associate with clinical manifestations, including hematuria, proteinuria, and serum creatinine of patients with IgAN. There was no somatic mutation detected in total 202 clones of 22 individuals. Conclusion The c.-347-190G>A polymorphism and the somatic mutation of encoding region of C1GALT1C1 gene were not significantly related to the genetic susceptibility to IgAN in Northern Chinese population. PMID:19778426

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

    PubMed

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

    2015-08-01

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

  17. Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau.

    PubMed

    Leng, Shuguang; Picchi, Maria A; Liu, Yushi; Thomas, Cynthia L; Willis, Derall G; Bernauer, Amanda M; Carr, Teara G; Mabel, Padilla T; Han, Younghun; Amos, Christopher I; Lin, Yong; Stidley, Christine A; Gilliland, Frank D; Jacobson, Marty R; Belinsky, Steven A

    2013-05-01

    Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 × 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners. PMID:23354305

  18. Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau

    PubMed Central

    Leng, Shuguang; Picchi, Maria A.; Liu, Yushi; Thomas, Cynthia L.; Willis, Derall G.; Bernauer, Amanda M.; Carr, Teara G.; Mabel, Padilla T.; Han, Younghun; Amos, Christopher I.; Lin, Yong; Stidley, Christine A.; Gilliland, Frank D.; Jacobson, Marty R.; Belinsky, Steven A.

    2013-01-01

    Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2×10?5) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners. PMID:23354305

  19. The genetics of rheumatoid arthritis: Influences on susceptibility, severity, and treatment response

    Microsoft Academic Search

    S. Louis Bridges

    1999-01-01

    There has been an explosion of knowledge of genetic variations among different populations and the influence of genetics on\\u000a complex diseases such as rheumatoid arthritis (RA). Although class II major histocompatibility complex (MHC) alleles are important\\u000a contributors, there are likely multiple other genes that modulate the disease phenotype. Genetic markers may allow prediction\\u000a of response to particular treatments. Given the

  20. Hürthle Cells Predict Hypothyroidism in Interferon-? Transgenic Mice of Different Genetic Backgrounds

    PubMed Central

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

    2012-01-01

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

  1. Hürthle cells predict hypothyroidism in interferon-? transgenic mice of different genetic backgrounds.

    PubMed

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

    2012-08-01

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

  2. Chronic pain and genetic background interact and influence opioid analgesia, tolerance, and physical dependence.

    PubMed

    Liang, De-Yong; Guo, TianZi; Liao, Guochun; Kingery, Wade S; Peltz, Gary; Clark, J David

    2006-04-01

    Opioids are commonly used in the treatment of moderate to severe pain. However, their chronic use is limited by analgesic tolerance and physical dependence. Few studies have examined how chronic pain affects the development of tolerance or dependence, and essentially no studies have looked at the role of both genetics and pain together. For these studies we used 12 strains of inbred mice. Groups of mice from each strain were tested at baseline for morphine analgesic sensitivity, mechanical nociceptive threshold, and thermal nociceptive threshold. Mice were then given morphine in a 4-day escalating morphine administration paradigm followed by reassessment of the morphine dose-response relationship. Finally, physical dependence was measured by administering naloxone. Parallel groups of mice underwent hind paw injection of complete Freund's adjuvant (CFA) to induce chronic hind paw inflammation 7 days prior to the beginning of testing. The data showed that CFA treatment tended to lower baseline ED(50) values for morphine and enhanced the degree of analgesic tolerance observed after 4 days of morphine treatment. In addition, the degree of jumping behavior indicative of physical dependence was often altered if mice had been treated with CFA. The influence of background strain was substantial for all traits measured. In silico haplotypic mapping of the tolerance and physical dependence data demonstrated that CFA pretreatment altered the pattern of the predicted associations and greatly reduced their statistical significance. We conclude that chronic inflammatory pain and genetics interact to modulate the analgesic potency of morphine, tolerance, and physical dependence. PMID:16516386

  3. Relationship between genetic polymorphisms of DNA ligase 1 and non-small cell lung cancer susceptibility and radiosensitivity.

    PubMed

    Tian, H; He, X; Yin, L; Guo, W J; Xia, Y Y; Jiang, Z X

    2015-01-01

    The aim of this study was to examine the relationship between genetic polymorphisms in DNA ligase 1 (LIG1) and non-small cell lung cancer (NSCLC) susceptibility and radiosensitivity in a Chinese population. This was a case-control study that included 352 NSCLC patients and 448 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was conducted to detect HaeIII polymorphisms in exon 6 of the LIG1 gene in this popula-tion. This information was used to observe the effects of radiation in pa-tients with different genotypes in order to determine the genotypes as-sociated with radiosensitivity. The CC genotype and C allele frequency were significantly higher in the NSCLC group than in the control group (P = 0.012 and P = 0.023, respectively). The relative risk of experienc-ing NSCLC was 2.55 [95% confidence interval (CI), 1.12-3.98] for CC homozygous patients and 0.87 (95%CI, 0.46-1.88) for AA homozygous patients. Analysis of LIG1 genetic polymorphisms and radiosensitiv-ity of NSCLC patients showed that AA homozygous patients were sig-nificantly more radiosensitive than the control group (AA vs AC, P = 0.014; AA vs CC, P < 0.001; AC vs CC, P = 0.023). Therefore, the LIG1 CC genotype was associated with susceptibility to NSCLC, and the AA genotype demonstrated increased radiosensitivity compared to the AC and CC genotypes. PMID:26125914

  4. High-Throughput Association Testing on DNA Pools to Identify Genetic Variants that Confer Susceptibility

    E-print Network

    California at Berkeley, University of

    High-Throughput Association Testing on DNA Pools to Identify Genetic Variants that Confer designed for nine candidate genetic variants in DNA repair and cell cycle/apoptotic regulatory genes, including Cyclin D1 [codon 870 splice site variant (A>G)]; BRCA1, P871L; ERCC2, K751Q; FAS À1377 (G>A); h

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

    PubMed

    Marshall, Ariela L; Christiani, David C

    2013-03-01

    Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. Early work focused on the presence of relatively prevalent but low-penetrance alterations in candidate genes leading to increased risk of lung cancer. Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients. PMID:23349013

  6. 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...

  7. Genetic analysis and antimicrobial susceptibility of Francisella noatunensis subsp. orientalis (sun. F. asiatica) isolates from fish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Francisella noatunensis subsp. orientalis (syn. F. asiatica) (Fno) is an emergent fish pathogen that causes acute to chronic disease in a wide variety of freshwater, brackish and marine fish. Due to the emergent nature of this bacterium, established protocols to measure antimicrobial susceptibility ...

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

    ERIC Educational Resources Information Center

    Soto-Cruz, Isabel; Legorreta-Herrera, Martha

    2009-01-01

    We have devised and implemented a module for an upper division undergraduate laboratory based on the amplification and analysis of a p53 polymorphism associated with cancer susceptibility. First, students collected a drop of peripheral blood cells using a sterile sting and then used FTA cards to extract the genomic DNA. The p53 region is then PCR…

  9. Blood chimerism confounds genetic relative susceptibility testing for classical scrapie in sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scrapie is a transmissible spongiform encephalopathy of sheep targeted for eradication in the U.S. Susceptibility of sheep to classical scrapie is linked with certain polymorphisms in the prion protein gene (PRNP), such as disease resistance associated with homozygosity for arginine at codon 171 (R1...

  10. Genetic background defines the regulation of postnatal cardiac growth by 17?-estradiol through a ?-catenin mechanism.

    PubMed

    Kararigas, Georgios; Nguyen, Ba Tiep; Zelarayan, Laura C; Hassenpflug, Maike; Toischer, Karl; Sanchez-Ruderisch, Hugo; Hasenfuss, Gerd; Bergmann, Martin W; Jarry, Hubertus; Regitz-Zagrosek, Vera

    2014-07-01

    Estrogen regulates several biological processes in health and disease. Specifically, estrogen exerts antihypertrophic effects in the diseased heart. However, its role in the healthy heart remains elusive. Our initial aim was to identify the effects of 17?-estradiol (E2) on cardiac morphology and global gene expression in the healthy mouse heart. Two-month-old C57BL/6J mice were ovariectomized and treated with E2 or vehicle for 3 months. We report that E2 induced physiological hypertrophic growth in the healthy C57BL/6J mouse heart characterized by an increase in nuclear ?-catenin. Hypothesizing that ?-catenin mediates these effects of E2, we employed a model of cardiac ?-catenin deletion. Our surprising finding is that E2 had the opposite effects in wild-type littermates, which were actually on the C57BL/6N background. Notably, E2 exerted no significant effect in hearts of mice with depleted ?-catenin. We further demonstrate an E2-dependent increase in glycogen synthase kinase 3? (GSK3?) phosphorylation and endosomal markers in C57BL/6J but not C57BL/6N mice. Together, these findings indicate an E2-driven inhibition of GSK3? and consequent activation of ?-catenin in C57BL/6J mice, whereas the opposite occurs in C57BL/6N mice. In conclusion, E2 exerts divergent effects on postnatal cardiac growth in mice with distinct genetic backgrounds modulating members of the GSK3?/?-catenin cascade. PMID:24731099

  11. Strain-specific nuclear genetic background differentially affects mitochondria-related phenotypes in Saccharomyces cerevisiae

    PubMed Central

    Montanari, Arianna; Francisci, Silvia; Fazzi D'Orsi, Mario; Bianchi, Michele Maria

    2014-01-01

    In the course of our studies on mitochondrial defects, we have observed important phenotypic variations in Saccharomyces cerevisiae strains suggesting that a better characterization of the genetic variability will be essential to define the relationship between the mitochondrial efficiency and the presence of different nuclear backgrounds. In this manuscript, we have extended the study of such relations by comparing phenotypic assays related to mitochondrial functions of three wild-type laboratory strains. In addition to the phenotypic variability among the wild-type strains, important differences have been observed among strains bearing identical mitochondrial tRNA mutations that could be related only to the different nuclear background of the cells. Results showed that strains exhibited an intrinsic variability in the severity of the effects of the mitochondrial mutations and that specific strains might be used preferentially to evaluate the phenotypic effect of mitochondrial mutations on carbon metabolism, stress responses, and mitochondrial DNA stability. In particular, while W303-1B and MCC123 strains should be used to study the effect of severe mitochondrial tRNA mutations, D273-10B/A1 strain is rather suitable for studying the effects of milder mutations. PMID:24700775

  12. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey.

    PubMed

    Roushdy-Hammady, I; Siegel, J; Emri, S; Testa, J R; Carbone, M

    2001-02-10

    Erionite present in stones used to build the villages of Karain and Tuzköy, Turkey, mined from nearby caves, is purported to cause mesothelioma in half of the villagers. We constructed genetic epidemiology maps to test whether some villagers were genetically predisposed to mesothelioma. Analysis of a six-generation extended pedigree of 526 individuals showed that mesothelioma was genetically transmitted, probably in an autosomal dominant way. This finding should lead to preventive strategies to lower the incidence of mesothelioma in future generations, and close monitoring of high-risk individuals might allow early detection and cure. PMID:11273069

  13. Physical activity reduces genetic susceptibility to increased central systolic pressure augmentation: a study of female twins

    Microsoft Academic Search

    Jerry R Greenfield; Katherine Samaras; Lesley V Campbell; Arthur B Jenkins; Paul J Kelly; Tim D Spector; Christopher S Hayward

    2003-01-01

    ObjectivesWe sought to examine associations between the augmentation index (AI) and metabolic, adiposity, and lifestyle factors, independent of genetic influences, and to determine whether gene-environment interactions modulate these relationships.

  14. The Conditional Nature of Genetic Interactions: The Consequences of Wild-Type Backgrounds on Mutational Interactions in a Genome-Wide Modifier Screen

    PubMed Central

    Chari, Sudarshan; Dworkin, Ian

    2013-01-01

    The phenotypic outcome of a mutation cannot be simply mapped onto the underlying DNA variant. Instead, the phenotype is a function of the allele, the genetic background in which it occurs and the environment where the mutational effects are expressed. While the influence of genetic background on the expressivity of individual mutations is recognized, its consequences on the interactions between genes, or the genetic network they form, is largely unknown. The description of genetic networks is essential for much of biology; yet if, and how, the topologies of such networks are influenced by background is unknown. Furthermore, a comprehensive examination of the background dependent nature of genetic interactions may lead to identification of novel modifiers of biological processes. Previous work in Drosophila melanogaster demonstrated that wild-type genetic background influences the effects of an allele of scalloped (sd), with respect to both its principal consequence on wing development and its interactions with a mutation in optomotor blind. In this study we address whether the background dependence of mutational interactions is a general property of genetic systems by performing a genome wide dominant modifier screen of the sdE3 allele in two wild-type genetic backgrounds using molecularly defined deletions. We demonstrate that ?74% of all modifiers of the sdE3 phenotype are background-dependent due in part to differential sensitivity to genetic perturbation. These background dependent interactions include some with qualitative differences in the phenotypic outcome, as well as instances of sign epistasis. This suggests that genetic interactions are often contingent on genetic background, with flexibility in genetic networks due to segregating variation in populations. Such background dependent effects can substantially alter conclusions about how genes influence biological processes, the potential for genetic screens in alternative wild-type backgrounds identifying new loci that contribute to trait expression, and the inferences of the topology of genetic networks. PMID:23935530

  15. XRCC1 and XPD genetic polymorphisms and susceptibility to age-related cataract: A meta-analysis

    PubMed Central

    Chi, Xin-Xin; Liu, You-Yu; Shi, Su-Ning; Cong, Zhuang; Liang, Yu-Qing

    2015-01-01

    Objective This meta-analysis aimed to determine the relationships between XRCC1 Arg399Gln (rs25487 G>A) and XPD Lys751Gln (rs1052559 A>C) polymorphisms and susceptibility to age-related cataract. Methods Medline (1966–2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980–2013), CINAHL (1982–2013), Web of Science (1945–2013) and the Chinese Biomedical Database (CBM; 1982–2013) were searched without language restrictions. Various combinations of the keywords and MeSH terms were used to screen for potentially relevant studies, specifically “genetic polymorphisms” or “SNPs” or “variation” or “single nucleotide polymorphism” or “polymorphism” or “mutation” or “variant”; “X-ray repair cross complementing protein 1” or “Xeroderma Pigmentosum Group D Protein” or “X-ray repair cross complementing protein 1” or “Xeroderma Pigmentosum Group D Protein” or “XPD” or “Xeroderma Pigmentosum Complementation Group D Protein” or “ERCC2” or “XRCC1” or “XRCC1 DNA repair protein”; and “Cataract” or “ Membranous Cataract” or “ Pseudoaphakia.” Meta-analyses were conducted using Stata 12.0 software. Crude odds ratios (ORs) and their corresponding 95% confidence intervals (95% CI) were calculated. Results Six independent case-control studies were included in the meta-analysis. Our results indicated that the association between the genetic polymorphisms of XRCC1 Arg399Gln G>A and XPD Lys751Gln A>C and increased susceptibility to age-related cataracts was statistically significant (XRCC1 Arg399Gln: OR=1.30, 95% CI=1.17–1.44, p<0.001; XPD Lys751Gln: OR=1.25, 95% CI=1.12–1.40, p<0.001, respectively). Ethnicity-stratified analysis indicated that the XRCC1 Arg399Gln G>A polymorphism was correlated with the development and progression of age-related cataract in China, India, and Turkey in the allele model and the dominant model. For the XPD Lys751Gln A>C variant, the association with the pathogenesis of age-related cataract in China and Turkey in the allele model and the dominant model was investigated. Conclusions The association of XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms with age-related cataract susceptibility observed in our meta-analyses supports the view that XRCC1 and XPD may play important roles in susceptibility to age-related cataract. PMID:25873778

  16. An ultrastructural investigation of Leishmania donovani infection in genetically resistant and susceptible mouse strains.

    PubMed

    Weldon, P R; Kongshavn, P A

    1985-03-01

    Natural resistance to the growth of Leishmania donovani in mice is controlled by a gene (Lsh) which is expressed, in an unknown fashion, in macrophages. Early net growth rate of the parasite is much higher in mice strains bearing the susceptible allele (Lshs) than in resistant (Lshr) mice. Intracellular events occurring in the Kupffer cells during this period have been studied at the ultrastructural level. It was found that the number of dividing amastigotes per thin section of infected cell was approximately 10-fold greater in susceptible (B10.A SgSn) than in resistant (A/J) strains of mice, both 7 and 14 days following infection. These findings support the hypothesis that high natural resistance to leishmaniasis (Lshr) is expressed as a microbistatic effect, exerted within the parasitized macrophage of the host. PMID:4039968

  17. Utilization of frozen-thawed epididymal ram semen to preserve genetic diversity in Scrapie susceptible sheep breeds.

    PubMed

    Ehling, C; Rath, D; Struckmann, C; Frenzel, A; Schindler, L; Niemann, H

    2006-12-01

    The European Union has introduced transmissible spongiform encephalopathy (TSE) resistance breeding programmes for several sheep breeds to cope with the genetic susceptibility to Scrapie infections. Due to the different allele frequencies among breeds, strong selection for ARR alleles is associated with a loss of genetic diversity in small populations and in larger populations with unfavourable ARR allele frequencies. To ensure maintenance of genetic diversity, an adhoc cryopreservation programme was initiated employing epididymal sperm from 109 rams representing 16 different breeds within one breeding season. Epididymal semen was chosen for this adhoc programme because time consuming training of rams for ejaculated semen collection via an artificial vagina was not possible. Prior to freezing, average sperm motility was 79.7% and acrosome integrity was 93.7%. After freezing, these levels were decreased to 60.5 and 72.8%, respectively. An insemination trial using frozen-thawed epididymal semen resulted in a lambing rate of 87.5%. Results show that this semen preservation method is robust and efficient and associated with high fertility. It may also be useful for other animal species. PMID:16905182

  18. Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations?

    PubMed Central

    Li, Xiao; Zhang, Wen; Tang, Jinsong; Tan, Liwen; Luo, Xiong-jian; Chen, Xiaogang; Yao, Yong-Gang

    2015-01-01

    Schizophrenia is one of the most prevalent psychiatric disorders with complex genetic etiology. Accumulating evidence suggests that energy metabolism and oxidative stress play important roles in the pathophysiology of schizophrenia. Dysfunction of mitochondrial respiratory chain and altered expression of complex I subunits were frequently reported in schizophrenia. To investigate whether nuclear-encoded core subunit genes of mitochondrial complex I are associated with schizophrenia, we performed a genetic association study in Han Chinese. In total, 46 tag single nucleotide polymorphisms (SNPs) from 7 nuclear-encoded core genes of mitochondrial complex I were genotyped in 918 schizophrenia patients and 1042 healthy controls. We also analyzed these SNPs in a large sample mainly composed of Europeans through using the available GWAS datasets from the Psychiatric Genomics Consortium (PGC). No significant associations were detected between these SNPs and schizophrenia in Han Chinese and the PGC data set. However, we observed nominal significant associations of 2 SNPs in the NDUFS1 gene and 4 SNPs in the NDUFS2 gene with early onset schizophrenia (EOS), but none of these associations survived the Bonferroni correction. Taken together, our results suggested that common SNPs in the nuclear-encoded core subunit genes of mitochondrial complex I may not confer genetic susceptibility to schizophrenia. PMID:26053550

  19. Genetic Susceptibility to Squamous Cell Carcinoma of the Lung in Relation to Cigarette Smoking Dose1

    Microsoft Academic Search

    Kei Nakachi; Kazue Imai; Shin-ichi Hayashi; Junko Watanabe; Kaname Kawajiri

    Cytochrome P450IÁ1 is responsible for the metabolic activation of benzo(a)pyrene in cigarette smoke; an association of lung cancer with DNA polymorphisms of P450IA1 gene was shown in our previous study. In this paper, we investigated the interindividual difference of geneti cally determined susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose. We tirsi compared the

  20. Genetic susceptibility, cigarette smoking, and wood dust exposure in lung cancer: Case control analyses

    Microsoft Academic Search

    Xifeng Wu

    1994-01-01

    This case control study was conducted to assess the association between lung cancer risk, mutagen sensitivity (a marker of cancer susceptibility), and a putative lung carcinogen, wood dust exposure. There were 165 cases (98 African-Americans, 67 Mexican-Americans) with newly diagnosed, previously untreated lung cancer, and 239 controls, frequency-matched on age, sex, and ethnicity.^ Mutagen sensitivity ($\\\\ge$1 break\\/cell) was associated with

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

    PubMed Central

    Arêas, Glauber P; Schuab, Rôde BB; Neves, Felipe PG; Barros, Rosana R

    2014-01-01

    Streptococcus pyogenes is responsible for a variety of infectious diseases and immunological complications. In this study, 91 isolates of S. pyogenes recovered from oropharynx secretions were submitted to antimicrobial susceptibility testing, emm typing and pulsed-field gel electrophoresis (PFGE) analysis. All isolates were susceptible to ceftriaxone, levofloxacin, penicillin G and vancomycin. Resistance to erythromycin and clindamycin was 15.4%, which is higher than previous reports from this area, while 20.9% of the isolates were not susceptible to tetracycline. The macrolide resistance phenotypes were cMLSB (10) and iMLSB (4). The ermB gene was predominant, followed by the ermA gene. Thirty-two emm types and subtypes were found, but five (emm1, emm4, emm12, emm22, emm81) were detected in 48% of the isolates. Three new emm subtypes were identified (emm1.74, emm58.14, emm76.7). There was a strong association between emm type and PFGE clustering. A variety of PFGE profiles as well as emm types were found among tetracycline and erythromycin-resistant isolates, demonstrating that antimicrobial resistant strains do not result from the expansion of one or a few clones. This study provides epidemiological data that contribute to the development of suitable strategies for the prevention and treatment of such infections in a poorly studied area. PMID:25410998

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

    PubMed Central

    2010-01-01

    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 step to develop effective and selective anti-cancer drugs. Thus, for the current study a cell culture model for malignant transformation was used: Primary human fibroblasts of the BJ strain were sequentially transduced with retroviral vectors encoding the genes for hTERT (cell line BJ-T), simian virus 40 early region (SV40 ER, cell line BJ-TE) and H-Ras V12 (cell line BJ-TER). Results The stepwise malignant transformation of human fibroblasts was analyzed on the protein level by differential proteome analysis. We observed 39 regulated protein spots and therein identified 67 different proteins. The strongest change of spot patterns was detected due to integration of SV40 ER. Among the proteins being significantly regulated during the malignant transformation process well known proliferating cell nuclear antigen (PCNA) as well as the chaperones mitochondrial heat shock protein 75 kDa (TRAP-1) and heat shock protein HSP90 were identified. Moreover, we find out, that TRAP-1 is already up-regulated by means of SV40 ER expression instead of H-Ras V12. Furthermore Peroxiredoxin-6 (PRDX6), Annexin A2 (p36), Plasminogen activator inhibitor 2 (PAI-2) and Keratin type II cytoskeletal 7 (CK-7) were identified to be regulated. For some protein candidates we confirmed our 2D-PAGE results by Western Blot. Conclusion These findings give further hints for intriguing interactions between the p16-RB pathway, the mitochondrial chaperone network and the cytoskeleton. In summary, using a cell culture model for malignant transformation analyzed with 2D-PAGE, proteome and cellular changes can be related to defined steps of tumorigenesis. PMID:20860785

  3. Genes determining yeast replicative life span in a long-lived genetic background

    E-print Network

    Dunham, Maitreya

    (three genetic models of calorie restriction) significantly enhanced longevity. In addition, over reserved. Keywords: Yeast aging; Caloric restriction; Genetic pathways 1. Introduction The budding yeast longevity genes and pathways whose counterparts can be examined in higher eukaryotes (Kaeberlein et al

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

    PubMed Central

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

    2015-01-01

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

  5. The connexin43-dependent transcriptome during brain development: Importance of genetic background

    PubMed Central

    Iacobas, S; Iacobas, DA; Spray, DC; Scemes, E

    2012-01-01

    Use of null mutant mice is a powerful way to evaluate the role of specific proteins in brain function. Studies performed on knockout mice have revealed some unexpected roles of the gap junction proteins (connexins). Thus, analyses of gene expression in connexin43 (Cx43) null brains indicated that deletion of a single gene (Gja1) induced expression level change of numerous other genes located on all chromosomes and involved in a wide diversity of functional pathways. The significant overlap between alterations in gene expression level, control and coordination in Cx43 knockout and knockdown astrocytes raised the possibility that Gja1 represents a transcriptomic node of gene regulatory networks. However, conditional deletion of Gja1 in astrocytes of two mouse strains resulted in remarkably different phenotypes. In order to evaluate the influence of the genetic background on the transcriptome, we performed microarray studies on brains of GFAP-Cre:Cx43f/f C57Bl/6 and 129/SVEV mice. The surprisingly low number of Cx43 core genes (regulated in all Cx43 nulls regardless of strain) and the high number of differently regulated genes in the two Cx43 conditional knockouts indicate high influence of mouse strain on brain transcriptome. PMID:22771707

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

    PubMed

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

    2015-01-01

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

  7. Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study

    PubMed Central

    2010-01-01

    Introduction Disturbance of the pro-coagulatant and anti-coagulant balance is associated with a poor outcome from critical illness. The objective of this study is to determine whether the Factor V Leiden (FVL) mutation is associated with susceptibility to or death from critical illness. Methods A genetic association study involving four case cohorts comprising two Gram negative sepsis, one invasive pneumococcal disease and one intensive care unit cohort with a total of 1,249 patients. Controls were derived from a population-based cohort study (N = 8,147). DNA from patients and controls was genotyped for the FVL mutation. Results When all patients were investigated together no significant difference in the frequency of FVL mutation was observed compared with controls (odds ratio (OR), 1.03; 95% confidence interval (CI), 0.83 to 1.29). However, when stratified among patients admitted to intensive care (N = 237), susceptibility and the likelihood of long-term death was influenced by the FVL mutation. In adjusted logistic regression analysis, FVL carriers had an increased risk of ICU admission compared to non-carriers (OR 1.62; 95% CI, 1.08 to 2.42). In adjusted Cox regression analysis, FVL carriers were at increased risk of long-term death compared to non-carriers (relative risk 1.78; 95% CI, 1.13 to 2.81). FVL carrier status did not predict either susceptibility to or outcome from Gram negative, Escherichia coli or Streptococcus pneumoniae sepsis. Conclusions Overall, the FVL mutation did not appear to increase the risk of admission due to severe invasive infections. Nevertheless, in the subgroup of patients admitted to intensive care an increased risk and a poorer long-term outcome for individuals with critical illness were observed for FVL mutation carriers. PMID:20202226

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

    PubMed Central

    Wilson, Gareth A.; Rakyan, Vardhman K.; Teschendorff, Andrew E.; Akan, Pelin; Stupka, Elia; Down, Thomas A.; Prokopenko, Inga; Morison, Ian M.; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M.; Hattersley, Andrew T.; McCarthy, Mark I.; Beck, Stephan; Hitman, Graham A.

    2010-01-01

    Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10?4, permutation p?=?1.0×10?3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10?7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

  9. Molecular Assay for Detection of Genetic Markers Associated with Decreased Susceptibility to Cephalosporins in Neisseria gonorrhoeae.

    PubMed

    Peterson, S W; Martin, I; Demczuk, W; Bharat, A; Hoang, L; Wylie, J; Allen, V; Lefebvre, B; Tyrrell, G; Horsman, G; Haldane, D; Garceau, R; Wong, T; Mulvey, M R

    2015-07-01

    The incidence of antimicrobial-resistant Neisseria gonorrhoeae continues to rise in Canada; however, antimicrobial resistance data are lacking for approximately 70% of gonorrhea infections that are diagnosed directly from clinical specimens by nucleic acid amplification tests (NAATs). We developed a molecular assay for surveillance use to detect mutations in genes associated with decreased susceptibility to cephalosporins that can be applied to both culture isolates and clinical samples. Real-time PCR assays were developed to detect single nucleotide polymorphisms (SNPs) in ponA, mtrR, penA, porB, and one N. gonorrhoeae-specific marker (porA). We tested the real-time PCR assay with 252 gonococcal isolates, 50 nongonococcal isolates, 24 N. gonorrhoeae-negative NAAT specimens, and 34 N. gonorrhoeae-positive NAAT specimens. Twenty-four of the N. gonorrhoeae-positive NAAT specimens had matched culture isolates. Assay results were confirmed by comparison with whole-genome sequencing data. For 252 N. gonorrhoeae strains, the agreement between the DNA sequence and real-time PCR was 100% for porA, ponA, and penA, 99.6% for mtrR, and 95.2% for porB. The presence of ?2 SNPs correlated with decreased susceptibility to ceftriaxone (sensitivities of >98%) and cefixime (sensitivities of >96%). Of 24 NAAT specimens with matched cultures, the agreement between the DNA sequence and real-time PCR was 100% for porB, 95.8% for ponA and mtrR, and 91.7% for penA. We demonstrated the utility of a real-time PCR assay for sensitive detection of known markers for the decreased susceptibility to cephalosporins in N. gonorrhoeae. Preliminary results with clinical NAAT specimens were also promising, as they correlated well with bacterial culture results. PMID:25878350

  10. Genetic studies of the susceptibility of classical and wild-derived inbred mouse strains to monkeypox virus.

    PubMed

    Earl, Patricia L; Americo, Jeffrey L; Moss, Bernard

    2015-07-01

    Previously, we screened 38 inbred mouse strains for susceptibility to monkeypox virus (MPXV) and focused on wild-derived CAST mice because of their extreme vulnerability. Here, we provide further analysis of inbred mouse strains. NZW/Lac and C58 mice exhibited more weight loss than other classical inbred strains but all survived intranasal challenges with 10(4) to10(6)PFU of MPXV. Mice from three wild derived strains, in addition to CAST, exhibited severe weight loss and died or were euthanized. LD50 values for CASA, MOLF and PERA were 100, 6800 and >10(5)PFU, respectively. CASA was inbred independently from the same founders as CAST, whereas MOLF and PERA are genetically and geographically distinct. The MPXV susceptibility of the F1 progeny of CAST and either C57BL/6 or BALB/c indicated that resistance is dominant. Back-crossing the F1 progeny of C57BL/6 and CAST to CAST suggested more than one independent resistant locus. PMID:25791934

  11. Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease.

    PubMed

    Peloso, Gina M; Demissie, Serkalem; Collins, Dorothea; Mirel, Daniel B; Gabriel, Stacey B; Cupples, L Adrienne; Robins, Sander J; Schaefer, Ernst J; Brousseau, Margaret E

    2010-12-01

    A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (?40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) significantly associated with case status were identified in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel findings of this study are the identification of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA, and the observation that genetic variation in SELP may influence CHD risk through its effects on HDL. PMID:20855565

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

    PubMed Central

    Muller, Erinn M.; van Woesik, Robert

    2014-01-01

    Outbreaks of coral diseases are one of the greatest threats to reef corals in the Caribbean, yet the mechanisms that lead to coral diseases are still largely unknown. Here we examined the spatial-temporal dynamics of white-pox disease on Acropora palmata coral colonies of known genotypes. We took a Bayesian approach, using Integrated Nested Laplace Approximation algorithms, to examine which covariates influenced the presence of white-pox disease over seven years. We showed that colony size, genetic susceptibility of the coral host, and high-water temperatures were the primary tested variables that were positively associated with the presence of white-pox disease on A. palmata colonies. Our study also showed that neither distance from previously diseased individuals, nor colony location, influenced the dynamics of white-pox disease. These results suggest that white-pox disease was most likely a consequence of anomalously high water temperatures that selectively compromised the oldest colonies and the most susceptible coral genotypes. PMID:25372835

  13. Common genetic variant on 14q13.3 contributes to thyroid cancer susceptibility: evidence based on 12 studies.

    PubMed

    Zheng, JiaoJiao; Li, Chen; Wang, Cong; Ai, Zhilong

    2015-06-01

    Several genome-wide association studies on thyroid cancer (TC) have reported similar findings of a new susceptibility locus, 14q13.3. After that, a number of studies reported that rs944289 polymorphism at chromosome 14q13.3 has been implicated in TC risk. However, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 12 studies involving a total of 7,598 TC cases, 53,613 controls, and 239 nuclear families for 14q13.3-rs944289 polymorphism to evaluate its effect on genetic susceptibility for TC. An overall random-effect per-allele OR of 1.30 (95 % CI 1.21-1.40, P < 10(-5)) was found for the polymorphism. Significant results were also observed for under dominant and recessive genetic models. In the subgroup analysis by ethnicity, we found similar significant results for both Caucasians (T allele: OR 1.29, 95 % CI 1.17-1.42, P < 10(-5)) and East Asians (T allele: OR 1.33, 95 % CI 1.18-1.49, P < 10(-5)). Further in stratified analyses according to study design and sample size, evidence of gene-disease association was also obtained. In addition, we found that rs944289 confers its risk, for both papillary thyroid carcinoma and follicular thyroid carcinoma when stratified by histological types of TC. Furthermore, our results on stratified analysis according to radiation exposure status showed an increased sporadic TC risk, while no associations were detected among radiation-related TCs for rs944289 polymorphism. Our result demonstrated that rs944289 polymorphism on 14q13.3 is a low penetrant risk factor for developing TC. PMID:25552255

  14. Head and Neck Cancer Susceptibility: A Genetic Marker in the Methylenetetrahydrofolate Reductase Gene

    Microsoft Academic Search

    Nelofar Kureshi; Shehzad Ghaffar; Sammer Siddiqui; Iftikhar Salahuddin; Philippe M. Frossard

    2004-01-01

    Progress in the elucidation of molecular genetic changes that lead to the development of tumors should soon bring novel diagnostic and therapeutic procedures into clinical practice. In this respect, methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. DNA methylation is an epigenetic feature that influences cellular development and function. Germ line mutation

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

    E-print Network

    Brenner, David Jonathan

    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

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

    Microsoft Academic Search

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

    2004-01-01

    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

  17. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression

    Microsoft Academic Search

    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

    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

  18. Genetic Variant rs10757278 on Chromosome 9p21 Contributes to Myocardial Infarction Susceptibility

    PubMed Central

    Chen, Guangyuan; Fu, Xiuhua; Wang, Guangyu; Liu, Guiyou; Bai, Xiuping

    2015-01-01

    Large-scale genome-wide association studies (GWAS) have revealed that rs10757278 polymorphism (or its proxy rs1333049) on chromosome 9p21 is associated with myocardial infarction (MI) susceptibility in individuals of Caucasian ancestry. Following studies in other populations investigated this association. However, some of these studies reported weak or no significant association. Here, we reevaluated this association using large-scale samples by searching PubMed and Google Scholar databases. Our results showed significant association between rs10757278 polymorphism and MI with p = 6.09 × 10?22, odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.22–1.36 in pooled population. We further performed a subgroup analysis, and found significant association between rs10757278 polymorphism and MI in Asian and Caucasian populations. We identified that the association between rs10757278 polymorphism and MI did not vary substantially by excluding any one study. However, the heterogeneity among the selected studies varies substantially by excluding the study from the Pakistan population. We found even more significant association between rs10757278 polymorphism and MI in pooled population, p = 3.55 × 10?53, after excluding the study from the Pakistan population. In summary, previous studies reported weak or no significant association between rs10757278 polymorphism and MI. Interestingly, our analysis suggests that rs10757278 polymorphism is significantly associated with MI susceptibility by analyzing large-scale samples. PMID:26006241

  19. Genetic diversity and antifungal susceptibility testing of Trichosporon asahii isolated of Intensive Care Units patients

    PubMed Central

    de Oliveira Silva, Rosana Bellan; Fusco-Almeida, Ana Marisa; Matsumoto, Marcelo Teruyuki; Baeza, Lilian Cristiane; Benaducci, Tatiane; Mendes-Giannini, Maria José Soares

    2008-01-01

    Trichosporon asahii is an opportunistic pathogen, associated with a high mortality rate in immunocompromised patients. In this study, ten isolates, recovered from oral cavity and urine of patients in Intensive Care Units (ICU) over six months, were identified by classical and molecular methods, typed by RAPD and tested in vitro for susceptibility to fluconazole, itraconazole, 5-flucytosine and amphotericin B. A total agreement between the identification of Trichosporon sp by PCR based on sequences of the Internal Transcribed Spacer Regions (ITS) and on the sequences of small-subunit (SSU) ribosomal DNA (rDNA) was found. Randomly amplified of polymorphic DNA (RAPD), with primers P6 and M13, was used to determine the genomic profiles. The dendogram analysis indicated that almost all strains showed similarity >0.9 among them and all strains were multidrug-resistant. This study brings new results on the identification and genotyping of T. asahii isolated from Brazilian ICU patients and information about their antifungal drugs susceptibility. PMID:24031270

  20. Genetic variants in 3'-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans.

    PubMed

    Joo Jeon, Young; Woo Kim, Jong; Mi Park, Hye; Kim, Jung O; Geun Jang, Hyo; Oh, Jisu; Gyu Hwang, Seong; Won Kwon, Sung; Oh, Doyeun; Keun Kim, Nam

    2015-01-01

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3'-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3'-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3'-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID:26046315

  1. Genetic variants in 3?-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans

    PubMed Central

    Joo Jeon, Young; Woo Kim, Jong; Mi Park, Hye; Kim, Jung O; Geun Jang, Hyo; Oh, Jisu; Gyu Hwang, Seong; Won Kwon, Sung; Oh, Doyeun; Keun Kim, Nam

    2015-01-01

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3?-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3?-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3?-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID:26046315

  2. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice

    PubMed Central

    Rangasamy, Tirumalai; Cho, Chung Y.; Thimmulappa, Rajesh K.; Zhen, Lijie; Srisuma, Sorachai S.; Kensler, Thomas W.; Yamamoto, Masayuki; Petrache, Irina; Tuder, Rubin M.; Biswal, Shyam

    2004-01-01

    Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke–induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2?-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells — predominantly endothelial and type II epithelial cells — as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke–induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis. PMID:15520857

  3. High transmission rates restore expression of genetically determined susceptibility of mice to nematode infections.

    PubMed

    Scott, M E

    2006-05-01

    This study investigated why the susceptible or resistance phenotype to the nematode Heligmosomoides polygyrus was lost when susceptible (C57BL/6) and resistant (Balb/c) strains of mice were housed together in indoor arenas with continuous transmission of the parasite larvae present in peat trays (Scott, 1991). First, both strains expressed their normal phenotype when given a controlled challenge while living in arenas, and when experimentally infected with only 5 parasite larvae. To test whether chronic exposure to peat altered the resistance phenotype, mice were given a challenge infection while living on peat. C57BL/6 mice living on peat had higher egg production and higher worm numbers than Balb/c mice, except at 2 months post-challenge. Finally, natural transmission rates were increased in arena experiments through either regular replacement of arena mice with naïve mice or direct introduction of additional larvae. A transient difference in infection levels between strains was detected in response to a modest increase in transmission whereas a 10-fold increase in transmission allowed C57BL/6 mice to exhibit the typical profile of high egg production and elevated worm numbers. These data indicate that C57BL/6 mice are less able to regulate parasite numbers at high transmission rates compared with lower transmission rates. PMID:16393368

  4. 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 ...

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

    E-print Network

    Mladenoff, David

    Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: Complement wasting disease Complement system Conditional logistic regression Prion Prnp Transmissible spongiform of complement C1q and prion protein (Prnp) genes and CWD infection in white-tailed deer from the CWD endemic

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

    PubMed Central

    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

    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

  7. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

    PubMed Central

    Chattopadhyay, Koushik

    2011-01-01

    Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals. PMID:22345983

  8. The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract.

    PubMed

    Delahaye-Sourdeix, Manon; Oliver, Javier; Timofeeva, Maria N; Gaborieau, Valérie; Johansson, Mattias; Chabrier, Amélie; Wozniak, Magdalena B; Brenner, Darren R; Vallée, Maxime P; Anantharaman, Devasena; Lagiou, Pagona; Holcátová, Ivana; Richiardi, Lorenzo; Kjaerheim, Kristina; Agudo, Antonio; Castellsagué, Xavier; Macfarlane, Tatiana V; Barzan, Luigi; Canova, Cristina; Thakker, Nalin S; Conway, David I; Znaor, Ariana; Healy, Claire M; Ahrens, Wolfgang; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Fabianova, Eleonora; Mates, Ioan Nicolae; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Curado, Maria Paula; Koifman, Sergio; Menezes, Ana; Wünsch-Filho, Victor; Eluf-Neto, José; Boffetta, Paolo; Garrote, Leticia Fernández; Serraino, Diego; Lener, Marcin; Jaworowska, Ewa; Lubi?ski, Jan; Boccia, Stefania; Rajkumar, Thangarajan; Samant, Tanuja A; Mahimkar, Manoj B; Matsuo, Keitaro; Franceschi, Silvia; Byrnes, Graham; Brennan, Paul; McKay, James D

    2015-01-01

    Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors. PMID:25793373

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

    PubMed Central

    Bowes, John; Budu-Aggrey, Ashley; Huffmeier, Ulrike; Uebe, Steffen; Steel, Kathryn; Hebert, Harry L.; Wallace, Chris; Massey, Jonathan; Bruce, Ian N.; Bluett, James; Feletar, Marie; Morgan, Ann W.; Marzo-Ortega, Helena; Donohoe, Gary; Morris, Derek W.; Helliwell, Philip; Ryan, Anthony W.; Kane, David; Warren, Richard B.; Korendowych, Eleanor; Alenius, Gerd-Marie; Giardina, Emiliano; Packham, Jonathan; McManus, Ross; FitzGerald, Oliver; McHugh, Neil; Brown, Matthew A.; Ho, Pauline; Behrens, Frank; Burkhardt, Harald; Reis, Andre; Barton, Anne

    2015-01-01

    Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8+ memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA. PMID:25651891

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

    PubMed Central

    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

    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

  11. Genetic background, and not ontogenetic effects, affects avian seasonal timing of reproduction.

    PubMed

    Gienapp, P; van Noordwijk, A J; Visser, M E

    2013-10-01

    Avian seasonal timing is a life-history trait with important fitness consequences and which is currently under directional selection due to climate change. To predict micro-evolution in this trait, it is crucial to properly estimate its heritability. Heritabilities are often estimated from pedigreed wild populations. As these are observational data, it leaves the possibility that the resemblance between related individuals is not due to shared genes but to ontogenetic effects; when the environment for the offspring provided by early laying pairs differs from that by late pairs and the laying dates of these offspring when they reproduce themselves is affected by this environment, this may lead to inflated heritability estimates. Using simulation studies, we first tested whether and how much such an early environmental effect can inflate heritability estimates from animal models, and we showed that pedigree structure determines by how much early environmental effects inflate heritability estimates. We then used data from a wild population of great tits (Parus major) to compare laying dates of females born early in the season in first broods and from sisters born much later, in second broods. These birds are raised under very different environmental conditions but have the same genetic background. The laying dates of first and second brood offspring do not differ when they reproduce themselves, clearly showing that ontogenetic effects are very small and hence, family resemblance in timing is due to genes. This finding is essential for the interpretation of the heritabilities reported from wild populations and for predicting micro-evolution in response to climate change. PMID:23837446

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

    PubMed Central

    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

    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

  13. Genetic Polymorphism of Folate and Methionine Metabolizing Enzymes and their Susceptibility to Malignant Lymphoma

    Microsoft Academic Search

    EMMAD EZZAT HABIB; MONA AZIZ; MAGD KOTB

    2005-01-01

    Background: Folate and methionine metabolism is involved in DNA synthesis and methylation. Polymor- phisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In the present study, 2 polymorphisms were evaluated for a folate met- abolic enzyme, methylene-tetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms MTHFR 677 C?T

  14. Association of pre-microRNAs genetic variants with susceptibility in systemic lupus erythematosus

    Microsoft Academic Search

    Junlong Zhang; Bin Yang; Binwu Ying; Dongdong Li; Yunying Shi; Xingbo Song; Bei Cai; Zhuochun Huang; Yongkang Wu; Lanlan Wang

    2011-01-01

    MicroRNAs (miRNAs) may play important roles in SLE, but genetic polymorphisms of miRNAs and their relationships with various\\u000a autoantibodies present in SLE patients remain unclear. Here, we report that 213 SLE patients and 209 healthy individuals of\\u000a Chinese had been taken into this case–control studies, which had been performed by selecting two miRNAs (hsa-mir-146a rs2910164\\u000a G>C, and hsa-mir-499 rs3746444 T>C)

  15. The role of genetic breast cancer susceptibility variants as prognostic factors

    PubMed Central

    Fasching, Peter A.; Pharoah, Paul D.P.; Cox, Angela; Nevanlinna, Heli; Bojesen, Stig E.; Karn, Thomas; Broeks, Annegien; van Leeuwen, Flora E.; van 't Veer, Laura J.; Udo, Renate; Dunning, Alison M.; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Shah, Mitul; Nordestgaard, Børge G.; Flyger, Henrik; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Garcia-Closas, Montserrat; Sherman, Mark; Lissowska, Jolanta; Seynaeve, Caroline; Huijts, Petra E.A.; Tollenaar, Rob A.E.M.; Ziogas, Argyrios; Ekici, Arif B.; Rauh, Claudia; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna-Marie; Glendon, Gord; Hall, Per; Czene, Kamila; Liu, Jianjun; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Nickels, Stefan; Dörk, Thilo; Schiekel, Maria; Bremer, Michael; Park-Simon, Tjoung-Won; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Hooning, Maartje J.; Martens, John W.M.; Jager, Agnes; Kriege, Mieke; Lindblom, Annika; Margolin, Sara; Couch, Fergus J.; Stevens, Kristen N.; Olson, Janet E.; Kosel, Matthew; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W.R.; Miron, Alexander; John, Esther M.; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Chenevix-Trench, Georgia; Lambrechts, Diether; Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik; Benitez, Javier; Milne, Roger L.; Zamora, M. Pilar; Pérez, José Ignacio Arias; Bonanni, Bernardo; Peissel, Bernard; Loris, Bernard; Peterlongo, Paolo; Rajaraman, Preetha; Schonfeld, Sara J.; Anton-Culver, Hoda; Devilee, Peter; Beckmann, Matthias W.; Slamon, Dennis J.; Phillips, Kelly-Anne; Figueroa, Jonine D.; Humphreys, Manjeet K.; Easton, Douglas F.; Schmidt, Marjanka K.

    2012-01-01

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09–1.35, P=0.0002 and HR=1.29; 95% CI: 1.12–1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. PMID:22532573

  16. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5).

    PubMed

    Walters, Dianne M; White, Kevin M; Patel, Ushma; Davis, Martin J; Veluci-Marlow, Roberta M; Bhupanapadu Sunkesula, Solomon Raju; Bonner, James C; Martin, Jessica R; Gladwell, Wes; Kleeberger, Steven R

    2014-03-01

    Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, and steel alloys. Pulmonary responses to V2O5, including dose-dependent increases in lung permeability, inflammation, collagen content, and dysfunction, were significantly greater in DBA/2J mice compared to C57BL/6J mice. Inflammatory and fibrotic responses persisted for 4 mo in DBA/2J mice, while limited responses in C57BL/6J mice resolved. We investigated the genetic basis for differential responses through genetic mapping of V2O5-induced lung collagen content in BXD recombinant inbred (RI) strains and identified significant linkage on chromosome 4 with candidate genes that associate with V2O5-induced collagen content across the RI strains. Results suggest that V2O5 may induce pulmonary fibrosis through mechanisms distinct from those in other models of pulmonary fibrosis. These findings should further advance our understanding of mechanisms involved in ILD and thereby aid in identification of new therapeutic targets. PMID:24285090

  17. 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 ...

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

    PubMed

    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

    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

  19. Protective effect of isoprinosine in genetically susceptible BALB/c mice infected with Leishmania major.

    PubMed Central

    Cillari, E; Dieli, M; Lo Campo, P; Sireci, G; Caffarelli, A; Maltese, E; Millott, S; Milano, S; Liew, F Y

    1991-01-01

    The effects of an immunopotentiating drug Inosine Pranobex (isoprinosine) were investigated in an experimental cutaneous leishmaniasis model. The highly susceptible BALB/c mice treated orally with isoprinosine developed significantly delayed onset of disease when infected with Leishmania major compared to untreated mice. The drug itself is not toxic to the parasite up to millimolar levels in vitro. The increase in resistance to L. major infection is accompanied by a marked decrease in the CD4+/CD8+ ratio and the leishmanial antigen-specific proliferative response of the spleen cells of isoprinosine-treated mice compared to untreated mice. There was a significant increase in the production of IFN-gamma but a decrease in the secretion of IL-3 and IL-4 by the spleen cells of isoprinosine-treated mice in response to concanavalin A with or without L. major infection compared to untreated controls. There was, however, no significant difference in the level of IL-2 production by the spleen cells between mice with or without isoprinosine treatment. These data are consistent with the interpretation that isoprinosine potentiates the resistance to leishmanial infection by up-regulating the host-protective Th1 cells and down-regulating the disease-promoting Th2 cells or, alternatively, by increasing CD8+ T-cell function. PMID:1718853

  20. Acetylation genotype and the genetic susceptibility to prostate cancer in a southern European population

    Microsoft Academic Search

    Sandra Costa; Daniela Pinto; Antonio Morais; André Vasconcelos; Jorge Oliveira; Carlos Lopes; Rui Medeiros

    2005-01-01

    BACKGROUND. Epidemiologic studies have suggested that environmental factors and diet are important risk factors in the pathogenesis of prostate cancer. The N-acetyltransferases (NAT) are important enzymes in activation and inactivation of various carcinogens, including those found in well-cooked meat and cigarette smoke. METHODS. We analyzed DNA samples from 146 prostate cancer patients and 174 healthy men. We used PCR-RFLP method

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

    Microsoft Academic Search

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

    2006-01-01

    BACKGROUND: DBA\\/2J (D2) mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP) and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s) are necessary for the distinct

  2. Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility

    PubMed Central

    Qureshi, Irfan A.; Mehler, Mark F.

    2015-01-01

    There are numerous examples of sex differences in brain and behavior and in susceptibility to a broad range of brain diseases. For example, gene expression is sexually dimorphic during brain development, adult life, and aging. These differences are orchestrated by the interplay between genetic, hormonal, and environmental influences. However, the molecular mechanisms that underpin these differences have not been fully elucidated. Because recent studies have highlighted the key roles played by epigenetic processes in regulating gene expression and mediating brain form and function, this chapter reviews emerging evidence that shows how epigenetic mechanisms including DNA methylation, histone modifications, and chromatin remodeling, and non-coding RNAs (ncRNAs) are responsible for promoting sexual dimorphism in the brain. Differential profiles of DNA methylation and histone modifications are found in dimorphic brain regions such as the hypothalamus as a result of sex hormone exposure during developmental critical periods. The elaboration of specific epigenetic marks is also linked with regulating sex hormone signaling pathways later in life. Furthermore, the expression and function of epigenetic factors such as the methyl-CpG-binding protein, MeCP2, and the histone-modifying enzymes, UTX and UTY, are sexually dimorphic in the brain. ncRNAs are also implicated in promoting sex differences. For example, X inactivation-specific transcript (XIST) is a long ncRNA that mediates X chromosome inactivation, a seminal developmental process that is particularly important in brain. These observations imply that understanding epigenetic mechanisms, which regulate dimorphic gene expression and function, is necessary for developing a more comprehensive view of sex differences in brain. These emerging findings also suggest that epigenetic mechanisms are, in part, responsible for the differential susceptibility between males and females that is characteristic of a spectrum of neurological and psychiatric disorders. PMID:21094887

  3. HSD3B and Gene-Gene Interactions in a Pathway-Based Analysis of Genetic Susceptibility to Bladder Cancer

    PubMed Central

    Andrew, Angeline S.; Hu, Ting; Gu, Jian; Gui, Jiang; Ye, Yuanqing; Marsit, Carmen J.; Kelsey, Karl T.; Schned, Alan R.; Tanyos, Sam A.; Pendleton, Eben M.; Mason, Rebecca A.; Morlock, Elaine V.; Zens, Michael S.; Li, Zhongze; Moore, Jason H.; Wu, Xifeng; Karagas, Margaret R.

    2012-01-01

    Bladder cancer is the 4th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case–control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3?UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31–2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06–12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40–3.25) than females (OR 1.56 95%CI 0.83–2.95), (SNP-gender interaction P?=?0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P?=?0.0003). The fact that bladder cancer incidence is 3–4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis. PMID:23284679

  4. Genetic basis of differences in myxospore count between whirling disease-resistant and -susceptible strains of rainbow trout

    USGS Publications Warehouse

    Fetherman, Eric R.; Winkelman, Dana L.; Schisler, George J.; Antolin, Michael F.

    2012-01-01

    We used a quantitative genetics approach and estimated broad sense heritability (h2b) of myxospore count and the number of genes involved in myxospore formation to gain a better understanding of how resistance to Myxobolus cerebralis, the parasite responsible for whirling disease, is inherited in rainbow trout Oncorhynchus mykiss. An M. cerebralis-resistant strain of rainbow trout, the German Rainbow (GR), and a wild, susceptible strain of rainbow trout, the Colorado River Rainbow (CRR), were spawned to create 3 intermediate crossed populations (an F1 cross, F2 intercross, and a B2 backcross between the F1 and the CRR). Within each strain or cross, h2b was estimated from the between-family variance of myxospore counts using full-sibling families. Estimates of h2b and average myxospore counts were lowest in the GR strain, F1 cross, and F2 intercross (h2b = 0.34, 0.42, and 0.34; myxospores fish?1 = 275, 9566, and 45780, respectively), and highest in the B2 backcross and CRR strain (h2b = 0.93 and 0.89; myxospores fish?1 = 97865 and 187595, respectively). Comparison of means and a joint-scaling test suggest that resistance alleles arising from the GR strain are dominant to susceptible alleles from the CRR strain. Resistance was retained in the intermediate crosses but decreased as filial generation number increased (F2) or backcrossing occurred (B2). The estimated number of segregating loci responsible for differences in myxospore count in the parental strains was 9 ± 5. Our results indicate that resistance to M. cerebralis is a heritable trait within these populations and would respond to either artificial selection in hatcheries or natural selection in the wild.

  5. Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants.

    PubMed

    Duan, Jubao; Sanders, Alan R; Moy, Winton; Drigalenko, Eugene I; Brown, Eric C; Freda, Jessica; Leites, Catherine; Göring, Harald H H; Gejman, Pablo V

    2015-08-15

    We searched a gene expression dataset comprised of 634 schizophrenia (SZ) cases and 713 controls for expression outliers (i.e., extreme tails of the distribution of transcript expression values) with SZ cases overrepresented compared with controls. These outlier genes were enriched for brain expression and for genes known to be associated with neurodevelopmental disorders. SZ cases showed higher outlier burden (i.e., total outlier events per subject) than controls for genes within copy number variants (CNVs) associated with SZ or neurodevelopmental disorders. Outlier genes were enriched for CNVs and for rare putative regulatory variants, but this only explained a small proportion of the outlier subjects, highlighting the underlying presence of additional genetic and potentially, epigenetic mechanisms. PMID:26022996

  6. Predictive impact of genetic polymorphisms in DNA repair genes on susceptibility and therapeutic outcomes to colorectal cancer patients.

    PubMed

    Sun, Kang; Gong, Aixia; Liang, Pin

    2015-03-01

    Several hereditary syndromes characterized by defective DNA repair are associated with high risk of colorectal cancer (CRC). To explore whether common polymorphisms in DNA repair genes affect risk and prognosis of CRC, we evaluated the association between single nucleotide polymorphisms (SNPs) in XPG, XPC, and WRN gene and susceptibility of CRC, and clinical outcomes in a population-based case-control study. A total of 890 CRC cases and 910 controls recruited into the study provided a biologic sample. Individuals with variant genotypes of XPC Ala499Val appeared to be associated with the increased risk of CRC. WRN Cys1367Arg variants carriers showed an increased susceptibility for CRC. More importantly, the risk of CRC increased further in a combined analysis of multiple polymorphisms. Furthermore, stratified analyses revealed that XPG Arg1104His polymorphism was associated with tumor differentiation of CRC patients (P?=?0.043). Log-rank test and adjusted multivariate Cox regression analysis verified that XPG Arg1104His variants were associated with a longer disease-free survival (DFS) [CG genotype: adjusted HR (95% confidence interval (CI))?=?0.163 (0.107-0.248), P?genetic variation in DNA repair genes involved in susceptibility for CRC and therapeutic outcomes in response to oxaliplatin-based chemotherapy. PMID:25355595

  7. Identity-by-descent approaches identify regions of importance for genetic susceptibility to hereditary esophageal squamous cell carcinoma.

    PubMed

    Ko, Josephine My; Zhang, Peng; Law, Simon; Fan, Yanhui; Song, You-Qiang; Zhao, Xue Ke; Wong, Elibe H W; Tang, Sa; Song, Xin; Lung, Maria Li; Wang, Li Dong

    2014-08-01

    Worldwide, the highest prevalence of esophageal cancer (EC) occurs in Northern China. High-density SNP arrays allow identification of identity-by-descent (IBD) segments in genomic DNAs representative of shared common ancestral regions. We utilized IBD approaches to map susceptibility loci associated with low-penetrance SNPs in high-risk Henan hereditary esophageal squamous cell carcinoma (ESCC) patients. Affymetrix GeneChip Human mapping SNP array IBD analysis was performed in 32 Henan family history-positive (FH+) ESCC patients, 18 Henan healthy unrelated individuals, and 45 Chinese individuals from a CHB HapMap dataset using PLink (scoring IBD segments individually) and Beagle (scoring of shared IBD segments among case/case vs. control/control pairs) software. Both analyses identified longer IBD segment lengths associated with FH+ ESCC compared to controls. However, there was no strong evidence for a genetic founder effect. Pairing IBD analysis with BEAGLE identified 8 critical IBD segments residing at 2q32.1-q32.2, 3p22.3-p22.2, 4q21.1-q21.21, 7p22.2, 8q23.2-q23.3, 10q23.33-q24.1, 14q24.3 and 16q11.2-q12.1, which were more significantly shared among case/case compared to control/control. The shared IBD segments in FH+ ESCC samples with no overlap with control/CHB Hapmap may encompass potential cancer susceptibility loci. Selected targeted genes, PLCE1, GPT2, SIAH1 and CYP2C-18, residing within the IBD segments at 10q23.33-q24.1 and 16q11.2-q12.1, had statistically significant differential expression in primary ESCC tissues and are likely involved in ESCC carcinogenesis. The importance of these IBD segments to the etiology and development of ESCC in high-risk areas requires further study with expanded sample sizes. This is the first report employing the pairing IBD approach for elucidation of the genetic basis of hereditary ESCC in Henan by applying high throughput SNP array analysis. PMID:24890309

  8. A high-density collection of EMS-induced mutations for TILLING in Landsberg erecta genetic background of Arabidopsis

    PubMed Central

    2009-01-01

    Background Arabidopsis thaliana is the main model species for plant molecular genetics studies and world-wide efforts are devoted to identify the function of all its genes. To this end, reverse genetics by TILLING (Targeting Induced Local Lesions IN Genomes) in a permanent collection of chemically induced mutants is providing a unique resource in Columbia genetic background. In this work, we aim to extend TILLING resources available in A. thaliana by developing a new population of ethyl methanesulphonate (EMS) induced mutants in the second commonest reference strain. In addition, we pursue to saturate the number of EMS induced mutations that can be tolerated by viable and fertile plants. Results By mutagenizing with different EMS concentrations we have developed a permanent collection of 3712 M2/M3 independent mutant lines in the reference strain Landsberg erecta (Ler) of A. thaliana. This population has been named as the Arabidopsis TILLer collection. The frequency of mutations per line was maximized by using M1 plants with low but sufficient seed fertility. Application of TILLING to search for mutants in 14 genes identified 21 to 46 mutations per gene, which correspond to a total of 450 mutations. Missense mutations were found for all genes while truncations were selected for all except one. We estimated that, on average, these lines carry one mutation every 89 kb, Ler population providing a total of more than five million induced mutations. It is estimated that TILLer collection shows a two to three fold higher EMS mutation density per individual than previously reported A. thaliana population. Conclusions Analysis of TILLer collection demonstrates its usefulness for large scale TILLING reverse genetics in another reference genetic background of A. thaliana. Comparisons with TILLING populations in other organisms indicate that this new A. thaliana collection carries the highest chemically induced mutation density per individual known in diploid species. PMID:20003424

  9. Effects of genetic background and environment on QTLs and epistasis for rice (Oryza sativa L.) panicle number

    Microsoft Academic Search

    C. Y. Liao; P. Wu; B. Hu; K. K. Yi

    2001-01-01

    A double-haploid (DH) population and a recombinant inbred (RI) line population, derived from a cross between a tropical japonica variety, Azucena, as male parent and two indica varieties, IR64 and IR1552, as female parents respectively, were used in both field and pot experiments for detecting QTLs\\u000a and epistasis for rice panicle number in different genetic backgrounds and different environments. Panicle

  10. Elucidation of Genetic Backgrounds Necessary for Chlorophyll a Biosynthesis Toward Artificial Creation of Oxygenic Photosynthesis

    NASA Astrophysics Data System (ADS)

    Tsukatani, Yusuke; Masuda, Shinji

    2015-05-01

    We succeeded to create the genetically modified purple photosynthetic bacterium capable of synthesizing chlorophyll a. The results indicate that not only chlorophyll synthase, but also an enzyme for galactolipid synthesis and reaction center proteins are required for accumulating chlorophyll a.

  11. Interaction between arsenic exposure from drinking water and genetic susceptibility in carotid intima-media thickness in Bangladesh.

    PubMed

    Wu, Fen; Jasmine, Farzana; Kibriya, Muhammad G; Liu, Mengling; Cheng, Xin; Parvez, Faruque; Paul-Brutus, Rachelle; Paul, Rina Rani; Sarwar, Golam; Ahmed, Alauddin; Jiang, Jieying; Islam, Tariqul; Slavkovich, Vesna; Rundek, Tatjana; Demmer, Ryan T; Desvarieux, Moise; Ahsan, Habibul; Chen, Yu

    2014-05-01

    Epidemiologic studies that evaluated genetic susceptibility for the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima-media thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (? 40.4 ?g/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9 ?m (95% CI = 14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (? = -5.1 ?m, 95% CI = -31.6, 21.3) or arsenic exposure alone (? = 7.2 ?m, 95% CI = -3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to the proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings. PMID:24593923

  12. Interaction between arsenic exposure from drinking water and genetic susceptibility in carotid intima-media thickness in Bangladesh

    PubMed Central

    Wu, Fen; Jasmine, Farzana; Kibriya, Muhammad G.; Liu, Mengling; Cheng, Xin; Parvez, Faruque; Paul-Brutus, Rachelle; Islam, Tariqul; Paul, Rina Rani; Sarwar, Golam; Ahmed, Alauddin; Jiang, Jieying; Islam, Tariqul; Slavkovich, Vesna; Rundek, Tatjana; Demmer, Ryan T.; Desvarieux, Moise; Ahsan, Habibul; Chen, Yu

    2014-01-01

    Epidemiologic studies that evaluated genetic susceptibility to the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1,078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima-medial thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (? 40.4 ?g/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9 ?m (95% CI = 14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (? = -5.1 ?m, 95% CI = -31.6, 21.3) or arsenic exposure alone (? = 7.2 ?m, 95% CI = -3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings. PMID:24593923

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

    PubMed Central

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

    2014-01-01

    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

  14. A genetic background for reintroduction program of the European bison ( Bison bonasus) in the Carpathians

    Microsoft Academic Search

    Wanda Olech; Kajetan Perzanowski

    2002-01-01

    The European bison, extirpated from the Carpathian Mountains over 200 years ago, was reintroduced to the Bieszczady Mountains in the 1960\\/1970s in two small, isolated herds, and is now threatened by high inbreeding and low genetic variability. A new program of re-establishing viable populations in the Carpathians is based on the genetic analysis of formerly released animals, using the European

  15. Genetic background of skin barrier dysfunction in the pathogenesis of psoriasis vulgaris

    PubMed Central

    Szczerkowska-Dobosz, Aneta; R?ba?a, Krzysztof; Purzycka-Bohdan, Dorota

    2015-01-01

    Psoriasis is a common inflammatory skin disease. It is known to be a complex condition with multifactorial mode of inheritance, however the associations between particular pathogenic pathways remain unclear. A novel report on the pathogenesis of psoriasis has recently included the genetic determination of the skin barrier dysfunction. In this paper, we focus on specific genetic variants associated with formation of the epidermal barrier and their role in the complex pathogenesis of the disease. PMID:26015782

  16. Paraoxonase-1 genetic polymorphisms and susceptibility to DNA damage in workers occupationally exposed to organophosphate pesticides

    SciTech Connect

    Singh, Satyender [Division of Biochemistry and Biotechnology, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054 (India); Kumar, Vivek [Environmental Biochemistry and Molecular Biology laboratory, Department of Biochemistry, University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi-110095 (India); Thakur, Sachin [Division of Biochemistry and Biotechnology, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054 (India); Presently at, Department of Biochemistry, University of Texas Health Science Center at San Antonio (UTHSCSA), 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Banerjee, Basu Dev [Environmental Biochemistry and Molecular Biology laboratory, Department of Biochemistry, University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi-110095 (India); Rautela, Rajender Singh; Grover, Shyam Sunder; Rawat, Devendra Singh [Division of Biochemistry and Biotechnology, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054 (India); Pasha, Syed Tazeen [National Programme for Prevention and Control of Fluorosis, DGHS, Ministry of Health and Family Welfare, Government of India, Nirman Bhavan, New Delhi 110011 (India); Jain, Sudhir Kumar [Centre for Epidemiology and Parasitic Diseases, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054 (India); Ichhpujani, Rattan Lal [Division of Biochemistry and Biotechnology, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054 (India); National Programme for Prevention and Control of Fluorosis, DGHS, Ministry of Health and Family Welfare, Government of India, Nirman Bhavan, New Delhi 110011 (India); Rai, Arvind, E-mail: arvindrai.nicd@gmail.com [Division of Biochemistry and Biotechnology, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054 (India)

    2011-04-15

    Human paraoxonase 1 (PON1) is a lipoprotein-associated enzyme involved in the detoxification of organophosphate pesticides (OPs) by hydrolyzing the bioactive oxons. Polymorphisms of the PON1 gene are responsible for variation in the expression and catalytic activity of PON1 enzyme. In the present study, we have determined (a) the prevalence of two common PON1 polymorphisms, (b) the activity of PON1 and acetylcholinesterase enzymes, and (c) the influence of PON1 genotypes and phenotypes variation on DNA damage in workers exposed to OPs. We examined 230 subjects including 115 workers exposed to OPs and an equal number of normal healthy controls. The results revealed that PON1 activity toward paraoxon (179.19 {+-} 39.36 vs. 241.52 {+-} 42.32 nmol/min/ml in controls) and phenylacetate (112.74 {+-} 17.37 vs. 134.28 {+-} 25.49 {mu}mol/min/ml in controls) was significantly lower in workers than in control subjects (p < 0.001). No significant difference was observed in the distribution of genotypes and allelic frequencies of PON1{sub 192}QR (Gln/Arg) and PON1{sub 55}LM (Leu/Met) in workers and control subjects (p > 0.05). The PON1 activity toward paraoxonase was found to be significantly higher in the R/R (Arg/Arg) genotypes than Q/R (Gln/Arg) and lowest in Q/Q (Gln/Gln) genotypes in both workers and control subjects (p < 0.001). For PON1{sub 55}LM (Leu/Met), PON1 activity toward paraoxonase was observed to be higher in individuals with L/L (Leu/Leu) genotypes and lowest in individuals with M/M (Met/Met) genotypes in both groups (p < 0.001). No influence of PON1 genotypes and phenotypes was seen on the activity of acetylcholinesterase and arylesterase. The DNA damage was observed to be significantly higher in workers than in control subjects (p < 0.05). Further, the individuals who showed least paraoxonase activity i.e., those with (Q/Q [Gln/Gln] and M/M [Met/Met]) genotypes showed significantly higher DNA damage compared to other isoforms in workers exposed to OPs (p < 0.05). The results indicate that the individuals with PON1 Q/Q and M/M genotypes are more susceptible toward genotoxicity. In conclusion, the study suggests wide variation in enzyme activities and DNA damage due to polymorphisms in PON1 gene, which might have an important role in the identification of individual risk factors in workers occupationally exposed to OPs.

  17. Role of genetic susceptibility in development of treatment-related adverse outcomes in cancer survivors.

    PubMed

    Bhatia, Smita

    2011-10-01

    Clear and unambiguous associations have been established between therapeutic exposures and specific complications. However, considerable interindividual variability is observed in the risk of developing an outcome for a given therapeutic exposure. Genetic predisposition and especially its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems, and can possibly explain the interindividual variability. This article provides a brief overview of the current knowledge about the role of genomic variation in the development of therapy-related complications. Relatively common outcomes with strong associations with therapeutic exposures, including cardiomyopathy, obesity, osteonecrosis, ototoxicity, and subsequent malignancies are discussed here. To develop a deeper understanding of the molecular underpinnings of therapy-related complications, comprehensive and near-complete collection of clinically annotated samples is critical. Methodologic issues such as study design, definition of the endpoints or phenotypes, identification of appropriate and adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, and selection of an appropriate approach or platform for genotyping are also discussed. Understanding the etiopathogenetic pathways that lead to the morbidity is critical to developing targeted prevention and intervention strategies, optimizing risk-based health care of cancer survivors, thus minimizing chronic morbidities and improving quality of life. PMID:21980013

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

    PubMed

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

    2012-04-23

    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

  19. BRIP1 variations analysis reveals their relative importance as genetic susceptibility factor for cervical cancer.

    PubMed

    Ma, X D; Cai, G Q; Zou, W; Huang, Y H; Zhang, J R; Wang, D T; Chen, B L

    2013-04-01

    To evaluate the association between gene variations in BRIP1 (BRCA1-interacting protein 1) and the risk of cervical cancer, we examined eight single nucleotide polymorphisms (SNPs: rs2048718, rs12937080, rs4988344, rs6504074, rs4988345, rs4986764, rs4986763, and rs11079454) in the BRIP1 gene in cervical tissue from a Chinese population using the MassARRAY system. The participants enrolled included 454 cervical cancer patients and 562 healthy controls. Quantitative real-time reverse transcription PCR (qRT-PCR) was performed to examine the potential correlation between functional BRIP1 SNP genotypes and mRNA levels in cervical cancer tissues. Our results first showed that rs4986764, located in exon 18 in the BRIP1 gene, was significantly associated with cervical cancer (?(2)=11.191, P=0.001, odds ratio (OR)=1.384, 95% confidence interval (CI)=1.144-1.675). Another significant association was observed for rs4986763 located in exon 20 in BRIP1 (?(2)=4.988, P=0.026, OR=1.241, 95% CI=1.027-1.500). Strong linkage disequilibrium was observed in the rs11079454-rs4986763-rs4986764 SNP block (D'>0.9). The frequencies of haplotype T-T-T are higher in controls than in these patients (P=2.01E-5). Moreover, cervical cancer tissues with a homozygous C/C genotype for rs4986764 had the lowest level of BRIP1, which was 2.8 and 2.9-fold lower than the C/T heterozygote and the T/T homozygote, respectively. These findings indicate a role for BRIP1 gene variations in cervical cancer and may be informative for future genetic or biological studies on cervical cancer. PMID:23473757

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

    SciTech Connect

    Bedford, Joel

    2014-04-18

    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.

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

    PubMed

    Banks, Gareth; Heise, Ines; Starbuck, Becky; Osborne, Tamzin; Wisby, Laura; Potter, Paul; Jackson, Ian J; Foster, Russell G; Peirson, Stuart N; Nolan, Patrick M

    2015-01-01

    The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep. PMID:25179226

  2. Genetic variation at the TNF-alpha promoter and malaria susceptibility in rhesus (Macaca mulatta) and long-tailed (Macaca fascicularis) macaques.

    PubMed

    Flynn, Shannon; Satkoski, Jessica; Lerche, Nicholas; Kanthaswamy, Sreetharan; Smith, David Glenn

    2009-09-01

    Polymorphisms within the promoter region of the TNF-alpha gene have been associated with altered expression of TNF-alpha and susceptibility to a variety of diseases in humans. Although macaques (Macaca spp.) are frequently used as models to study human diseases, little is known about the extent of genetic variation at the TNF-alpha locus and its consequences for disease susceptibility in these species. The TNF-alpha promoter region was sequenced in a sample of 40 macaques including five M. mulatta of Chinese and Indian ancestry and 35 M. fascicularis of Malaysian, Mauritian, Indonesian, and Philippine ancestry. These groups were chosen because they exhibit differences in their susceptibilities to severe malaria upon infection with Plasmodium parasites. Sequence analysis revealed a total of 14 single nucleotide polymorphisms (SNPs), five of which are newly described, and 20 unique haplotypes. In addition, the TFSEARCH program was used to investigate the potential of these polymorphisms to influence transcription factor binding. While both species exhibited a similarly high degree of genetic variability at the TNF-alpha promoter, AMOVA analysis and FST values indicated that most of the variation is shared between species and among populations. However, two of the most common haplotypes, describing 31.7% of the observed variation, and three potentially functional polymorphisms at positions -781, -535, and -10, were exclusive to M. fascicularis. Polymorphisms in the human ortholog of the TNF-alpha promoter which are known to be associated with malaria susceptibility in humans were not shared with macaques. PMID:19570728

  3. Genetic basis of the effects of ultraviolet light B on cutaneous immunity. Evidence that polymorphism at the Tnfa and Lps loci governs susceptibility

    Microsoft Academic Search

    Takeshi Yoshikawa; J. Wayne Streilein

    1990-01-01

    The ability of local ultraviolet B (UVB) irradiation to impair the induction of dinitrofluorobenzene (DNFB)-specific contact hypersensitivity (CH) in mice has been shown to be genetically determined. We have explored the possibility that the mouse Tnfa and Lps loci are involved. We demonstrate that C3H\\/HeN (Lpsn strains are UVB-susceptible, whereas C3H\\/HeJ (Lpsd) strains are UVB-resistant. Our results indicate that local

  4. Incorporating Biomarkers of Exposure and Genetic Susceptibility Into Smoking Cessation Treatment: Effects on Smoking-Related Cognitions, Emotions, and Behavior Change

    Microsoft Academic Search

    Caryn Lerman; Karen Gold; Janet Audrain; Ting Hsiang Lin; Neal R. Boyd; C. Tracy Orleans; Ben Wilfond; Greg Louben; Neil Caporaso

    1997-01-01

    In this article the authors report on the short-term impact of incorporating biomarker feedback about exposure and genetic susceptibility into minimal-contact quit-smoking counseling (QSC). Four hundred and twenty-seven smokers were randomized to 1 of 3 treatments: (a) QSC, (b) QSC + exposure biomarker feedback (EBF) about carbon monoxide in exhaled breath, or (b) QSC + EBF + biomarker feedback about

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

    Microsoft Academic Search

    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

    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

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

    PubMed Central

    2014-01-01

    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

  7. Influence of Genetic Background on Anthocyanin and Co-Pigment Profile and Stability of Colored Corn 

    E-print Network

    Collison, Amy Elizabeth

    2014-08-05

    stability of several experimental hybrid varieties of corn from four phenotypes (red, purple, blue, and red/blue). The goal was to determine if genetics/phenotype can be utilized to selectively breed for pigmented corn lines with greater stability during...

  8. Brain immune responses cognitive decline and dementia: relationship with phenotype expression and genetic background

    Microsoft Academic Search

    Federico Licastro; Martina Chiappelli

    2003-01-01

    Alzheimer's disease (AD) is a progressive degenerative disease of the brain and the most frequent cause of dementia among elderly. The etiology of AD is still obscure, but genetic and environmental factors appear to play differential roles in the disease. Several evidence suggest that inflammation or altered immune responses may play an important role in this disease. The following topics

  9. Elucidation of Genetic Backgrounds Necessary for Chlorophyll a Biosynthesis Toward Artificial Creation of Oxygenic Photosynthesis.

    PubMed

    Tsukatani, Yusuke; Masuda, Shinji

    2015-09-01

    We succeeded to create the genetically modified purple photosynthetic bacterium capable of synthesizing chlorophyll a. The results indicate that not only chlorophyll synthase, but also an enzyme for galactolipid synthesis and reaction center proteins are required for accumulating chlorophyll a. PMID:26021277

  10. Chronic pain and genetic background interact and influence opioid analgesia, tolerance, and physical dependence

    Microsoft Academic Search

    De-Yong Liang; TianZi Guo; Guochun Liao; Wade S. Kingery; Gary Peltz; J. David Clark

    2006-01-01

    Opioids are commonly used in the treatment of moderate to severe pain. However, their chronic use is limited by analgesic tolerance and physical dependence. Few studies have examined how chronic pain affects the development of tolerance or dependence, and essentially no studies have looked at the role of both genetics and pain together. For these studies we used 12 strains

  11. In Vitro Matured Oocytes Are More Susceptible than In Vivo Matured Oocytes to Mock ICSI Induced Functional and Genetic Changes

    PubMed Central

    Salian, Sujit Raj; Singh, Vikram Jeet; Kalthur, Guruprasad; Adiga, Satish Kumar

    2015-01-01

    Background Concerns regarding the safety of ICSI have been intensified recently due to increased risk of birth defects in ICSI born children. Although fertilization rate is significantly higher in ICSI cycles, studies have failed to demonstrate the benefits of ICSI in improving the pregnancy rate. Poor technical skill, and suboptimal in vitro conditions may account for the ICSI results however, there is no report on the effects of oocyte manipulations on the ICSI outcome. Objective The present study elucidates the influence of mock ICSI on the functional and genetic integrity of the mouse oocytes. Methods Reactive Oxygen Species (ROS) level, mitochondrial status, and phosphorylation of H2AX were assessed in the in vivo matured and IVM oocytes subjected to mock ICSI. Results A significant increase in ROS level was observed in both in vivo matured and IVM oocytes subjected to mock ICSI (P<0.05-0.001) whereas unique mitochondrial distribution pattern was found only in IVM oocytes (P<0.01-0.001). Importantly, differential H2AX phosphorylation was observed in both in vivo matured and IVM oocytes subjected to mock ICSI (P <0.001). Conclusion The data from this study suggests that mock ICSI can alter genetic and functional integrity in oocytes and IVM oocytes are more vulnerable to mock ICSI induced changes. PMID:25786120

  12. The SDF-1?3?A Genetic Variation Is Correlated with Susceptibility of Asthma in Iranian Patients

    PubMed Central

    Rafatpanah, Houshang; Ghasemshirazi, Mohsen; Kazemiarababadi, Mohammad; Khorramdelazad, Hossein; Abousaidi, Hamid; Shabani, Ziba; Sayadi, Ahmadreza; Hassanshahi, Gholamhossein; Samadi, Jamile

    2013-01-01

    Background and Aim. Chemokine/receptor axis is a predominant actor of clinical disorders. They are key factors of pathogenesis of almost all clinical situations including asthma. Correspondingly, CXCL12 is involved in the immune responses. Therefore, this study was designed to explore the association between gene polymorphism at position +801 of CXCL12, known as SDF-1?3?A, and susceptibility to asthma in Iranian patients. Material and Methods. In this experimental study, samples were taken from 162 asthma patients and 189 healthy controls on EDTA. DNA was extracted and analyzed for CXCL12 polymorphisms using PCR-RLFP. The demographic information was also collected in parallel with the experimental part of the study by a questionnaire which was designed specifically for this study. Findings. Our results indicated a significant difference (P < 0.0001) between the A/A, A/G, and G/G genotypes and A and G alleles of polymorphisms at position +801 of CXCL12. We also showed an elevated level of CXCL12 circulating level in Iranian asthma patients. Conclusion. Our findings suggest that SDF-1?3?A (CXCL12) polymorphism plays a role in pathogenesis of asthma. It can also be concluded that circulatory level of CXCL12 presumably can be used as one of the pivotal biological markers in diagnosis of asthma. PMID:24024210

  13. Persistence Criteria for Susceptibility Genes for Schizophrenia: a Discussion from an Evolutionary Viewpoint

    Microsoft Academic Search

    Nagafumi Doi; Yoko Hoshi; Masanari Itokawa; Chie Usui; Takeo Yoshikawa; Hirokazu Tachikawa

    2009-01-01

    BackgroundThe central paradox of schizophrenia genetics is that susceptibility genes are preserved in the human gene-pool against a strong negative selection pressure. Substantial evidence of epidemiology suggests that nuclear susceptibility genes, if present, should be sustained by mutation-selection balance without heterozygote advantage. Therefore, putative nuclear susceptibility genes for schizophrenia should meet special conditions for the persistence of the disease as

  14. HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).

    PubMed

    Xu, Jianfeng; Lange, Ethan M; Lu, Lingyi; Zheng, Siqun L; Wang, Zhong; Thibodeau, Stephen N; Cannon-Albright, Lisa A; Teerlink, Craig C; Camp, Nicola J; Johnson, Anna M; Zuhlke, Kimberly A; Stanford, Janet L; Ostrander, Elaine A; Wiley, Kathleen E; Isaacs, Sarah D; Walsh, Patrick C; Maier, Christiane; Luedeke, Manuel; Vogel, Walther; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo; Schaid, Daniel; McDonnell, Shannon K; DeRycke, Melissa S; Cancel-Tassin, Geraldine; Cussenot, Olivier; Wiklund, Fredrik; Grönberg, Henrik; Eeles, Ros; Easton, Doug; Kote-Jarai, Zsofia; Whittemore, Alice S; Hsieh, Chih-Lin; Giles, Graham G; Hopper, John L; Severi, Gianluca; Catalona, William J; Mandal, Diptasri; Ledet, Elisa; Foulkes, William D; Hamel, Nancy; Mahle, Lovise; Moller, Pal; Powell, Isaac; Bailey-Wilson, Joan E; Carpten, John D; Seminara, Daniela; Cooney, Kathleen A; Isaacs, William B

    2013-01-01

    Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer. PMID:23064873

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

    PubMed Central

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

    2014-01-01

    Critically endangered breeds and populations are often crossed with more common breeds or subspecies. This results in genetic admixture that can be undesirable when it challenges the genetic integrity of wild and domestic populations, causing a loss in special characteristics or unique genetic material and ultimately extinction. Here, we present two genomic selection strategies, using genome-wide DNA markers, to recover the genomic content of the original endangered population from admixtures. Each strategy relies on the estimation of the proportion of nonintrogressed genome in individuals based on a different method: either genomic prediction or identification of breed-specific haplotypes. Then, breeding programs that remove introgressed genomic information can be designed. To test these strategies, we used empirical 50K SNP array data from two pure sheep breeds, Merino (used as target breed), Poll Dorset and an existing admixed population of both breeds. Sheep populations with varying degrees of introgression and admixture were simulated starting from these real genotypes. Both strategies were capable of identifying segment origin, and both removed up to the 100% of the Poll Dorset segments. While the selection process led to substantial inbreeding, we controlled it by imposing a minimum number of individuals contributing to the next generation. PMID:24567744

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

    PubMed Central

    Di Gaetano, Cornelia; Fiorito, Giovanni; Ortu, Maria Francesca; Rosa, Fabio; Guarrera, Simonetta; Pardini, Barbara; Cusi, Daniele; Frau, Francesca; Barlassina, Cristina; Troffa, Chiara; Argiolas, Giuseppe; Zaninello, Roberta; Fresu, Giovanni; Glorioso, Nicola; Piazza, Alberto; Matullo, Giuseppe

    2014-01-01

    The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods - fixation index, inflation factor, principal component analysis and ancestry estimation - we were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs>0.5 Mb (FRoH%0.5) when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces. PMID:24651212

  17. Sardinians genetic background explained by runs of homozygosity and genomic regions under positive selection.

    PubMed

    Di Gaetano, Cornelia; Fiorito, Giovanni; Ortu, Maria Francesca; Rosa, Fabio; Guarrera, Simonetta; Pardini, Barbara; Cusi, Daniele; Frau, Francesca; Barlassina, Cristina; Troffa, Chiara; Argiolas, Giuseppe; Zaninello, Roberta; Fresu, Giovanni; Glorioso, Nicola; Piazza, Alberto; Matullo, Giuseppe

    2014-01-01

    The peculiar position of Sardinia in the Mediterranean sea has rendered its population an interesting biogeographical isolate. The aim of this study was to investigate the genetic population structure, as well as to estimate Runs of Homozygosity and regions under positive selection, using about 1.2 million single nucleotide polymorphisms genotyped in 1077 Sardinian individuals. Using four different methods--fixation index, inflation factor, principal component analysis and ancestry estimation--we were able to highlight, as expected for a genetic isolate, the high internal homogeneity of the island. Sardinians showed a higher percentage of genome covered by RoHs>0.5 Mb (F(RoH%0.5)) when compared to peninsular Italians, with the only exception of the area surrounding Alghero. We furthermore identified 9 genomic regions showing signs of positive selection and, we re-captured many previously inferred signals. Other regions harbor novel candidate genes for positive selection, like TMEM252, or regions containing long non coding RNA. With the present study we confirmed the high genetic homogeneity of Sardinia that may be explained by the shared ancestry combined with the action of evolutionary forces. PMID:24651212

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

    PubMed

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

    2014-02-25

    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

  19. Effect of the genetic background on recombination frequency in the cn-vg region of the second chromosome of natural populations of Drosophila melanogaster.

    PubMed

    Hofmanová, J

    1975-01-01

    Newly established test stocks made it possible to follow the effect of three different defined genetic backgrounds (first and third chromosomes) on recombination frequency in the cn-vg region of the second chromosomes isolated from four natural populations of Drosophila melanogaster. One background was composed of the chromosomes with inversions obtained from the stock (see article) and another two backgrounds were of the standard type consisting one-half of the original chromosomes from the natural population and one-half of the chromosomes of the stocks Oregon R or Samarkand. Using the analysis of variance significant differences in RF values were found between and within populations and especially between the different backgrounds. Some simple and double interactions between the above factors played a role. The highest RF values were obtained on the background [corrected] with inversions. The effect of the different genetic backgrounds [corrected] by the action of the genetic modifiers of RF. The different genetic backgrounds affected the variations in RF values in individual populations and the different populations reacted differentially to the changed genetic background. The design of the experiment permitted an estimation of the causal compoenents of variance and heritability of RF from the sib analysis. The additive component of variance was present in only two of the populations under test; the respective estimates of heritability were very low. PMID:804421

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Near-isogenic lines (NILs) are useful tools for investigating gene expression, detecting closely linked markers, or cloning the genes. However, the reliability of using NILs for genetic and genomic analysis relies on the homogeneity of the genetic background. In this study, a set of eight NILs (Car...

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

    SciTech Connect

    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

    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.

  2. Individual Genetic Susceptibility

    SciTech Connect

    Eric J. Hall

    2008-12-08

    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.

  3. Recent perspectives on the genetic background of neural tube defects with special regard to iniencephaly.

    PubMed

    Joó, József Gábor

    2009-04-01

    Iniencephaly is a rare and mostly lethal type of neural tube defect. The pattern of inheritance of this group of malformations is multifactorial, rendering the identification of the underlying causes. Numerous studies have been conducted to elucidate the genetic basis of human neurulation. Essential signaling pathways of the development of the CNS include the planar cell polarity pathway, which is important for the initiation of neural tube closure, as well as the sonic hedgehog pathway, which regulates the neural plate bending. Genes influencing the different stages of neurulation have been investigated for their eventual role in the development of these malformations. Among the environmental factors, folic acid seems to be the most important modifier of the risk of human neural tube defects. Genes of the folate metabolism pathways have also been investigated to identify mutations resulting in increased risk of neural tube defects. In this review we have attempted to summarize the knowledge on iniencephaly and neural tube defects, with special regard to genetic factors of the etiology. PMID:19379086

  4. Influence of Genetic Background on Anthocyanin and Copigment Composition and Behavior during Thermoalkaline Processing of Maize.

    PubMed

    Collison, Amy; Yang, Liyi; Dykes, Linda; Murray, Seth; Awika, Joseph M

    2015-06-10

    Visual color is a primary quality factor for foods purchase; identifying factors that influence in situ color quality of pigmented maize during processing is important. Twenty-four genetically distinct pigmented maize hybrids (red/blue, blue, red, and purple) were used to investigate the effect of pigment and copigment composition on color stability during nixtamalization and tortilla chip processing. The red/blue and blue samples generally contained higher proportions of acylated anthocyanins (mainly cyanidin-3-(6?-malonylglucoside)) than the red and purple color classes. Phenolic amides were the major extractable copigments in all samples (450-764 ?g/g), with red samples containing the most putrescines and blue samples containing the most spermidines. Even though samples with higher proportions of acylated anthocyanins retained more pigments during processing, this did not relate to final product color quality. In general, the red/blue samples retained their color quality the best and thus are good candidates for genetic improvement for direct processing into alkalized products. PMID:26010030

  5. Genetic background and risk of postpartum haemorrhage: results from an Italian cohort of 3219 women.

    PubMed

    Biguzzi, E; Franchi, F; Acaia, B; Ossola, W; Nava, U; Paraboschi, E M; Asselta, R; Peyvandi, F

    2014-11-01

    Postpartum haemorrhage (PPH) is a leading cause of maternal mortality, particularly in the developing countries, and of severe maternal morbidity worldwide. To investigate the impact of genetic influences on postpartum haemorrhage, in association with maternal and intrapartum risk factors, using a candidate gene approach. All women (n = 6694) who underwent a vaginal delivery at the Obstetric Unit of a large University hospital in Milan (Italy) between July 2007 and September 2009 were enrolled. The first consecutive 3219 women entered the genetic study. Postpartum haemorrhage was defined as ?500 mL blood loss. Eight functional polymorphisms in seven candidate genes were chosen because of their potential role in predisposing to or protecting from haemorrhagic conditions: tissue factor (F3), factor V (F5), tissue factor pathway inhibitor (TFPI), platelet glycoprotein Ia/IIa (ITGA2), prothrombin (F2), platelet glycoproteins Ib? (GP1BA) and angiotensin-converting enzyme (ACE). After correction for the already known PPH risk factors, only the promoter polymorphism of the tissue factor gene (F3 -603A>G) showed a significant association with PPH, the G allele exerting a protective effect (P = 0.00053; OR = 0.79, 95% CI = 0.69-0.90). The protective effect against PPH of the TF -603A>G polymorphism is biologically plausible since the G allele is associated with an increased protein expression and Tissue Factor is strongly represented in the placenta at term, particularly in decidual cells of maternal origin. PMID:25333208

  6. Genome scan for susceptibility loci for schizophrenia and bipolar disorder

    Microsoft Academic Search

    Ursula Bailer; Friedrich Leisch; Kurt Meszaros; Elisabeth Lenzinger; Ulrike Willinger; Rainer Strobl; Angela Heiden; Christian Gebhardt; Elisabeth Döge; Karoline Fuchs; Werner Sieghart; Siegfried Kasper; Kurt Hornik; Harald N Aschauer

    2002-01-01

    Background: Despite the widely accepted view that schizophrenia and bipolar disorder represent independent illnesses and modes of inheritance, some data in the literature suggest that the diseases may share some genetic susceptibility. The objective of our analyses was to search for vulnerability loci for the two disorders.Methods: A genomewide map of 388 microsatellite DNA markers was genotyped in five schizophrenia

  7. [Background analysis of chromosome controling genetic of water use efficiency of Triticum].

    PubMed

    Zhang, Z B; Shan, L; Xu, Q

    2000-01-01

    Water use efficiency (WUE) of flag leaf of different genetic material was measured by LCA-3 model photosynthesis apparatus. The results show as follows: The order of flag leaf WUE of different chromosome set is AA > BB > DD > RR. Among twenty Chinese Spring ditelosomic, the flag leaf WUE of A ditelosomic set is the highest, the high WUE genes locate on 1AL, 2AL, 2AS and 7AS chromosome arm. Among seven wheat-S. Cereals addition lines, the high WUE gene locates on 4R chromosome, the flag leaf WUE of 5R chromosome is the lowest. In the end of this paper, the research advance of stress resistance gene location on the fourth chromosome set of Triticum was discussed. PMID:10887696

  8. A Novel Differential Susceptibility Gene: "CHRNA4" and Moderation of the Effect of Maltreatment on Child Personality

    ERIC Educational Resources Information Center

    Grazioplene, Rachael G.; DeYoung, Colin G.; Rogosch, Fred A.; Cicchetti, Dante

    2013-01-01

    Background: The differential susceptibility hypothesis states that some genetic variants that confer risk in adverse environments are beneficial in normal or nurturing environments. The cholinergic system is promising as a source of susceptibility genes because of its involvement in learning and neural plasticity. The cholinergic receptor gene…

  9. Contaminant driven genetic erosion and associated hypotheses on alleles loss, reduced population growth rate and increased susceptibility to future stressors: an essay.

    PubMed

    Ribeiro, Rui; Lopes, Isabel

    2013-07-01

    Microevolution due to pollution can occur mainly through genetic drift bottlenecks, especially of small sized populations facing intense lethal pulses of contaminants, through mutations, increasing allelic diversity, and through natural selection, with the disappearance of the most sensitive genotypes. This loss of genotypes can lead to serious effects if coupled to specific hypothetical scenarios. These may be categorized as leading, first, to the loss of alleles-the recessive tolerance inheritance hypothesis. Second, leading to a reduction of the population growth rate-the mutational load and fitness costs hypotheses. Third, leading to an increased susceptibility of further genetic erosion both at future inputs of the same contaminant-differential physiological recovery, endpoints (dis)association, and differential phenotypic plasticity hypotheses-and at sequential or simultaneous inputs of other contaminants-the multiple stressors differential tolerance hypothesis. Species in narrowly fluctuating environments (tropics and deep sea) may have a particularly high susceptibility to genetic erosion-the Plus ça change (plus c'est la meme chose) hypothesis. A discussion on the consequences of these hypotheses is what this essay aimed at. PMID:23604582

  10. ENVIRONMENTAL AND GENETIC INTERACTIONS IN HYPERTENSIVE RATS: OXIDATIVE STRESS AS A COMMON SUSCEPTABILITY ATTRIBUTE FOR NON-CANCER RISKS

    EPA Science Inventory

    Individuals compromised with preexisting conditions are likely to be more susceptible to environmental exposures, and the uncertainty factors employed to correct for this concern may not be adequate. Although diseases such as congestive heart failure, chronic pulmonary disease;...

  11. RBE and genetic susceptibility of mouse and rat spermatogonial stem cells to protons, heavy charged particles and 1.5 MeV neutrons

    NASA Astrophysics Data System (ADS)

    Vaglenov, A.; Fedorenko, B.; Kaltenboeck, B.

    The main purpose of the present study is to provide data on RBE and genetic susceptibility in the mouse and the rat when exposed to protons, HZE particles and neutrons. Genetic damage from exposure to 50 MeV and 9 GeV protons, 4 GeV/nucleon helium ions, 4 GeV/nucleon carbon ions and 1.5 MeV neutrons was studied in adult (CBA × C57Bl/6J) F1 mice. Damage from 9 GeV protons and 4 GeV helium ions was studied in adult Wistar rats. The incidence of reciprocal translocations (RT) induced in the spermatogonial stem cells of each species was recorded. RBE values were derived by comparing linear regression coefficients from dose-responses within the same dose-range for each of the radiation types tested and 60Co ?-rays or by means of a direct nonparametric method. RT yields measured after mouse and rat spermatogonial irradiation with protons, heavy charged particles and neutrons fit the linear model of the dose-response relationship. Relative to 60Co ?-rays, RBE values are as follows for mouse spermatogonia: 0.9 for 50 MeV protons; 1.3 for 9 GeV protons; 0.7 for 4 GeV helium ions; and 1.3 for 4 GeV carbon ions. For rat spermatogonia, values were: 1.7 for 9 GeV protons and 1.3 for helium ions. Compared to mice irradiated using the same experimental design, rats were more susceptible to high-LET radiations, with susceptibility assessed by genetic damage to their spermatogonial stem cells. The RBE of 1.5 MeV neutron is about 6.6.

  12. Quantify environmental effects in shaping the genetic diversification pattern of Oncomelania hupensis and its implications in surveillance of human susceptibility to Schistosomiasis

    NASA Astrophysics Data System (ADS)

    Liang, L.; Liao, J. S.; Gong, P.

    2012-12-01

    The transmission and distribution of schistomiasis, one of the most serious infectious diseases in East and Southeast Asia, tied closely to its unique intermediate snail host Oncomelania hupensis. The coevolved relationships of O. hupensis populations with its parasite Schistosoma japonisum are important in understanding the mechanism of disease spread. The genetic diversification pattern within population is supposed to influence the amount of parasite loads, and the susceptibility of snails determined the chance for human or mammals to get infected. Meanwhile, intervening environmental features had been long suggested to affect snail population dynamics and evolutionary trajectories of species. However, no comprehensive study referring to the above topics has been carried out on O.hupensis populations before. In this study, we reanalyzed published data in mainland China to evaluate whether human infection rate and genetic diversification patterns are related under natural environment. Besides that, we used an array of remotely sensed image derived environmental variables to quantify the amount of variation in population genetic structure that could be explained by those factors by landscape genetic analysis. We found that human schistosomiasis infection rate is positively correlated with intra-population genetic diversification and inter-population genetic exchange, which is contradictory with the Red Queen hypothesis. The patterns of genetic diversification are better revealed when non-Euclidean, environmentally determined distance measures or features are used in large heterogeneous landscape. The impact of stream connectivity on the snail inter-population genetic distances does not so evident unless taking wetlands into calculation, and thus control activities planned solely along river systems may be suboptimal. Climate features have a stronger impact on genetic structure of snails than topology, and precipitation seasonality dominates the highest proportion of explanation in genetic diversification. Different types of genes respond different to landscape effects, and it is suspected to be related with their evolution rate. Our study raises an important opportunity for public health decision making by combining geo-informatics and bio-informatics technology. Since the schistomiasis disease persistence, establishment, and intervention optimization are dependent on the genetic diversification pattern of O.hupensis populations, and that pattern is strongly environmentally determined, then certain key environmental features or landscape distances have the potential to inform public health decisions such as where to focus surveillance efforts, or disrupt the connection to stop the gene exchange. This is especially useful for Yangze River basin region under both extensive anthropogenic activities and climate change.

  13. Genetic Polymorphism of Apolipoprotein A5 Gene and Susceptibility to Type 2 Diabetes Mellitus: A Meta-Analysis of 15,137 Subjects

    PubMed Central

    Yin, Yan-Wei; Sun, Qian-Qian; Wang, Pei-Jian; Qiao, Li; Hu, Ai-Min; Liu, Hong-Li; Wang, Qi; Hou, Zhi-Zhen

    2014-01-01

    Background Several studies have investigated whether the polymorphism in the apolipoprotein A5 (APOA5) is associated with type 2 diabetes mellitus (T2DM) risk. However, those studies have produced inconsistent results. The purpose of this study was to investigate whether the APOA5 -1131T/C polymorphism (rs662799) confers significant susceptibility to T2DM using a meta-analysis. Methods PubMed, Embase, Web of Science, Cochrane database, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0. Results A total of 19 studies included 4,767 T2DM cases and 10,370 controls (four studies involving 555 T2DM cases and 2958 controls were performed among Europeans and 15 studies involving 4212 T2DM cases and 7412 controls were performed among Asians) were combined showing significant association between the APOA5 -1131T/C polymorphism and T2DM risk (for C allele vs. T allele: OR?=?1.28, 95% CI?=?1.17–1.40, p<0.00001; for C/C vs. T/T: OR?=?1.57, 95% CI?=?1.35–1.83, p<0.00001; for C/C vs. T/C+T/T: OR?=?1.36, 95% CI?=?1.18–1.57, p<0.0001; for C/C+T/C vs. T/T: OR?=?1.32, 95% CI?=?1.16–1.51, p<0.0001). In the subgroup analysis by ethnicity, significant association was also found among Asians (for C allele vs. T allele: OR?=?1.31, 95% CI?=?1.22–1.40, p<0.00001; for C/C vs. T/T: OR?=?1.61, 95% CI?=?1.38–1.88, p<0.00001; for C/C vs. T/C+T/T: OR?=?1.39, 95% CI?=?1.20–1.61, p<0.0001; for C/C+T/C vs. T/T: OR?=?1.42, 95% CI?=?1.25–1.62, p<0.00001). However, no significant association was found between the APOA5 -1131T/C polymorphism and T2DM risk among Europeans. Conclusions The present meta-analysis suggests that the APOA5 -1131T/C polymorphism is associated with an increased T2DM risk in Asian population. PMID:24586566

  14. The Dominance Effect of the Adaptive Transposable Element Insertion Bari-Jheh Depends on the Genetic Background

    PubMed Central

    Guio, Lain; González, Josefa

    2015-01-01

    Although adaptive mutations are often considered to be dominant, it has been recently shown that a substantial proportion of adaptive mutations should display heterozygote advantage. In this work, we take advantage of a recently characterized transposable element insertion mediating oxidative stress response in Drosophila melanogaster to test the dominance effect of an adaptive mutation. The comparison of the survival curves of heterozygous and the two corresponding homozygous flies indicated that the dominance effect of Bari-Jheh depends on the genetic background. Both in homozygous and in heterozygous flies, Bari-Jheh was associated with upregulation of Jheh1 (Juvenile Hormone Epoxyde Hydrolase 1) and/or Jheh2 genes. Our results add to the limited number of studies in which the dominance effect of adaptive mutations has been empirically estimated and highlights the complexity of their inheritance. PMID:25912044

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed

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

    2015-01-01

    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

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

    PubMed Central

    2014-01-01

    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

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

    SciTech Connect

    Hoff, R.J.; Minggao, S.

    1994-02-01

    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.

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

    USGS Publications Warehouse

    Blanchong, Julie A.; Heisey, Dennis M.; Scribner, Kim T.; Libants, Scot V.; Johnson, Chad; Aiken, Judd M.; Langenberg, Julia A.; Samuel, Michael D.

    2009-01-01

    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.

  20. Genetic susceptibility to multicase hypersensitivity pneumonitis is associated with the TNF-238 GG genotype of the promoter region and HLA-DRB1*04 bearing HLA haplotypes.

    PubMed

    Falfán-Valencia, Ramcés; Camarena, Angel; Pineda, César Landa; Montaño, Martha; Juárez, Armida; Buendía-Roldán, Ivette; Pérez-Rubio, Gloria; Reséndiz-Hernández, Juan Manuel; Páramo, Ignacio; Vega, Anita; Granados, Julio; Zúñiga, Joaquín; Selman, Moisés

    2014-01-01

    Hypersensitivity Pneumonitis (HP) is a lung inflammatory disorder caused by inhalation of organic particles by a susceptible host. Since only a small proportion of individuals exposed to HP-related antigens develop the disease, a genetic predisposition is largely suspected. However, studies regarding genetic susceptibility in this disease are scanty. We have previously found evidence supporting increased risk associated to the major histocompatibility complex (MHC) in sporadic HP. In the present study, we conducted a family-based research that includes nine multicase families with at least two related HP patients (RHP). We evaluated 19 RHP individuals, 25 additional healthy first-degree relatives (REA) and 246 healthy unrelated individuals (HUI). HLA class II typing (DRB1/3/4/5, DQA1, DQB1, DPA1, DPB1, DMA and DMB), and -863, -308 and -238 polymorphisms in the promoter region of TNF-? were performed by PCR based methods. We identified an increased frequency of HLA-DRB1*04:07, DRB1*04:05, DRB1*11:01 and DRB1*13:01 alleles in RHP individuals compared to healthy controls (p < 0.05). A significant higher frequency of DRB1*04:07-DQB1*03:02, DRB1*04:05-DQB1*03:02, and DRB1*04:03-DQB1*03:02 haplotypes was also detected in the group of patients. Likewise, TNF-238 GG genotype was more frequent in the RHP group as compared to REA (p = 0.01, OR = 7.2). Finally, the combination of HLA-DRB1*04 alleles and TNF-238 GG was significantly increased in the RHP group (p = 0.01, OR = 6.93). These findings indicate that genes located within the MHC region confer susceptibility to familial HP in Mexicans. PMID:24291122

  1. Host genetic variations in glutathione-S-transferases, superoxide dismutases and catalase genes influence susceptibility to malaria infection in an Indian population.

    PubMed

    Fernandes, Rayzel C; Hasan, Marriyah; Gupta, Himanshu; Geetha, K; Rai, Padmalatha S; Hande, Manjunath H; D'Souza, Sydney C; Adhikari, Prabha; Brand, Angela; Satyamoorthy, Kapaettu

    2015-06-01

    Antioxidant enzymes can contribute to disease susceptibility or determine response to therapy in individuals with malaria. Genetic variations due to polymorphisms in host genes encoding antioxidant enzymes such as glutathione S-transferases-theta, mu, pi (GSTT, GSTM, GSTP), superoxide dismutases (SOD) and catalase (CAT), may therefore, influence inter-individual response to malaria pathology and propensity of infection caused by Plasmodium vivax (Pv) and Plasmodium falciparum (Pf). Therefore, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing, we investigated the association of deletions of GSTT1 and GSTM1, single nucleotide polymorphisms (SNPs) of GSTP1 (rs1695), SOD1 (rs2234694), SOD2 (rs4880, rs1141718), SOD3 (rs2536512) and CAT (rs1001179) in individuals infected with Pf (n = 100) and Pv (n = 100) against healthy controls (n = 150). Our data suggest a significant role for GSTM1 deletions in complicated Pv (p = 0.0007) malaria with ODDs ratio 3.8 [with 95 % confidence interval (CI) 1.9-7.4]. The results also indicated that polymorphisms present in GSTP1, SOD1 and CAT genes may be associated with malaria susceptibility (p < 0.05), whereas SOD3 polymorphism may play a role in malarial resistance (p < 0.05). In addition, we observed significant SNP-SNP interactions with synergistic genetic effects in SOD2, SOD3 and CAT genes for Pv and in SOD2 and SOD3 genes for Pf. In conclusion, our results provide convincing evidence for a relationship between polymorphisms in host antioxidant enzymes and susceptibility to malaria infection. PMID:25573779

  2. Candidate Genetic Modifiers of Individual Susceptibility to Renal Cell Carcinoma: A Study of Polymorphic Human Xenobiotic-metabolizing Enzymes1

    Microsoft Academic Search

    Sandrine Longuemaux; Claudine Delomenie; Catherine Gallou; Arnaud Mejean; Monique Vincent-Viry; Raymonde Bouvier; Dominique Droz; Rajagopal Krishnamoorthy; Marie-Madeleine Galteau; Claudine Junien; Christophe Beroud; Jean-Marie Dupret

    The steady increase in sporadic renal cell carcinoma (RCC) observed in industrialized countries supports the notion that certain carcinogens pres- ent in the environment (tobacco smoke, drugs, pollutants, and dietary constituents) may affect the occurrence of RCC. Many of the enzymes dealing with such environmental factors are polymorphic and may, there- fore, confer variable susceptibility to RCC. This case-control study

  3. The Intracranial Aneurysm Susceptibility Genes HSPG2 and CSPG2 Are Not Associated With Abdominal Aortic Aneurysm

    Microsoft Academic Search

    Annette F. Baas; Jelena Medic; Ruben van t Slot; Jean-Paul P. M. de Vries; Eric L. G. Verhoeven; Bart P. Boll; Diederick E. Grobbee; Cisca Wijmenga; Jan D. Blankensteijn; Ynte M. Ruigrok

    2010-01-01

    Background: A genetic variant on chromosome 9p21 associates with abdominal aortic aneurysm (AAA) and intracranial aneurysm (IA), indicating that despite the differences in pathology there are shared genetic risk factors. We investigated whether the IA susceptibility genes heparan sulfate proteoglycan 2 (HSPG2) and chondroitin sulfate proteoglycan 2 (CSPG2) associate with AAA as well. Methods: Using tag single nucleotide polymorphisms (SNPs),

  4. Genetics

    NSDL National Science Digital Library

    The Tech Museum of Innovation

    2004-01-01

    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

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

    Microsoft Academic Search

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

    2010-01-01

    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

  6. Family-Based Analysis Using a Dense Single-Nucleotide Polymorphism–Based Map Defines Genetic Variation at PSORS1, the Major Psoriasis-Susceptibility Locus

    PubMed Central

    Veal, Colin D.; Capon, Francesca; Allen, Michael H.; Heath, Emma K.; Evans, Julie C.; Jones, Andrew; Patel, Shanta; Burden, David; Tillman, David; Barker, Jonathan N. W. N.; Trembath, Richard C.

    2002-01-01

    Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen–C [HLA-C], ?-helix–coiled-coil–rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent–affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis. PMID:12148091

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

    PubMed Central

    Hirasawa, Tadashi

    2014-01-01

    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

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

    Microsoft Academic Search

    Maria Karayiorgou; Christina Sobin; Maude L. Blundell; Brandi L. Galke; Lubomira Malinova; Pablo Goldberg; Jurg Ott; Joseph A. Gogos

    1999-01-01

    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

  9. Developmental Analysis and Influence of Genetic Background on the Lhx3 W227ter Mouse Model of Combined Pituitary Hormone Deficiency Disease

    PubMed Central

    Prince, Kelly L.; Colvin, Stephanie C.; Park, Soyoung; Lai, Xianyin; Witzmann, Frank A.

    2013-01-01

    Combined pituitary hormone deficiency (CPHD) diseases result in severe outcomes for patients including short stature, developmental delays, and reproductive deficiencies. Little is known about their etiology, especially the developmental profiles and the influences of genetic background on disease progression. Animal models for CPHD provide valuable tools to investigate disease mechanisms and inform diagnostic and treatment protocols. Here we examined hormone production during pituitary development and the influence of genetic background on phenotypic severity in the Lhx3W227ter/W227ter mouse model. Lhx3W227ter/W227ter embryos have deficiencies of ACTH, ?-glycoprotein subunit, GH, PRL, TSH?, and LH? during prenatal development. Furthermore, mutant mice have significant reduction in the critical pituitary transcriptional activator-1 (PIT1). Through breeding, the Lhx3W227ter/W227ter genotype was placed onto the 129/Sv and C57BL/6 backgrounds. Intriguingly, the genetic background significantly affected viability: whereas Lhx3W227ter/W227ter animals were found in the expected frequencies in C57BL/6, homozygous animals were not viable in the 129/Sv genetic environment. The hormone marker and PIT1 reductions observed in Lhx3W227ter/W227ter mice on a mixed background were also seen in the separate strains but in some cases were more severe in 129/Sv. To further characterize the molecular changes in diseased mice, we conducted a quantitative proteomic analysis of pituitary proteins. This showed significantly lower levels of PRL, pro-opiomelanocortin (ACTH), and ?-glycoprotein subunit proteins in Lhx3W227ter/W227ter mice. Together, these data show that hormone deficiency disease is apparent in early prenatal stages in this CPHD model system. Furthermore, as is noted in human disease, genetic background significantly impacts the phenotypic outcome of these monogenic endocrine diseases. PMID:23288907

  10. Identification and verification of QTL associated with growth traits in two genetic backgrounds of Barramundi (Lates calcarifer).

    PubMed

    Wang, C M; Lo, L C; Feng, F; Zhu, Z Y; Yue, G H

    2008-02-01

    Quantitative trait loci (QTL) affecting growth traits have previously been mapped in linkage groups (LG) 2, 3 and 23 of Barramundi (Lates carcalifer), but these QTL have not been verified in different genetic backgrounds and environments. Here, we report the identification and verification of QTL for growth traits on LG2, 3, 10 and 23 in F(1) families constructed using brooders from the Singapore Marine Aquaculture Center (MAC) and from wild stocks collected in Thailand (THAI). The previously detected QTL for body weight and length linked to marker Lca371 on LG2 were confirmed in both the MAC and THAI families, whereas other QTL previously mapped to LG3 and 23 were only detected in one of the two families. QTL for body weight and length were identified in the MAC family, but not in the THAI family, in a region where the insulin-like growth factor 2 (IGF2) and tyrosine hydroxylase 1 (TH1) genes are located on LG10. Significant epistatic interactions were identified between markers Lca287 on LG2 and IGF2 on LG10 for growth trait QTL in the MAC family, but not in the THAI family. Effects of the IGF2, TH1 and parvalbumin 1 candidate genes were family-specific. Our results indicate that some but not all QTL are family-specific in Barramundi. PMID:18076743

  11. Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background

    PubMed Central

    Cox, M.M.; Tucker, A.M.; Tang, J.; Talbot, K.; Richer, D.C.; Yeh, L.; Arnold, S.E.

    2009-01-01

    Sandy mice have a deletion mutation in the gene encoding dysbindin-1, Dtnbp1, with consequent reduction of the protein in heterozygotes and its loss in homozygotes. The sandy mouse thus serves as an animal model of dysbindin-1 function. Since this protein is concentrated in synaptic tissue and affects transmitter release, it may affect neuronal processes that mediate behavior. To investigate the neurobehavioral effects of the Dtnbp1 mutation, we studied littermate sandy and wild-type controls on a C57BL/6J genetic background. The three animal groups were indistinguishable in their external physical characteristics, sensorimotor skills, and indices of anxiety-like behaviors. In the open field, however, homozygous animals were hyperactive and appeared to show less habituation to the initially novel environment. In the Morris water maze, homozygous animals displayed clear deficits in spatial learning and memory with marginal deficits in visual association learning. Apart from the last mention deficits, these abnormalities are consistent with hippocampal dysfunction and in some cases with elevated dopaminergic transmission via D2 dopamine receptors. Since similar deficits in spatial learning and memory have been found in schizophrenia, where decreased dysbindin-1 has been found in the hippocampus, the sandy mouse may also model certain aspects of cognition and behavior relevant to schizophrenia. PMID:19220483

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

    SciTech Connect

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

    1996-11-01

    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.

  13. The frequency of precocious segregation of sister chromatids in mouse female meiosis I is affected by genetic background.

    PubMed

    Danylevska, Anna; Kovacovicova, Kristina; Awadova, Thuraya; Anger, Martin

    2014-09-01

    Mammalian female gametes frequently suffer from numerical chromosomal aberrations, the main cause of miscarriages and severe developmental defects. The underlying mechanisms responsible for the development of aneuploidy in oocytes are still not completely understood and remain a subject of extensive research. From studies focused on prevalence of aneuploidy in mouse oocytes, it has become obvious that reported rates of aneuploidy are strongly dependent on the method used for chromosome counting. In addition, it seems likely that differences between mouse strains could influence the frequency of aneuploidy as well; however, up till now, such a comparison has not been available. Therefore, in our study, we measured the levels of aneuploidy which has resulted from missegregation in meiosis I, in oocytes of three commonly used mouse strains-CD-1, C3H/HeJ, and C57BL/6. Our results revealed that, although the overall chromosomal numerical aberration rates were similar in all three strains, a different number of oocytes in each strain contained prematurely segregated sister chromatids (PSSC). This indicates that a predisposition for this type of chromosome segregation error in oocyte meiosis I is dependent on genetic background. PMID:24935618

  14. Cancer Genetics Professionals

    Cancer.gov

    The information below is from the NCI Cancer Genetics Services Directory.  This directory lists professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, and others). Professionals

  15. Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.

    PubMed

    Whalley, Heather C; Papmeyer, Martina; Romaniuk, Liana; Sprooten, Emma; Johnstone, Eve C; Hall, Jeremy; Lawrie, Stephen M; Evans, Kathryn L; Blumberg, Hilary P; Sussmann, Jessika E; McIntosh, Andrew M

    2012-11-01

    A recent 'mega-analysis' combining genome-wide association study data from over 40,000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as 'RISK-' for GT and GG individuals, and 'RISK+' for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK- individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype(*)group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK- genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ. PMID:22850735

  16. Impact of a microRNA MIR137 Susceptibility Variant on Brain Function in People at High Genetic Risk of Schizophrenia or Bipolar Disorder

    PubMed Central

    Whalley, Heather C; Papmeyer, Martina; Romaniuk, Liana; Sprooten, Emma; Johnstone, Eve C; Hall, Jeremy; Lawrie, Stephen M; Evans, Kathryn L; Blumberg, Hilary P; Sussmann, Jessika E; McIntosh, Andrew M

    2012-01-01

    A recent ‘mega-analysis' combining genome-wide association study data from over 40?000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as ‘RISK?' for GT and GG individuals, and ‘RISK+' for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK? individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype*group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK? genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ. PMID:22850735

  17. Genetic Variation in NFKB1 and NFKBIA and Susceptibility to Coronary Artery Disease in a Chinese Uygur Population

    PubMed Central

    Yang, Yi-Ning; Ma, Yi-Tong; Xu, Rui; Pan, Shuo; Zhai, Hui; Liu, Fen; Chen, Bang-Dang; Zhao, Qian

    2015-01-01

    Objectives Coronary artery disease (CAD) is the most common chronic inflammatory disease worldwide. NF-?B, a central regulator of inflammation, is involved in various inflammatory diseases. The aim of this study was to investigate the association between NFKB1 and NFKBIA polymorphisms and the susceptibility to CAD and their impact on plasma levels of IL-6 in a Chinese Uygur population. Methods We genotyped NFKB1-94ins/del ATTG (rs28362491) and NFKBIA3’ UTR A/G (rs696) using TaqMan SNP genotyping assays in 960 Uygur CAD cases and Uygur 1060 CAD-negtive controls. IL-6 plasma levels were measured in 360 stable angina pectoris (SAP) cases and 360 controls using ELISA method. Results There was no significant difference in the distribution of the genotypes and alleles of rs696 polymorphism in CAD cases and controls. Significant difference in the frequency of genotypes (P = 0.001) and alleles (P = 0.001) of rs28362491 polymorphism was observed in CAD cases compared to controls. In multivariate logistic regression analysis, SNP rs28362491 was consistently associated with CAD risk in a recessive model after adjustment for cardiovascular risk factors (OR = 1.581, 95% CI 1.222 to 2.046, P<0.001). SAP cases had significantly higher plasma levels of IL-6 compared to controls (P<0.001). General linear model analysis showed rs28362491 was independently associated with increased IL-6 levels by analyses of a recessive model (P<0.001) after adjustment for covariates. Conclusions Our study indicates that NFKB1-94 ins/del ATTG polymorphism may play a role in CAD susceptibility in Chinese Uygur population and is functionally associated with IL-6 expression, suggesting a mechanistic link between NFKB1-94 ins/del ATTG polymorphism and CAD susceptibility. PMID:26075620

  18. Genetic evidence for the neuronal nitric oxide synthase gene (NOS1) as a susceptibility locus for infantile pyloric stenosis

    SciTech Connect

    Chung, E.; Chen, G.; Gardiner, M. [Rayne Inst., London (United Kingdom)] [and others

    1996-02-01

    The etiological role of the gene for neuronal nitric oxide synthase (NOS1) in infantile pyloric stenosis (PS) was investigated by analysis of two intragenic polymorphisms (NOS1a and NOS1b) in 27 families. There was significant overall transmission disequilibrium between PS and NOS1a (P=.006). Consideration of each allele independently revealed a highly significant tendency for allele 7 (210 bp) to be preferentially transmitted to the affected offspring (P=.0006). These observations suggest that NOS1 is a susceptibility locus for PS. 38 refs., 1 fig., 3 tabs.

  19. The Moroccan Genetic Disease Database (MGDD): a database for DNA variations related to inherited disorders and disease susceptibility.

    PubMed

    Charoute, Hicham; Nahili, Halima; Abidi, Omar; Gabi, Khalid; Rouba, Hassan; Fakiri, Malika; Barakat, Abdelhamid

    2014-03-01

    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

  20. Copyright 2000 by the Genetics Society of America Bacillus thuringiensis (Bt) Toxin Susceptibility and Isolation of Resistance Mutants

    E-print Network

    Aroian, Raffi V.

    and resistance pathways in target insects since these organisms are not ideal for molecular genetic studies alternative to studies in insects and to explore the potential of Bt toxins as nematode control agents, we nematodes, we are studying Bt toxin action and resistance in Caenorhabditis elegans. We demonstrate

  1. Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions

    PubMed Central

    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

    2015-01-01

    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

  2. Comparative Expression Profiling of Leishmania: Modulation in Gene Expression between Species and in Different Host Genetic Backgrounds

    PubMed Central

    Depledge, Daniel P.; Evans, Krystal J.; Ivens, Alasdair C.; Aziz, Naveed; Maroof, Asher; Kaye, Paul M.; Smith, Deborah F.

    2009-01-01

    Background Genome sequencing of Leishmania species that give rise to a range of disease phenotypes in the host has revealed highly conserved gene content and synteny across the genus. Only a small number of genes are differentially distributed between the three species sequenced to date, L. major, L. infantum and L. braziliensis. It is not yet known how many of these genes are expressed in the disease-promoting intracellular amastigotes of these species or whether genes conserved between the species are differentially expressed in the host. Methods/Principal Findings We have used customised oligonucleotide microarrays to confirm that all of the differentially distributed genes identified by genome comparisons are expressed in intracellular amastigotes, with only a few of these subject to regulation at the RNA level. In the first large-scale study of gene expression in L. braziliensis, we show that only ?9% of the genes analysed are regulated in their RNA expression during the L. braziliensis life cycle, a figure consistent with that observed in other Leishmania species. Comparing amastigote gene expression profiles between species confirms the proposal that Leishmania transcriptomes undergo little regulation but also identifies conserved genes that are regulated differently between species in the host. We have also investigated whether host immune competence influences parasite gene expression, by comparing RNA expression profiles in L. major amastigotes derived from either wild-type (BALB/c) or immunologically compromised (Rag2?/? ?c?/?) mice. While parasite dissemination from the site of infection is enhanced in the Rag2?/? ?c?/? genetic background, parasite RNA expression profiles are unperturbed. Conclusion/Significance These findings support the hypothesis that Leishmania amastigotes are pre-adapted for intracellular survival and undergo little dynamic modulation of gene expression at the RNA level. Species-specific parasite factors contributing to virulence and pathogenicity in the host may be limited to the products of a small number of differentially distributed genes or the differential regulation of conserved genes, either of which are subject to translational and/or post-translational controls. PMID:19582145

  3. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.

    PubMed

    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; Esk, 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

    2011-04-26

    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

  4. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

    PubMed Central

    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

    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

  5. Genetic polymorphism of the human cytochrome CYP2A13 in a French population: implication in lung cancer susceptibility

    Microsoft Academic Search

    Christelle Cauffiez; Jean-Marc Lo-Guidice; Sylvie Quaranta; Delphine Allorge; Dany Chevalier; Sylvie Cenée; Rima Hamdan; Michel Lhermitte; Jean-Jacques Lafitte; Christian Libersa; Jean-Frédéric Colombel; Isabelle Stücker; Franck Broly

    2004-01-01

    The human cytochrome CYP2A13, which is mainly expressed in the respiratory tract, has been shown to be highly efficient in vitro in the metabolism of tobacco-smoke carcinogens and procarcinogens such as 4-methylnitroso-1-(3-pyridyl)-1-butanone (NNK). In order to investigate the extent of CYP2A13 genetic polymorphism in a French Caucasian population of 102 individuals, a screening for sequence variations in the 5?-untranslated and

  6. Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy

    Microsoft Academic Search

    G-S Li; H Zhang; J-C Lv; Y Shen; H-Y Wang

    2007-01-01

    IgA nephropathy (IgAN) is a polygenic disorder and the precise role of genetic factors remains elusive. Increasing evidences have implicated the aberrant galactosylation of IgA1 molecules in the pathogenesis of IgAN. The galactosyltransferase, core 1 ?3-Gal-T, and its chaperone, Cosmc, play important roles in ?1,3 glycosylation of IgA1 molecule. A case–control association study was performed to investigate the association between

  7. Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon

    Microsoft Academic Search

    Nobuhiko Hiraga; Michio Imamura; Masataka Tsuge; Chiemi Noguchi; Shoichi Takahashi; Eiji Iwao; Yoshifumi Fujimoto; Hiromi Abe; Toshiro Maekawa; Hidenori Ochi; Chise Tateno; Katsutoshi Yoshizato; Akihito Sakai; Yoshio Sakai; Masao Honda; Shuichi Kaneko; Takaji Wakita; Kazuaki Chayama

    2007-01-01

    We developed a reverse genetics system of hepatitis C virus (HCV) genotypes 1a and 2a using infectious clones and human hepatocyte chimeric mice. We inoculated cell culture-produced genotype 2a (JFH-1) HCV intravenously. We also injected genotype 1a CV-H77C clone RNA intrahepatically. Mice inoculated with HCV by both procedures developed measurable and transmissible viremia. Interferon (IFN) alpha treatment resulted in greater

  8. Germline Genetic Variants Disturbing the Let7\\/LIN28 Double-Negative Feedback Loop Alter Breast Cancer Susceptibility

    Microsoft Academic Search

    Ao-Xiang Chen; Ke-Da Yu; Lei Fan; Ji-Yu Li; Chen Yang; A-Ji Huang; Zhi-Ming Shao

    2011-01-01

    Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7\\/LIN28 loop and breast cancer risk. We initially demonstrated that the T\\/C variants of

  9. Picosecond-resolved FRET on non-amplified DNA for identifying individuals genetically susceptible to type-1 diabetes

    NASA Astrophysics Data System (ADS)

    Nardo, Luca; Tosi, Giovanna; Bondani, Maria; Accolla, Roberto; Andreoni, Alessandra

    2012-06-01

    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.

  10. Population Genetics and Antimicrobial Susceptibility of Canine Campylobacter Isolates Collected before and after a Raw Feeding Experiment

    PubMed Central

    Roine, Johanna; Hänninen, Marja-Liisa; Hielm-Björkman, Anna; Kivistö, Rauni

    2015-01-01

    In recent years, increasing numbers of consumers have become interested in feeding raw food for their pet dogs as opposed to commercial dry food, in the belief of health advantages. However, raw meat and internal organs, possibly contaminated by pathogens such as Campylobacter spp., may pose a risk of transmission of zoonoses to the pet owners. Campylobacter jejuni is the leading cause of bacterial gastroenteritis in humans but C. upsaliensis has also been associated with human disease. In this study we investigated the effect of different feeding strategies on the prevalence of Campylobacter spp. in Finnish dogs. We further characterized the isolates using multilocus sequence typing (MLST), whole-genome (wg) MLST and antimicrobial susceptibility testing. Dogs were sampled before and after a feeding period consisting of commercial raw feed or dry pellet feed. Altogether 56% (20/36) of the dogs yielded at least one Campylobacter-positive fecal sample. C. upsaliensis was the major species detected from 39% of the dogs before and 30% after the feeding period. Two C. jejuni isolates were recovered, both from raw-fed dogs after the dietary regimen. The isolates represented the same genotype (ST-1326), suggesting a common infection source. However, no statistically significant correlation was found between the feeding strategies and Campylobacter spp. carriage. The global genealogy of MLST types of dog and human C. upsaliensis isolates revealed weakly clonal population structure as most STs were widely dispersed. Major antimicrobial resistance among C. upsaliensis isolates was against streptomycin (STR MIC > 4mg/l). Apart from that, all isolates were highly susceptible against the antimicrobials tested. Mutations were found in the genes rpsL or rpsL and rsmG in streptomycin resistant isolates. In conclusion, increasing trend to feed dogs with raw meat warrants more studies to evaluate the risk associated with raw feeding of pets in transmission of zoonoses to humans. PMID:26172151

  11. Recovery of native genetic background in admixed populations using haplotypes, phenotypes, and pedigree information - using cika cattle as a case breed.

    PubMed

    Sim?i?, Mojca; Smetko, Anamarija; Sölkner, Johann; Seichter, Doris; Gorjanc, Gregor; Kompan, Dragomir; Medugorac, Ivica

    2015-01-01

    The aim of this study was to obtain unbiased estimates of the diversity parameters, the population history, and the degree of admixture in Cika cattle which represents the local admixed breeds at risk of extinction undergoing challenging conservation programs. Genetic analyses were performed on the genome-wide Single Nucleotide Polymorphism (SNP) Illumina Bovine SNP50 array data of 76 Cika animals and 531 animals from 14 reference populations. To obtain unbiased estimates we used short haplotypes spanning four markers instead of single SNPs to avoid an ascertainment bias of the BovineSNP50 array. Genome-wide haplotypes combined with partial pedigree and type trait classification show the potential to improve identification of purebred animals with a low degree of admixture. Phylogenetic analyses demonstrated unique genetic identity of Cika animals. Genetic distance matrix presented by rooted Neighbour-Net suggested long and broad phylogenetic connection between Cika and Pinzgauer. Unsupervised clustering performed by the admixture analysis and two-dimensional presentation of the genetic distances between individuals also suggest Cika is a distinct breed despite being similar in appearance to Pinzgauer. Animals identified as the most purebred could be used as a nucleus for a recovery of the native genetic background in the current admixed population. The results show that local well-adapted strains, which have never been intensively managed and differentiated into specific breeds, exhibit large haplotype diversity. They suggest a conservation and recovery approach that does not rely exclusively on the search for the original native genetic background but rather on the identification and removal of common introgressed haplotypes would be more powerful. Successful implementation of such an approach should be based on combining phenotype, pedigree, and genome-wide haplotype data of the breed of interest and a spectrum of reference breeds which potentially have had direct or indirect historical contribution to the genetic makeup of the breed of interest. PMID:25923207

  12. Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease

    PubMed Central

    Johnson, Matthew P.; Brennecke, Shaun P.; East, Christine E.; Dyer, Thomas D.; Roten, Linda T.; Proffitt, J. Michael; Melton, Phillip E.; Fenstad, Mona H.; Aalto-Viljakainen, Tia; Mäkikallio, Kaarin; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Laivuori, Hannele; Austgulen, Rigmor; Blangero, John; Moses, Eric K.; Pouta, Anneli; Kivinen, Katja; Ekholm, Eeva; Hietala, Reija; Sainio, Susanna; Saisto, Terhi; Uotila, Jukka; Klemetti, Miira; Inkeri Lokki, Anna; Georgiadis, Leena; Huovari, Elina; Kortelainen, Eija; Leminen, Satu; Lähdesmäki, Aija; Mehtälä, Susanna; Salmen, Christina

    2013-01-01

    Pre-eclampsia is an idiopathic pregnancy disorder promoting morbidity and mortality to both mother and child. Delivery of the fetus is the only means to resolve severe symptoms. Women with pre-eclamptic pregnancies demonstrate increased risk for later life cardiovascular disease (CVD) and good evidence suggests these two syndromes share several risk factors and pathophysiological mechanisms. To elucidate the genetic architecture of pre-eclampsia we have dissected our chromosome 2q22 susceptibility locus in an extended Australian and New Zealand familial cohort. Positional candidate genes were prioritized for exon-centric sequencing using bioinformatics, SNPing, transcriptional profiling and QTL-walking. In total, we interrogated 1598 variants from 52 genes. Four independent SNP associations satisfied our gene-centric multiple testing correction criteria: a missense LCT SNP (rs2322659, P = 0.0027), a synonymous LRP1B SNP (rs35821928, P = 0.0001), an UTR-3 RND3 SNP (rs115015150, P = 0.0024) and a missense GCA SNP (rs17783344, P = 0.0020). We replicated the LCT SNP association (P = 0.02) and observed a borderline association for the GCA SNP (P = 0.07) in an independent Australian case–control population. The LRP1B and RND3 SNP associations were not replicated in this same Australian singleton cohort. Moreover, these four SNP associations could not be replicated in two additional case–control populations from Norway and Finland. These four SNPs, however, exhibit pleiotropic effects with several quantitative CVD-related traits. Our results underscore the genetic complexity of pre-eclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVD-related risk factors. PMID:23420841

  13. Genetics

    MedlinePLUS

    Homozygous; Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  14. Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender.

    PubMed

    Kovács, Attila D; Pearce, David A

    2015-04-01

    Mutations in the CLN3 gene cause a fatal neurodegenerative disorder: juvenile CLN3 disease, also known as juvenile Batten disease. The two most commonly utilized mouse models of juvenile CLN3 disease are Cln3-knockout (Cln3(-/-)) and Cln3(?ex7/8)-knock-in mice, the latter mimicking the most frequent disease-causing human mutation. To determine which mouse model has the most pronounced neurological phenotypes that can be used as outcome measures for therapeutic studies, we compared the exploratory activity, motor function and depressive-like behavior of 1-, 3- and 6-month-old Cln3(-/-) and Cln3(?ex7/8)-knock-in mice on two different genetic backgrounds (129S6/SvEv and C57BL/6J). Although, in many cases, the behavior of Cln3(-/-) and Cln3(?ex7/8) mice was similar, we found genetic-background-, gender- and age-dependent differences between the two mouse models. We also observed large differences in the behavior of the 129S6/SvEv and C57BL/6J wild-type strains, which highlights the strong influence that genetic background can have on phenotype. Based on our results, Cln3(-/-) male mice on the 129S6/SvEv genetic background are the most appropriate candidates for therapeutic studies. They exhibit motor deficits at 1 and 6 months of age in the vertical pole test, and they were the only mice to show impaired motor coordination in the rotarod test at both 3 and 6 months. Cln3(-/-) males on the C57BL/6J background and Cln3(?ex7/8) males on the 129S6/SvEv background also provide good outcome measures for therapeutic interventions. Cln3(-/-) (C57BL/6J) males had serious difficulties in climbing down (at 1 and 6 months) and turning downward on (at 1, 3 and 6 months) the vertical pole, whereas Cln3(?ex7/8) (129S6/SvEv) males climbed down the vertical pole drastically slower than wild-type males at 3 and 6 months of age. Our study demonstrates the importance of testing mouse models on different genetic backgrounds and comparing males and females in order to find the most appropriate disease model for therapeutic studies. PMID:26035843

  15. Genetic polymorphism of tumor necrosis factor promoter region and susceptibility to develop Hodgkin lymphoma in a Mexican population.

    PubMed

    Torres-Espíndola, Luz María; Velázquez-Cruz, Rafael; Falfán-Valencia, Ramcés; Chavez-Pacheco, Juan Luis; Salcedo-Vargas, Mauricio; de Jesús Nambo-Lucio, María; Salinas-Lara, Citaltepetl; Alemón-Medina, Radames; Granados-Montiel, Julio; Reyes-Servín, Miguel Angel; Granados, Julio; de Jesús Castillejos-López, Manuel

    2014-06-01

    Hodgkin lymphoma (HL) is a rare neoplasm of the lymphatic system, in which inflammation and allelic variants in cytokines have been proposed as etiological factors. Epstein-Barr virus infection is often associated as a risk factor in HL and since cytokines are involved in the humoral response to viral infection. Our aim was to study the association between single nucleotide polymorphisms (SNPs) located in the tumor necrosis factor (TNF) gene (- 376G> A, - 238G> A and 581G> A) in a sample of Mexican patients (56 cases) and their susceptibility to develop HL, comparing these SNPs among healthy individuals (127 controls). Frequencies for TNF - 238G> A and TNF 581G> A showed no significant differences between cases and controls. However, the proportion of cases with the GA genotype of - 376 SNP showed a significant difference as compared to controls, odds ratio = 4.41 (95% confidence interval: 1.21-16.6), p = 0.02. We found that in this group of patients from Mexico the SNP - 376G> A in TNF shows an association with higher risk for HL. PMID:24033107

  16. Role of Genetic Background in Determining Phenotypic Severity Throughout Postnatal Development and at Peak Bone Mass in Col1a2 Deficient Mice (oim)

    PubMed Central

    Carleton, Stephanie M.; McBride, Daniel J.; Carson, William L.; Huntington, Carolyn E.; Twenter, Kristin L.; Rolwes, Kristin M.; Winkelmann, Christopher T.; Morris, J. Steve; Taylor, Jeremy F.; Phillips, Charlotte L.

    2008-01-01

    Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disease characterized by extreme bone fragility. Although fracture numbers tend to decrease post-puberty, OI patients can exhibit significant variation in clinical outcome, even among related individuals harboring the same mutation. OI most frequently results from mutations in type I collagen genes, yet how genetic background impacts phenotypic outcome remains unclear. Therefore, we analyzed the phenotypic severity of a known pro?2(I) collagen gene defect (oim) on two genetic backgrounds (congenic C57BL/6J and outbred B6C3Fe) throughout postnatal development to discern the phenotypic contributions of the Col1a2 locus relative to the contribution of the genetic background. To this end, femora and tibiae were isolated from wildtype (Wt) and homozygous (oim/oim) mice of each strain at 1, 2 and 4 months of age. Femoral geometry was determined via µCT prior to torsional loading to failure to assess bone structural and material biomechanical properties. Changes in mineral composition, collagen content and bone turnover were determined using neutron activation analyses, hydroxyproline content and serum pyridinoline crosslinks. µCT analysis demonstrated genotype-, strain- and age-associated changes in femoral geometry as well as a marked decrease in the amount of bone in oim/oim mice of both strains. Oim/oim mice of both strains, as well as C57BL/6J (B6) mice of all genotypes, had reduced femoral biomechanical strength properties compared to Wt at all ages, although they improved with age. Mineral levels of fluoride, magnesium and sodium were associated with biomechanical strength properties in both strains and all genotypes at all ages. Oim/oim animals also had reduced collagen content as compared to Wt at all ages. Serum pyridinoline crosslinks were highest at two months of age, regardless of strain or genotype. Strain differences in bone parameters exist throughout development, implicating a role for genetic background in determining biomechanical strength. Age-associated improvements indicate that oim/oim animals partially compensate for their weaker bone material, but never attain Wt levels. These studies indicate the importance of genetic background in determining phenotypic severity, but the presence of the pro?2(I) collagen gene defect and age of the animal are the primary determinants of phenotypic severity. PMID:18313376

  17. A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

    PubMed Central

    Carmona, F. David; Mackie, Sarah L.; Martín, Jose-Ezequiel; Taylor, John C.; Vaglio, Augusto; Eyre, Stephen; Bossini-Castillo, Lara; Castañeda, Santos; Cid, Maria C.; Hernández-Rodríguez, José; Prieto-González, Sergio; Solans, Roser; Ramentol-Sintas, Marc; González-Escribano, M. Francisca; Ortiz-Fernández, Lourdes; Morado, Inmaculada C.; Narváez, Javier; Miranda-Filloy, José A.; Martínez-Berriochoa, Agustín; Unzurrunzaga, Ainhoa; Hidalgo-Conde, Ana; Madroñero-Vuelta, Ana B.; Fernández-Nebro, Antonio; Ordóñez-Cañizares, M. Carmen; Escalante, Begoña; Marí-Alfonso, Begoña; Sopeña, Bernardo; Magro, César; Raya, Enrique; Grau, Elena; Román, José A.; de Miguel, Eugenio; López-Longo, F. Javier; Martínez, Lina; Gómez-Vaquero, Carmen; Fernández-Gutiérrez, Benjamín; Rodríguez-Rodríguez, Luis; Díaz-López, J. Bernardino; Caminal-Montero, Luis; Martínez-Zapico, Aleida; Monfort, Jordi; Tío, Laura; Sánchez-Martín, Julio; Alegre-Sancho, Juan J.; Sáez-Comet, Luis; Pérez-Conesa, Mercedes; Corbera-Bellalta, Marc; García-Villanueva, M. Jesús; Fernández-Contreras, M. Encarnación; Sanchez-Pernaute, Olga; Blanco, Ricardo; Ortego-Centeno, Norberto; Ríos-Fernández, Raquel; Callejas, José L.; Fanlo-Mateo, Patricia; Martínez-Taboada, Víctor M.; Beretta, Lorenzo; Lunardi, Claudio; Cimmino, Marco A.; Gianfreda, Davide; Santilli, Daniele; Ramirez, Giuseppe A.; Soriano, Alessandra; Muratore, Francesco; Pazzola, Giulia; Addimanda, Olga; Wijmenga, Cisca; Witte, Torsten; Schirmer, Jan H.; Moosig, Frank; Schönau, Verena; Franke, Andre; Palm, Øyvind; Molberg, Øyvind; Diamantopoulos, Andreas P.; Carette, Simon; Cuthbertson, David; Forbess, Lindsy J.; Hoffman, Gary S.; Khalidi, Nader A.; Koening, Curry L.; Langford, Carol A.; McAlear, Carol A.; Moreland, Larry; Monach, Paul A.; Pagnoux, Christian; Seo, Philip; Spiera, Robert; Sreih, Antoine G.; Warrington, Kenneth J.; Ytterberg, Steven R.; Gregersen, Peter K.; Pease, Colin T.; Gough, Andrew; Green, Michael; Hordon, Lesley; Jarrett, Stephen; Watts, Richard; Levy, Sarah; Patel, Yusuf; Kamath, Sanjeet; Dasgupta, Bhaskar; Worthington, Jane; Koeleman, Bobby P.C.; de Bakker, Paul I.W.; Barrett, Jennifer H.; Salvarani, Carlo; Merkel, Peter A.; González-Gay, Miguel A.; Morgan, Ann W.; Martín, Javier

    2015-01-01

    We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10?40, OR = 1.73). A multivariate model including class II amino acids of HLA-DR?1 and HLA-DQ?1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1?04. An omnibus test on polymorphic amino acid positions highlighted DR?1 13 (p = 4.08 × 10?43) and HLA-DQ?1 47 (p = 4.02 × 10?46), 56, and 76 (both p = 1.84 × 10?45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10?6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10?6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10?5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. PMID:25817017

  18. Sex differences in lung cancer susceptibility: A review

    Microsoft Academic Search

    Chikako Kiyohara; Yoshiyuki Ohno

    2010-01-01

    Background: Several epidemiologic and molecular epidemiologic studies have indicated that, for a given number of cigarettes smoked, women may be at higher risk of lung cancer compared with men.Objective: The objective of this article was to address sex differences in lung cancer susceptibility, with special emphasis on genetic, biological, and sex-related hormonal factors.Methods: Using the search terms gender or sex

  19. Hemizygous Le-Cre Transgenic Mice Have Severe Eye Abnormalities on Some Genetic Backgrounds in the Absence of LoxP Sites

    PubMed Central

    Dorà, Natalie J.; Collinson, J. Martin; Hill, Robert E.; West, John D.

    2014-01-01

    Eye phenotypes were investigated in Le-CreTg/?; Pax6fl/+ mice, which were expected to show tissue-specific reduction of Pax6 in surface ectoderm derivatives. To provide a better comparison with our previous studies of Pax6+/? eye phenotypes, hemizygous Le-CreTg/? and heterozygous Pax6fl/+mice were crossed onto the CBA/Ca genetic background. After the Le-Cre transgene had been backcrossed to CBA/Ca for seven generations, significant eye abnormalities occurred in some hemizygous Le-CreTg/?; Pax6+/+ controls (without a floxed Pax6fl allele) as well as experimental Le-CreTg/?; Pax6fl/+ mice. However, no abnormalities were seen in Le-Cre?/?; Pax6fl/+ or Le-Cre?/?; Pax6+/+ controls (without the Le-Cre transgene). The severity and frequency of the eye abnormalities in Le-CreTg/?; Pax6+/+ control mice diminished after backcrossing Le-CreTg/? mice to the original FVB/N strain for two generations, showing that the effect was reversible. This genetic background effect suggests that the eye abnormalities are a consequence of an interaction between the Le-Cre transgene and alleles of unknown modifier genes present in certain genetic backgrounds. The abnormalities were also ameliorated by introducing additional Pax6 gene copies on a CBA/Ca background, suggesting involvement of Pax6 depletion in Le-CreTg/?; Pax6+/+ mice rather than direct action of Cre recombinase on cryptic pseudo-loxP sites. One possibility is that expression of Cre recombinase from the Pax6-Le regulatory sequences in the Le-Cre transgene depletes cofactors required for endogenous Pax6 gene expression. Our observation that eye abnormalities can occur in hemizygous Le-CreTg/?; Pax6+/+ mice, in the absence of a floxed allele, demonstrates the importance of including all the relevant genetic controls in Cre-loxP experiments. PMID:25272013

  20. Genetic-Background Modulation of Core and Variable Autistic-Like Symptoms in Fmr1 Knock-Out Mice

    E-print Network

    Boyer, Edmond

    a promising strategy. The Fmr1-KO mouse is an example of this approach, modeling Fragile X syndrome, a well of this approach: it is a confirmed model of Fragile X syndrome (FXS), a genetic disorder due to a mutation

  1. A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers

    Microsoft Academic Search

    R P Young; R J Hopkins; B A Hay; M J Epton; G D Mills; H D Gardner; R Sullivan; G D Gamble

    2010-01-01

    Background: Epidemiological and family studies suggest that lung cancer results from the combined effects of age, smoking and genetic factors. Chronic obstructive pulmonary disease (COPD) is also an independent risk factor for lung cancer and coexists in 40-60% of lung cancer cases. Methods: In a two-stage case-control association study, genetic markers associated with either susceptibility or protection against lung cancer

  2. Genetic counseling for susceptibility loci and neurodevelopmental disorders: the del15q11.2 as an example.

    PubMed

    De Wolf, Veerle; Brison, Nathalie; Devriendt, Koenraad; Peeters, Hilde

    2013-11-01

    In recent years, several recurrent copy number variations (CNVs) that confer risk of neurodevelopmental disorders have been identified (e.g., del and dup 16p11.2, del15q13.3, del and dup 1q21.1, del16p13.3, del15q11.2). They are often inherited from an unaffected parent and lack phenotypic specificity. Although there is growing evidence from association studies to consider them as susceptibility CNVs, their clinical utility is debated. Yet the clinician is frequently challenged to deal with these counseling situations without guidelines or consensus. In this report, counseling issues and research opportunities are discussed, with the recurrent 15q11.2 BP1-BP2 (including CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability, schizophrenia, epilepsy, and ASD. In this report we discuss how patient-specific and family-specific information may alter the interpretation of del15q11.2 as a contributing factor to the disorder in practical counseling situations. In addition, an association study for ASD in a Belgian Flemish cohort and an overview of reported association studies, clinical reports and genomics data for del15q11.2 are presented. PMID:24123946

  3. First evidence for the contribution of the genetic variations of BRCA1-interacting protein 1 (BRIP1) to the genetic susceptibility of cervical cancer.

    PubMed

    Ma, X D; Cai, G Q; Zou, W; Huang, Y H; Zhang, J R; Wang, D T; Chen, B L

    2013-07-25

    BRIP1 (BRCA1-interacting protein 1), a DNA-dependent ATPase and a DNA helicase, is critical for BRCA-associated DNA damage repair functions, and may be involved in the development of cervical cancer. Genetic markers in different regions of the BRIP1 gene have a plausible role in modulating the risk of cervical cancer. In this study, we evaluate the association between the BRIP1 variations and the risk of cervix cancer. We examined the potential association between cervical cancer and eighteen single nucleotide polymorphisms (SNPs, rs2048718, rs16945692, rs4968451, rs6504074, rs4988344, rs8077088, rs10515211, rs9897121, rs9906313, rs2159450, rs4986764, rs11871785, rs4986763, rs11079454, rs7213430, rs34289250, rs4988345 and rs12937080) of the BRIP1 gene using the MassARRAY system. The participants enrolled in this study included 298 patients with cervical cancer and 286 healthy women as the healthy controls from a Chinese Han population. The results showed that rs16945692 (intron 1), rs4968451 (intron 4), rs4986764 (exon 18) and rs7213430 (3'UTR) were significantly associated with cervical cancer (P<0.05). Furthermore, strong linkage disequilibrium (LD) was observed in three blocks (D'>0.9), and significantly more T-A-C-A haplotypes (block 1) (P=0.001) were found in the patients with cervical cancer. Significantly higher frequencies of C-A-T haplotypes (block 2) (P=0.018) and A-A haplotypes (block 3) (P=0.009) were detected in the healthy controls than in the patients with cervical cancer, suggesting that they may show protective effects against cervical cancer. These findings point to a role for the BRIP1 gene polymorphisms in cervical cancer in a Chinese Han population, and may be informative for future genetic or biological studies on cervical cancer. PMID:23644138

  4. Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer.

    PubMed

    Zhang, Xuemei; Miao, Xiaoping; Guo, Yongli; Tan, Wen; Zhou, Yifeng; Sun, Tong; Wang, Yonggang; Lin, Dongxin

    2006-01-01

    The tumor suppressor TP53 pathway plays a crucial role in preventing carcinogenesis through its ability to impose cell cycle arrest and apoptosis following DNA damage and oncogene activation. MDM2 is a key negative regulator of the TP53 pathway and is overexpressed in many cancers as oncoprotein. We investigated the association between genetic variation in the promoter region of MDM2 (c.-5+309G>T, rs2279744:g.G>T) and the coding region of TP53 (c.215G>C, rs1042522:g.G>C, designated Arg72Pro) and the risk of developing lung cancer. The genotypes of 1,106 patients and 1,420 controls were determined by tetra-primer amplification refractory mutation system (ARMS)-PCR or PCR-based restriction fragment length polymorphism (RFLP). Associations with risk of lung cancer were estimated by logistic regression. We observed an increased lung cancer risk associated with the MDM2 GG (odds ratio [OR] = 1.83, 95% confidence interval [CI] = 1.45-2.32) and TG (OR = 1.33, 95% CI = 1.09-1.63) genotypes. An increased risk was also associated with the TP53 Pro/Pro genotype (OR = 1.47, 95% CI = 1.17-1.85, P = 0.003) compared to the Arg/Arg genotype. The gene-gene interaction of MDM2 and TP53 polymorphisms increased lung cancer risk in a supermultiplicative manner (OR for the presence of both MDM2 GG and TP53 Pro/Pro genotypes = 4.56, 95% CI = 2.76-7.54). Significant interactions were observed between these polymorphisms (respectively and jointly) and smoking (OR = 10.41, 95% CI = 5.26-20.58) for smokers with both the MDM2 GG and TP53 Pro/Pro genotypes. In conclusion, genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 contribute to the risk of developing lung cancer. PMID:16287156

  5. Genetic Basis for Vancomycin-Enhanced Cephalosporin Susceptibility in Vancomycin-Resistant Enterococci Revealed Using Counterselection with Dominant-Negative Thymidylate Synthase

    PubMed Central

    Djori?, Dušanka; Little, Jaime L.

    2014-01-01

    Antibiotic-resistant enterococci are major causes of hospital-acquired infections. All enterococci are intrinsically resistant to most cephalosporins, antibiotics in the beta-lactam family that impair peptidoglycan synthesis by inactivating the transpeptidases responsible for cross-linking. In addition, clinical isolates of enterococci often possess acquired resistance to vancomycin, a glycopeptide antibiotic that impairs peptidoglycan biosynthesis by a mechanism distinct from that of the beta-lactams, namely, by binding to the d-Ala-d-Ala termini found in peptidoglycan precursors to prevent their utilization by biosynthetic transglycosylases. Antimicrobial synergism between vancomycin and beta-lactams against vancomycin-resistant enterococci was originally described decades ago, but the genetic basis for synergy has remained unknown. Because a complete understanding of the mechanism underlying synergy between vancomycin and beta-lactams might suggest new targets or strategies for therapeutic intervention against antibiotic-resistant enterococci, we explored the genetic basis for synergy between vancomycin and cephalosporins in Enterococcus faecalis. To do so, we developed a counterselection strategy based on a dominant-negative mutant of thymidylate synthase and implemented this approach to create a panel of mutants in vancomycin-resistant E. faecalis. Our results confirm that vancomycin promotes synergy by inducing expression of the van resistance genes, as a mutant in which the van genes are expressed in the absence of vancomycin exhibits susceptibility to cephalosporins. Further, we show that peptidoglycan precursors substituted with d-Ala-d-Lac are not required for vancomycin-enhanced cephalosporin sensitivity. Instead, production of the d,d-carboxypeptidase VanYB is both necessary and sufficient to dramatically sensitize E. faecalis to cephalosporins. PMID:24366749

  6. Integrative gene network analysis provides novel regulatory relationships, genetic contributions and susceptible targets in autism spectrum disorders

    PubMed Central

    Lee, Tin-Lap; Raygada, Margarita J; Rennert, Owen M

    2012-01-01

    Autism spectrum disorders (ASDs) are a group of diseases exhibiting impairment in social drive, communication/language skills and stereotyped behaviors. Though an increased number of candidate genes and molecular interactions have been identified by various approaches, the pathogenesis remains elusive. Based on clinical observations, data from accessible GWAS and expression datasets we identified ASDs gene candidates. Integrative gene network and a novel CNV-centric Node Network (CNN) analysis method highlighted ASDs-associated key elements and biological processes. Functional analysis identified neurological functions including synaptic cholinergic receptor (CHRNA) families, dopamine receptor (DRD2), and correlations between social behavior and oxytocin related pathways. CNN analysis of genome-wide genetic and expression data identified inheritance-related clusters related to PTEN/TSC1/FMR1 and mTor/PI3K regulation. Integrative analysis identified potential regulators of networks, specifically TNF and beta-estradiol, suggesting a potential central role in ASDs. Our data provides information on potential disease mechanisms, and key regulators that may generate novel postulations, and diagnostic molecular biomarkers. PMID:22306264

  7. Two female siblings with West syndrome: Familial idiopathic West syndrome with genetic susceptibility and variable phenotypic expression.

    PubMed

    Caglayan, Ahmet Okay; Gumus, Hakan; Kato, Mitsuhiro

    2010-07-01

    The West syndrome (WS) is a characteristic form of epilepsy which usually begins in the first year of life. We describe two female siblings, aged 4 and 2 years, respectively, born from third degree consanguineous parents, with infantile spasms and developmental delay. Epileptic spasms had not a good outcome under antiepileptic drug treatment. Clinical and imaging features were of different severity in both siblings. Routine biochemical tests, metabolic investigations, and chromosomal analysis were normal. We analyzed CDKL5 gene by direct sequences and denaturing high-performance liquid chromatography using Transgenomic WAVE system. Analysis of the CDKL5 gene, which is responsible for female patient with WS, did not show any disease-causing mutation. WS has heterogeneous backgrounds, and may be more than one gene is responsible for its familial forms. In this family, consanguinity is observed in parents, which usually suggests that autosomal recessive inheritance is likely. PMID:21559165

  8. Exposure to Drinking Water Trihalomethanes and Their Association with Low Birth Weight and Small for Gestational Age in Genetically Susceptible Women

    PubMed Central

    Danileviciute, Asta; Grazuleviciene, Regina; Vencloviene, Jone; Paulauskas, Algimantas; Nieuwenhuijsen, Mark J.

    2012-01-01

    Little is known about genetic susceptibility to individual trihalomethanes (THM) in relation to adverse pregnancy outcomes. We conducted a nested case-control study of 682 pregnant women in Kaunas (Lithuania) and, using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, estimated an internal THM dose. We used logistic regression to evaluate the relationship between internal THM dose, birth outcomes and individual and joint (modifying) effects of metabolic gene polymorphisms. THM exposure during entire pregnancy and specific trimesters slightly increased low birth weight (LBW) risk. When considering both THM exposure and maternal genotypes, the largest associations were found for third trimester among total THM (TTHM) and chloroform-exposed women with the GSTM1–0 genotype (OR: 4.37; 95% CI: 1.36–14.08 and OR: 5.06; 95% CI: 1.50–17.05, respectively). A test of interaction between internal THM dose and GSTM1–0 genotype suggested a modifying effect of exposure to chloroform and bromodichloromethane on LBW risk. However, the effect on small for gestational age (SGA) was not statistically significant. These data suggest that THM internal dose may affect foetal growth and that maternal GSTM1 genotype modifies the THM exposure effects on LBW. PMID:23222181

  9. The Emerging Role of Complement Lectin Pathway in Trypanosomatids: Molecular Bases in Activation, Genetic Deficiencies, Susceptibility to Infection, and Complement System-Based Therapeutics

    PubMed Central

    Evans-Osses, Ingrid; de Messias-Reason, Iara; Ramirez, Marcel I.

    2013-01-01

    The innate immune system is evolutionary and ancient and is the pivotal line of the host defense system to protect against invading pathogens and abnormal self-derived components. Cellular and molecular components are involved in recognition and effector mechanisms for a successful innate immune response. The complement lectin pathway (CLP) was discovered in 1990. These new components at the complement world are very efficient. Mannan-binding lectin (MBL) and ficolin not only recognize many molecular patterns of pathogens rapidly to activate complement but also display several strategies to evade innate immunity. Many studies have shown a relation between the deficit of complement factors and susceptibility to infection. The recently discovered CLP was shown to be important in host defense against protozoan microbes. Although the recognition of pathogen-associated molecular patterns by MBL and Ficolins reveal efficient complement activations, an increase in deficiency of complement factors and diversity of parasite strategies of immune evasion demonstrate the unsuccessful effort to control the infection. In the present paper, we will discuss basic aspects of complement activation, the structure of the lectin pathway components, genetic deficiency of complement factors, and new therapeutic opportunities to target the complement system to control infection. PMID:23533355

  10. The emerging role of complement lectin pathway in trypanosomatids: molecular bases in activation, genetic deficiencies, susceptibility to infection, and complement system-based therapeutics.

    PubMed

    Evans-Osses, Ingrid; de Messias-Reason, Iara; Ramirez, Marcel I

    2013-01-01

    The innate immune system is evolutionary and ancient and is the pivotal line of the host defense system to protect against invading pathogens and abnormal self-derived components. Cellular and molecular components are involved in recognition and effector mechanisms for a successful innate immune response. The complement lectin pathway (CLP) was discovered in 1990. These new components at the complement world are very efficient. Mannan-binding lectin (MBL) and ficolin not only recognize many molecular patterns of pathogens rapidly to activate complement but also display several strategies to evade innate immunity. Many studies have shown a relation between the deficit of complement factors and susceptibility to infection. The recently discovered CLP was shown to be important in host defense against protozoan microbes. Although the recognition of pathogen-associated molecular patterns by MBL and Ficolins reveal efficient complement activations, an increase in deficiency of complement factors and diversity of parasite strategies of immune evasion demonstrate the unsuccessful effort to control the infection. In the present paper, we will discuss basic aspects of complement activation, the structure of the lectin pathway components, genetic deficiency of complement factors, and new therapeutic opportunities to target the complement system to control infection. PMID:23533355

  11. Exposure to drinking water trihalomethanes and their association with low birth weight and small for gestational age in genetically susceptible women.

    PubMed

    Danileviciute, Asta; Grazuleviciene, Regina; Vencloviene, Jone; Paulauskas, Algimantas; Nieuwenhuijsen, Mark J

    2012-12-01

    Little is known about genetic susceptibility to individual trihalomethanes (THM) in relation to adverse pregnancy outcomes. We conducted a nested case-control study of 682 pregnant women in Kaunas (Lithuania) and, using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, estimated an internal THM dose. We used logistic regression to evaluate the relationship between internal THM dose, birth outcomes and individual and joint (modifying) effects of metabolic gene polymorphisms. THM exposure during entire pregnancy and specific trimesters slightly increased low birth weight (LBW) risk. When considering both THM exposure and maternal genotypes, the largest associations were found for third trimester among total THM (TTHM) and chloroform-exposed women with the GSTM1-0 genotype (OR: 4.37; 95% CI: 1.36-14.08 and OR: 5.06; 95% CI: 1.50-17.05, respectively). A test of interaction between internal THM dose and GSTM1-0 genotype suggested a modifying effect of exposure to chloroform and bromodichloromethane on LBW risk. However, the effect on small for gestational age (SGA) was not statistically significant. These data suggest that THM internal dose may affect foetal growth and that maternal GSTM1 genotype modifies the THM exposure effects on LBW. PMID:23222181

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

    PubMed

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

    2011-06-01

    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 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 with breast cancer risk due to their role in the double-strand break repair pathway and their close association with BRCA1 and BRCA2. Two truncating mutations in PALB2 (Q66X and W1038X), one of which is has not been reported before, were detected in an independent Australian cohort of 70 individuals with breast or ovarian cancer, and have strong family histories of breast or breast/ovarian cancer. In addition, six missense variants predicted to be causative were detected, one in BRIP1 and five in PALB2. No causative variants were identified in RAD51C. This study supports recent observations that although rare, PALB2 mutations are present in a small but substantial proportion of inherited breast cancer cases, and indicates that RAD51C at a population level does not account for a substantial number of familial breast cancer cases. PMID:21409391

  13. Copy Number Variants and Genetic Polymorphisms in TBX21, GATA3, Rorc, Foxp3 and Susceptibility to Behcet's Disease and Vogt-Koyanagi-Harada Syndrome

    PubMed Central

    Liao, Dan; Hou, Shengping; Zhang, Jun; Fang, Jing; Liu, Yunjia; Bai, Lin; Cao, Qingfeng; Aize Kijlstra; Yang, Peizeng

    2015-01-01

    This study aimed to investigate the role of genetic variants including single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) of TBX21, GATA3, Rorc and Foxp3 genes in Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in a Chinese Han population. Genotyping of 25 SNPs was performed by iPLEX system (Sequenom) or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). TaqMan real time PCR was used to assess CNVs. The expression of Rorc and Foxp3 were examined by real-time PCR and cytokine production was measured by ELISA. High Rorc CNV was associated with the susceptibility to BD (P = 8.99 × 10?8, OR = 3.0), and low Foxp3 CNV predisposed to BD in female patients (P = 1.92 × 10?5, OR = 3.1). CNVs for the investigated genes were not altered in VKH syndrome. Further functional studies demonstrated that the relative mRNA expression levels of Rorc were increased in individuals with high Rorc copy number, but not for Foxp3. Increased production of IL-1? and IL-6 was found in individuals carrying a high CNV of Rorc. Our study showed that high CNVs of Rorc and low CNVs of Foxp3 confer risk for BD but not for VKH syndrome. The tested 25 SNPs in TBX21, GATA3, Rorc and Foxp3 did not associate with BD and VKH syndrome. PMID:25873156

  14. The role of mouse strain differences in the susceptibility to fibrosis: a systematic review

    PubMed Central

    2013-01-01

    In humans, a number of genetic factors have been linked to the development of fibrosis in a variety of different organs. Seeking a wider understanding of this observation in man is ethically important. There is mounting evidence suggesting that inbred mouse strains with different genetic backgrounds demonstrate variable susceptibility to a fibrotic injury. We performed a systematic review of the literature describing strain and organ specific response to injury in order to determine whether genetic susceptibility plays a role in fibrogenesis. Data were collected from studies that were deemed eligible for analysis based on set inclusion criteria, and findings were assessed in relation to strain of mouse, type of injury and organ of investigation. A total of 44 studies were included covering 21 mouse strains and focusing on fibrosis in the lung, liver, kidney, intestine and heart. There is evidence that mouse strain differences influence susceptibility to fibrosis and this appears to be organ specific. For instance, C57BL/6J mice are resistant to hepatic, renal and cardiac fibrosis but susceptible to pulmonary and intestinal fibrosis. However, BALB/c mice are resistant to pulmonary fibrosis but susceptible to hepatic fibrosis. Few studies have assessed the effect of the same injury stimulus in different organ systems using the same strains of mouse. Such mouse strain studies may prove useful in elucidating the genetic as well as epigenetic factors in humans that could help determine why some people are more susceptible to the development of certain organ specific fibrosis than others. PMID:24294831

  15. Genetic and Functional Evidence Implicating DLL1 as the Gene That Influences Susceptibility to Visceral Leishmaniasis at Chromosome 6q27

    PubMed Central

    Fakiola, Michaela; Miller, E. Nancy; Fadl, Manal; Mohamed, Hiba S.; Jamieson, Sarra E.; Francis, Richard W.; Cordell, Heather J.; Peacock, Christopher S.; Raju, Madhuri; Khalil, Eltahir A.; Elhassan, Ahmed; Musa, Ahmed M.; Silveira, Fernando; Shaw, Jeffrey J.; Sundar, Shyam; Jeronimo, Selma M. B.; Ibrahim, Muntaser E.

    2011-01-01

    Background.?Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum chagasi. Genome-wide linkage studies from Sudan and Brazil identified a putative susceptibility locus on chromosome 6q27. Methods.?Twenty-two single-nucleotide polymorphisms (SNPs) at genes PHF10, C6orf70, DLL1, FAM120B, PSMB1, and TBP were genotyped in 193 VL cases from 85 Sudanese families, and 8 SNPs at genes PHF10, C6orf70, DLL1, PSMB1, and TBP were genotyped in 194 VL cases from 80 Brazilian families. Family-based association, haplotype, and linkage disequilibrium analyses were performed. Multispecies comparative sequence analysis was used to identify conserved noncoding sequences carrying putative regulatory elements. Quantitative reverse-transcription polymerase chain reaction measured expression of candidate genes in splenic aspirates from Indian patients with VL compared with that in the control spleen sample. Results.?Positive associations were observed at PHF10, C6orf70, DLL1, PSMB1, and TBP in Sudan, but only at DLL1 in Brazil (combined P = 3 × 10?4 at DLL1 across Sudan and Brazil). No functional coding region variants were observed in resequencing of 22 Sudanese VL cases. DLL1 expression was significantly (P = 2 × 10?7) reduced (mean fold change, 3.5 [SEM, 0.7]) in splenic aspirates from patients with VL, whereas other 6q27 genes showed higher levels (1.27 × 10?6 < P < .01) than did the control spleen sample. A cluster of conserved noncoding sequences with putative regulatory variants was identified in the distal promoter of DLL1. Conclusions.?DLL1, which encodes Delta-like 1, the ligand for Notch3, is strongly implicated as the chromosome 6q27 VL susceptibility gene. PMID:21742847

  16. Contribution of eNOS variants to the genetic susceptibility of coronary artery disease in a Tunisian population.

    PubMed

    Ben Ali, Marwa; Messaoudi, Safia; Ezzine, Houda; Mahjoub, Touhami

    2015-04-01

    Nitric oxide (NO), produced by the enzyme endothelial nitric oxide synthase (eNOS), has critical roles in the regulation of vascular homeostasis and prevention of atherogenesis by inhibiting leukocytes, platelet activation, and smooth muscle cell proliferation. There is strong experimental and clinical evidence that abnormalities in eNOS availability play an important role in the pathophysiology of coronary artery disease (CAD). Controversial results regarding the association of eNOS gene polymorphisms with CAD have been reported. The aim of this study is to investigate the relationship of the 894G>T (rs1799983) and 4a/4b (rs61722009) polymorphisms of the eNOS gene with the presence of CAD in the Tunisian population. A total of 332 patients with CAD and 368 controls were included in this study. The 894G>T (rs1799983) single-nucleotide polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism, and 4a/4b (rs61722009) polymorphism just by polymerase chain reaction (PCR). eNOS rs1799983 was significantly associated with CAD under the additive, dominant, but not recessive, models (additive model OR: 2.81; 95% CI [2.05-3.85]; p<0.001, dominant model OR: 2.84; 95% CI [2.09-3.86]; p<0.001, and recessive models p=0.09). This remained significant after adjustment for age, gender, diabetes, smoking, and hypertension. In contrast to eNOS rs1799983, eNOS rs61722009 was not associated with CAD under any of the genetic models tested. These findings suggest that the G894T (rs1799983) polymorphism of the eNOS gene was associated with CAD in Tunisian patients. PMID:25748584

  17. Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder

    PubMed Central

    Cichon, Sven; Mühleisen, Thomas W.; Degenhardt, Franziska A.; Mattheisen, Manuel; Miró, Xavier; Strohmaier, Jana; Steffens, Michael; Meesters, Christian; Herms, Stefan; Weingarten, Moritz; Priebe, Lutz; Haenisch, Britta; Alexander, Michael; Vollmer, Jennifer; Breuer, René; Schmäl, Christine; Tessmann, Peter; Moebus, Susanne; Wichmann, H.-Erich; Schreiber, Stefan; Müller-Myhsok, Bertram; Lucae, Susanne; Jamain, Stéphane; Leboyer, Marion; Bellivier, Frank; Etain, Bruno; Henry, Chantal; Kahn, Jean-Pierre; Heath, Simon; Hamshere, Marian; O'Donovan, Michael C.; Owen, Michael J.; Craddock, Nick; Schwarz, Markus; Vedder, Helmut; Kammerer-Ciernioch, Jutta; Reif, Andreas; Sasse, Johanna; Bauer, Michael; Hautzinger, Martin; Wright, Adam; Mitchell, Philip B.; Schofield, Peter R.; Montgomery, Grant W.; Medland, Sarah E.; Gordon, Scott D.; Martin, Nicholas G.; Gustafsson, Omar; Andreassen, Ole; Djurovic, Srdjan; Sigurdsson, Engilbert; Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari; Kapur-Pojskic, Lejla; Oruc, Liliana; Rivas, Fabio; Mayoral, Fermín; Chuchalin, Alexander; Babadjanova, Gulja; Tiganov, Alexander S.; Pantelejeva, Galina; Abramova, Lilia I.; Grigoroiu-Serbanescu, Maria; Diaconu, Carmen C.; Czerski, Piotr M.; Hauser, Joanna; Zimmer, Andreas; Lathrop, Mark; Schulze, Thomas G.; Wienker, Thomas F.; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Rietschel, Marcella; Nöthen, Markus M.

    2011-01-01

    We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10?8; odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10?4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10?9 (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies. PMID:21353194

  18. Bayes factor analysis for the genetic background of physiological and vitality variables of F2 Iberian × Meishan newborn piglets1

    Microsoft Academic Search

    L. Varona; J. Casellas; J. Piedrafita; A. Sanchez; P. Garcia-Casado; M. Arque; J. L. Noguera

    2010-01-01

    The Bayes factor (BF) procedure was applied to examine the additive genetic component of several physiological and vitality variables for newborn pigs. Nine variables were studied: heart rate, arterial oxygen saturation, rectal temperature (all at birth and 60 min later), birth weight, interval between birth and first teats contact, and interval between birth and first colostrum intake. The available numbers

  19. Genome-Wide Linkage Screen for Systolic Blood Pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and Confirmation of a Major Susceptibility Locus on Chromosome 6q14.1

    Microsoft Academic Search

    Sobha Puppala; Dawn K. Coletta; Jennifer Schneider; Shirley L. Hu; Vidya S. Farook; Thomas D. Dyer; Rector Arya; John Blangero; Ravindranath Duggirala; Ralph A. DeFronzo; Christopher P. Jenkinson

    2011-01-01

    Objective: Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). Methods: Using data from 1,089 individuals distributed across 266 families, we

  20. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth.

    PubMed Central

    Lichtman, S N; Okoruwa, E E; Keku, J; Schwab, J H; Sartor, R B

    1992-01-01

    Jejunal self-filling blind loops with subsequent small bowel bacterial overgrowth (SBBO) induce hepatobiliary injury in genetically susceptible Lewis rats. Lesions consist of portal tract inflammation, bile duct proliferation, and destruction. To determine the pathogenesis of SBBO-induced hepatobiliary injury, we treated Lewis rats with SBBO by using several agents with different mechanisms of activity. Buffer treatment, ursodeoxycholic acid, prednisone, methotrexate, and cyclosporin A failed to prevent SBBO-induced injury as demonstrated by increased plasma aspartate aminotransferase (AST) and elevated histology scores. However, hepatic injury was prevented by mutanolysin, a muralytic enzyme whose only known activity is to split the beta 1-4 N-acetylmuramyl-N-acetylglucosamine linkage of peptidoglycan-polysaccharide (PG-PS), a bacterial cell wall polymer with potent inflammatory and immunoregulatory properties. Mutanolysin therapy started on the day blind loops were surgically created and continued for 8 wk significantly diminished AST (101 +/- 37 U/liter) and liver histology scores (2.2 +/- 2.7) compared to buffer-treated rats (228 +/- 146 U/liter, P < 0.05, 8.2 +/- 1.9, P < 0.001 respectively). Mutanolysin treatment started during the early phase of hepatic injury, 16-21 d after surgery, decreased AST in 7 of 11 rats from 142 +/- 80 to 103 +/- 24 U/liter contrasted to increased AST in 9 of 11 buffer-treated rats from 108 +/- 52 to 247 +/- 142 U/liter, P < 0.05. Mutanolysin did not change total bacterial numbers within the loop, eliminate Bacteroides sp., have in vitro antibiotic effects, or diminish mucosal PG-PS transport. However, mutanolysin treatment prevented elevation of plasma anti-PG antibodies and tumor necrosis factor-alpha (TNF alpha) levels which occurred in buffer treated rats with SBBO and decreased TNF alpha production in isolated Kupffer cells stimulated in vitro with PG-PS. Based on the preventive and therapeutic activity of this highly specific muralytic enzyme, we conclude that systemic uptake of PG-PS derived from endogenous enteric bacteria contributes to hepatobiliary injury induced by SBBO in susceptible rat strains. PMID:1401067

  1. Genetic Diversity of the KIR/HLA System and Susceptibility to Hepatitis C Virus-Related Diseases

    PubMed Central

    De Re, Valli; Caggiari, Laura; De Zorzi, Mariangela; Repetto, Ombretta; Zignego, Anna Linda; Izzo, Francesco; Tornesello, Maria Lina; Buonaguro, Franco Maria; Mangia, Alessandra; Sansonno, Domenico; Racanelli, Vito; De Vita, Salvatore; Pioltelli, Pietro; Vaccher, Emanuela; Beretta, Massimiliano; Mazzaro, Cesare; Libra, Massimo; Gini, Andrea; Zucchetto, Antonella; Cannizzaro, Renato; De Paoli, Paolo

    2015-01-01

    Background The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. Methods and Findings We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher’s exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. Conclusions Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-? therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases. PMID:25700262

  2. Temporal and Anatomical Host Resistance to Chronic Salmonella Infection Is Quantitatively Dictated by Nramp1 and Influenced by Host Genetic Background

    PubMed Central

    Loomis, Wendy P.; Johnson, Matthew L.; Brasfield, Alicia; Blanc, Marie-Pierre; Yi, Jaehun; Miller, Samuel I.; Cookson, Brad T.; Hajjar, Adeline M.

    2014-01-01

    The lysosomal membrane transporter, Nramp1, plays a key role in innate immunity and resistance to infection with intracellular pathogens such as non-typhoidal Salmonella (NTS). NTS-susceptible C57BL/6 (B6) mice, which express the mutant Nramp1D169 allele, are unable to control acute infection with Salmonella enterica serovar Typhimurium following intraperitoneal or oral inoculation. Introducing functional Nramp1G169 into the B6 host background, either by constructing a congenic strain carrying Nramp1G169 from resistant A/J mice (Nramp-Cg) or overexpressing Nramp1G169 from a transgene (Nramp-Tg), conferred equivalent protection against acute Salmonella infection. In contrast, the contributions of Nramp1 for controlling chronic infection are more complex, involving temporal and anatomical differences in Nramp1-dependent host responses. Nramp-Cg, Nramp-Tg and NTS-resistant 129×1/SvJ mice survived oral Salmonella infection equally well for the first 2–3 weeks, providing evidence that Nramp1 contributes to the initial control of NTS bacteremia preceding establishment of chronic Salmonella infection. By day 30, increased host Nramp1 expression (Tg>Cg) provided greater protection as indicated by decreased splenic bacterial colonization (Tgsusceptible mice, 2) restriction of systemic bacterial growth in the spleens of NTS-susceptible mice is enhanced by Nramp1 expression and dose-dependent, and 3) host genes other than Nramp1 also contribute to the ability of NTS-resistant 129×1/SvJ mice to control bacterial replication during chronic infection. PMID:25350459

  3. Population genetics of the blue crab Callinectes sapidus : modest population structuring in a background of high gene flow

    Microsoft Academic Search

    Anne L. McMillen-Jackson; Theresa M. Bert; Philip Steele

    1994-01-01

    To determine the genetic population structure of blue crabs (Callinectes sapidus Rathbun), electrophoretic allozyme analysis was performed on 750 individuals collected from 16 nearshore locations ranging from New York to Texas, USA. Twenty enzymes and non-enzymatic proteins coded by 31 presumptive loci were examined. Twenty-two loci were either monomorphic or polymorphic at less than theP95 level; alleles for these polymorphic

  4. Genetic study of two single nucleotide polymorphisms within corresponding microRNAs and susceptibility to tuberculosis in a Chinese Tibetan and Han population.

    PubMed

    Li, Dongdong; Li, Dingdong; Wang, Tingting; Song, Xingbo; Qucuo, MeiLang; Yang, Bin; Zhang, Junlong; Wang, Jun; Ying, Binwu; Tao, Chuanmin; Wang, Lanlan

    2011-07-01

    MicroRNAs (miRNA) are thought to play important roles in the pathogenesis of diseases. Single nucleotide polymorphisms (SNPs) within miRNAs can change their characteristics via altering their target selection and/or expression, resulting in functional and/or phenotypic changes. We decided to investigate the genetic association with pulmonary tuberculosis with 2 nucleotide variations within corresponding microRNAs regulating the Toll-like receptor (TLR)-mediating signal pathway. MiRNAs potentially regulating the TLR-mediating signal pathway were predicted via bioinformatics. Finally, 2 SNPs, rs2910164 G>C and rs3746444 T>C within miR-146a and miR-499, were selected as candidates in accordance with some criteria. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism and validated by sequencing to demonstrate their association with susceptibility to pulmonary tuberculosis (PTB) in 337 PTB cases and 738 healthy controls, including 318 Tibetan and 757 Han individuals. Bioinformatics databases were searched to support the association between miRNAs and PTB. There was no association between rs3746444 and PTB risk (p = 0.118) in the Han population, but subjects carrying the C allele exhibited decreased PTB risk (odds ratio [OR] = 0.403 [95% confidence interval (95% CI) 0.278-0.583]). However, there was an association between rs3746444 and PTB in the Tibetan population, and individuals carrying the C allele exhibited increased PTB risk (OR = 1.870 [95% CI 1.218-2.871]). A polymorphism (rs2910164 G>C) indicated an association with PTB risk in both Tibetan (p = 0.031) and Han (p = 0.000) populations. However, the role of the G allele of rs2910164, like the C allele in rs3746444, differed in the Tibetan (OR = 1.509, p < 0.05) and Han (OR = 0.575, p < 0.05) groups. This is the first report to suggest that a genetic association with pulmonary tuberculosis with SNPs within the corresponding miRNAs potentially regulates the TLR signal pathway. It is interesting that both the G allele (rs2910164) and the C allele (rs3746444) play different roles in 2 populations. Further functional analysis of the SNP and its impact on mRNA targets is required to confirm the relationship between genotype and phenotype. PMID:21524676

  5. Distinctive cellular immunity in genetically susceptible BALB/c mice recovered from Leishmania major infection or after subcutaneous immunization with killed parasites

    SciTech Connect

    Liew, F.Y.; Dhaliwal, J.S.

    1987-06-15

    Genetically susceptible BALB/c mice are refractory to further infection after recovery from Leishmania major infection after a sublethal dose of gamma-irradiation. In contrast, mice immunized with killed promastigotes s.c. develop exacerbated lesions after infection. Both groups of mice produce only a low level of specific antibody and no detectable cytotoxic T cells, but do have a strong antigen-specific DTH, which is adoptively transferable with Lyt-1+2-, L3T4+ T cells. Kinetic and histological studies revealed that mice immunized s.c. developed Jones-Mote hypersensitivity, peaking at 15 hr. with little mononuclear cell infiltration at the site of antigen administration; whereas mice that had recovered from infection developed tuberculin-type of reactivity, peaking at 24 to 48 hr, with intense mononuclear cell infiltration. Splenic T cells from recovered mice, when injected into the footpads of normal recipients together with live promastigotes, were able to retard lesion development; whereas T cells from s.c. immunized mice, when similarly transferred, accelerated disease progression. Antigen-specific culture supernatant of spleen cells from recovered mice also activated normal resident peritoneal macrophages to kill intracellular L. major amastigotes and tumor cells. Culture supernatants of spleen cells from s.c. immunized or normal mice were devoid of such activities. Part of the macrophage-activating potential can be inhibited by antibody specific for IFN-gamma. These results therefore demonstrate that whereas the Jones-Mote reaction is correlated with disease exacerbation, the tuberculin-type of DTH may be protective. Furthermore, in vivo immunity is directly related to the capacity of T cells to produce macrophage-activating factor.

  6. Clustering of malaria treatment failure (TF) in Daraweesh: hints for host genetic susceptibility to TF with emphasis on immune-modulating SNPs.

    PubMed

    Giha, Hayder A; ElGhazali, Gehad; Nasr, Amre; Iriemenam, Nnaemeka C; Berzins, Klavs; Troye-Blomberg, Marita; Theander, Thor G; Arnot, David

    2010-05-01

    In malaria, drug resistance and treatment failure (TF) are not synonymous, although are escalating together. Over 9 years of surveillances for malaria morbidity and TF in Daraweesh village in eastern Sudan (1991-2004), 136 donors (15-78 years) from 43 households, treated for 278 malaria episodes and had experienced 46 incident of TF, were included in this study. Blood obtained from the donors in 2005, was used for measurement of IgG subclasses against Pf332-C231 antigen and GM/KM allotyping and for genotyping of the donors for; FcgammaRIIA 131 (HH, RH, RR), CRP 286 (Cgenetic susceptibility to TF, as some of the tested polymorphisms showed trends but no significant association with TF. PMID:20215002

  7. GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma

    PubMed Central

    Skibola, Christine F.; Darabi, Hatef; Conde, Lucia; Hjalgrim, Henrik; Kumar, Vikrant; Chang, Ellen T.; Rothman, Nathaniel; Cerhan, James R.; Brooks-Wilson, Angela R.; Rehnberg, Emil; Irwan, Ishak D.; Ryder, Lars P.; Brown, Peter N.; Bracci, Paige M.; Agana, Luz; Riby, Jacques; Cozen, Wendy; Davis, Scott; Hartge, Patricia; Morton, Lindsay M.; Severson, Richard K.; Wang, Sophia S.; Slager, Susan L.; Fredericksen, Zachary S.; Novak, Anne J.; Kay, Neil E.; Habermann, Thomas M.; Armstrong, Bruce; Kricker, Anne; Milliken, Sam; Purdue, Mark P.; Vajdic, Claire M.; Boyle, Peter; Lan, Qing; Zahm, Shelia H.; Zhang, Yawei; Zheng, Tongzhang; Leach, Stephen; Spinelli, John J.; Smith, Martyn T.; Chanock, Stephen J.; Padyukov, Leonid; Alfredsson, Lars; Klareskog, Lars; Glimelius, Bengt; Melbye, Mads; Liu, Edison T.; Adami, Hans-Olov; Humphreys, Keith; Liu, Jianjun

    2011-01-01

    Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined?=?0.64, Pcombined?=?2×10?21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted?=?0.70, Padjusted?=?4×10?12; rs10484561:ORadjusted?=?1.64, Padjusted?=?5×10?15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined?=?1.36, Pcombined?=?1.4×10?7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL. PMID:21533074

  8. Effects of Cu/Zn Superoxide Dismutase (sod1) Genotype and Genetic Background on Growth, Reproduction and

    E-print Network

    Blouin, Michael S.

    of injectionP ! .001 drug users in transmission among HETs over time. Conclusions. Our analysis suggests (1 Diseases, Regional Hospital Lugano, Lugano, Switzerland Background. Sequence data from resistance testing acquiring HIV through heterosexual contact (HETs) and injection drug users (IDUs) (12 transmission clusters

  9. Modelling Leaf Shape Evolution Background and Motivation. The foundations of evolution and population genetics respectively can be

    E-print Network

    Goldschmidt, Christina

    Modelling Leaf Shape Evolution Background and Motivation. The foundations of evolution. This project will only focus on simple models of shape evolution and their application to leaf shapes. Shape in the Tsiantis group (Piazza et al, 2010; Hay and Tsiantis, 2006). Leaf shape can be described as simple

  10. The Role of TLR4 896 A>G and 1196 C>T in Susceptibility to Infections: A Review and Meta-Analysis of Genetic Association Studies

    PubMed Central

    Ziakas, Panayiotis D.; Prodromou, Michael L.; El Khoury, Joseph; Zintzaras, Elias; Mylonakis, Eleftherios

    2013-01-01

    Background Toll-like receptor 4 plays a role in pathogen recognition, and common polymorphisms may alter host susceptibility to infectious diseases. Purpose To review the association of two common polymorphisms (TLR4 896A>G and TLR4 1196C>T) with infectious diseases. Data Sources We searched PubMed and EMBASE up to March 2013 for pertinent literature in English, and complemented search with references lists of eligible studies. Study Selection We included all studies that: reported an infectious outcome; had a case-control design and reported the TLR4 896A>G and/or TLR4 1196C>T genotype frequencies; 59 studies fulfilled these criteria and were analyzed. Data Extraction Two authors independently extracted study data. Data Synthesis The generalized odds ratio metric (ORG) was used to quantify the impact of TLR4 variants on disease susceptibility. A meta-analysis was undertaken for outcomes reported in >1 study. Eleven of 37 distinct outcomes were significant. TLR4 896 A>G increased risk for all parasitic infections (ORG 1.59; 95%CI 1.05-2.42), malaria (1.31; 95%CI 1.04-1.66), brucellosis (2.66; 95%CI 1.66-4.27), cutaneous leishmaniasis (7.22; 95%CI 1.91-27.29), neurocysticercosis (4.39; 95%CI 2.53-7.61), Streptococcus pyogenes tonsillar disease (2.93; 95%CI 1.24-6.93) , typhoid fever (2.51; 95%CI 1.18-5.34) and adult urinary tract infections (1.98; 95%CI 1.04-3.98), but was protective for leprosy (0.36; 95%CI 0.22-0.60). TLR4 1196 C>T effects were similar to TLR4 896 A>G for brucellosis, cutaneous leishmaniasis, leprosy, typhoid fever and S. pyogenes tonsillar disease, and was protective for bacterial vaginosis in pregnancy (0.55; 95%CI 0.31-0.98) and Haemophilus influenzae tonsillar disease (0.42; 95%CI 0.17-1.00). The majority of significant associations were among predominantly Asian populations and significant associations were rare among European populations. Conclusions Depending on the type of infection and population, TLR4 polymorphisms are associated with increased, decreased or no difference in infectious disease. This may be due to differential functional expression of TLR4, the co-segregation of TLR4 variants or a favorable inflammatory response. PMID:24282567

  11. Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12

    Microsoft Academic Search

    Silke Schmidt; William K Scott; Eric A Postel; Anita Agarwal; Elizabeth R Hauser; John R Gilbert; Michael B Gorin; Jonathan L Haines; Margaret A Pericak-Vance

    2004-01-01

    BACKGROUND: Age-related macular degeneration (AMD) is a complex disorder that is responsible for the majority of central vision loss in older adults living in developed countries. Phenotypic and genetic heterogeneity complicate the analysis of genome-wide scans for AMD susceptibility loci. The ordered subset analysis (OSA) method is an approach for reducing heterogeneity, increasing statistical power for detecting linkage, and helping

  12. Spectrum and Prevalence of Mutations Involving BrS1-12-Susceptibility Genes in a Cohort of Unrelated Patients Referred for Brugada Syndrome Genetic Testing: Implications for Genetic Testing

    PubMed Central

    Crotti, Lia; Kellen, Cherisse A.; Tester, David J.; Castelletti, Silvia; Giudicessi, John R.; Torchio, Margherita; Medeiros-Domingo, Argelia; Simone, Savastano; Will, Melissa L; Dagradi, Federica; Schwartz, Peter J.; Ackerman, Michael J.

    2012-01-01

    Objective To provide the spectrum and prevalence of mutations in the 12 Brugada Syndrome (BrS)-susceptibility genes discovered to date, in a single large BrS cohort. Background BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST segment elevation in the right precordial leads (V1-V3; type-1 Brugada ECG pattern) and the presence of a personal/family history of cardiac events. Methods Using PCR, DHPLC, and DNA sequencing, comprehensive mutational analysis of BrS1-12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS [46 with clinically diagnosed BrS (ECG pattern plus personal/family history of a cardiac event) and 83 with type 1 ECG pattern only]. Results Overall, 27 (21%) patients had a putative pathogenic mutation, absent in 1400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 CACNB2B, 1 KCNJ8, 1 KCND3, 1 SCN1Bb, and 1 HCN4. The overall mutation yield was 23% in type 1 ECG pattern only patients versus 17% in clinically diagnosed BrS patients, was significantly greater among young men < 20 years of age with clinically diagnosed BrS, and among patients who had a prolonged PQ interval. Conclusions We identified putative pathogenic mutations in ~20% of our BrS cohort, with BrS2-12 accounting for < 5%. Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval. PMID:22840528

  13. Accumulation of mtDNA variations in human single CD34+ cells from maternally related individuals: effects of aging and family genetic background

    PubMed Central

    Yao, Yong-Gang; Kajigaya, Sachiko; Feng, Xingmin; Samsel, Leigh; McCoy, J. Philip; Torelli, Giuseppe; Young, Neal S.

    2014-01-01

    Marked sequence variation in the mtDNA control region has been observed in human single CD34+ cells, which persist in vivo and are present also in differentiated hematopoietic cells. In this study, we analyzed 5071 single CD34+ cells from 49 individuals (including 31 maternally related members from four families and 18 unrelated donors) in order to determine the mutation spectrum within the mtDNA control region in single cells, as related to aging and family genetic background. Many highly mutated sites among family members were hypervariable sites in the mtDNA control region. Further, CD34+ cells from members of the same family also shared several unique mtDNA variants, suggesting pedigree-specific occurrence of these variants. Overall age-related accumulation of mtDNA mutations in CD34+ cells varied in different families, suggesting a specific accumulation pattern, which might be modulated by family genetic background. Our current findings have implications for the occurrence of mtDNA mutations in hematopoietic stem cells and progenitors. PMID:23455392

  14. Influence of the hypogonadism ( hgn ) locus on female reproduction and ovarian development in an altered genetic background

    Microsoft Academic Search

    Hiroetsu Suzuki; Kumi Daigo; Mika Okada; Mio Yagi; Eijiro Nakamiya; Kenichi Saito; Katsushi Suzuki

    2006-01-01

    Background and Aims  The hypogonadic rat (hgn\\/hgn) shows male sterility controlled by a single recessive gene hgn. The hgn\\/hgn females detected by the presence of renal hypoplasia in the HGN inbred strain show a reduced fertility. Recently the gene\\u000a responsible for male hypogonadism was mapped on chromosome 10 by a linkage analysis using only male backcross progeny. Because\\u000a backcross females could

  15. The mecA Homolog mecC Confers Resistance against ?-Lactams in Staphylococcus aureus Irrespective of the Genetic Strain Background

    PubMed Central

    Ballhausen, Britta; Kriegeskorte, André; Schleimer, Nina; Peters, Georg

    2014-01-01

    In staphylococci, methicillin resistance is mediated by mecA-encoded penicillin-binding protein 2a (PBP2a), which has a low affinity for beta-lactams. Recently, a novel PBP2a homolog was described as being encoded by mecC, which shares only 70% similarity to mecA. To prove that mecC is the genetic determinant that confers methicillin resistance in Staphylococcus aureus, a mecC knockout strain was generated. The S. aureus ?mecC strain showed considerably reduced oxacillin and cefoxitin MICs (0.25 and 4 ?g/ml, respectively) compared to those of the corresponding wild-type methicillin-resistant S. aureus (MRSA) strain (8 and 16 ?g/ml, respectively). Complementing the mutant in trans with wild-type mecC restored the resistance to oxacillin and cefoxitin. By expressing mecC and mecA in different S. aureus clonal lineages, we found that mecC mediates resistance irrespective of the genetic strain background, yielding oxacillin and cefoxitin MIC values comparable to those with mecA. In addition, we showed that mecC expression is inducible by oxacillin, which supports the assumption that a functional beta-lactam-dependent regulatory system is active in MRSA strains possessing staphylococcal cassette chromosome mec (SCCmec) type XI. In summary, we showed that mecC is inducible by oxacillin and mediates beta-lactam resistance in SCCmec type XI-carrying strains as well as in different S. aureus genetic backgrounds. Furthermore, our results could explain the comparatively low MICs for clinical mecC-harboring S. aureus isolates. PMID:24752255

  16. Identification and characterisation of functional expressed sequence tags-derived simple sequence repeat (eSSR) markers for genetic linkage mapping of Schistosoma mansoni juvenile resistance and susceptibility loci in Biomphalaria glabrata.

    PubMed

    Ittiprasert, Wannaporn; Miller, André; Su, Xin-zhuan; Mu, Jianbing; Bhusudsawang, Ganlayarat; Ukoskit, Kitipat; Knight, Matty

    2013-07-01

    Biomphalaria glabrata susceptibility to Schistosoma mansoni has a strong genetic component, offering the possibility for investigating host-parasite interactions at the molecular level, perhaps leading to novel control approaches. The identification, mapping and molecular characterisation of genes that influence the outcome of parasitic infection in the intermediate snail host is, therefore, seen as fundamental to the control of schistosomiasis. To better understand the evolutionary processes driving disease resistance/susceptibility phenotypes, we previously identified polymorphic random amplification of polymorphic DNA and genomic simple sequence repeats from B. glabrata. In the present study we identified and characterised polymorphic expressed simple sequence repeats markers (Bg-eSSR) from existing B. glabrata expressed sequence tags. Using these markers, and with previously identified genomic simple sequence repeats, genetic linkage mapping for parasite refractory and susceptibility phenotypes, the first known for B. glabrata, was initiated. Data mining of 54,309 expressed sequence tag, produced 660 expressed simple sequence repeats of which dinucleotide motifs (TA)n were the most common (37.88%), followed by trinucleotide (29.55%), mononucleotide (18.64%) and tetranucleotide (10.15%). Penta- and hexanucleotide motifs represented <3% of the Bg-eSSRs identified. While the majority (71%) of Bg-eSSRs were monomorphic between resistant and susceptible snails, several were, however, useful for the construction of a genetic linkage map based on their inheritance in segregating F2 progeny snails derived from crossing juvenile BS-90 and NMRI snails. Polymorphic Bg-eSSRs assorted into six linkage groups at a logarithm of odds score of 3. Interestingly, the heritability of four markers (Prim1_910, Prim1_771, Prim6_1024 and Prim7_823) with juvenile snail resistance were, by t-test, significant (P<0.05) while an allelic marker, Prim24_524, showed linkage with the juvenile snail susceptibility phenotype. On the basis of our results it is possible that the gene(s) controlling juvenile resistance and susceptibility to S. mansoni infection in B. glabrata are not only on the same linkage group but lie within a short distance (42cM) of each other. PMID:23643514

  17. Genetic Susceptibility of Colorectal Cancer

    Cancer.gov

    Skip to Main Content at the National Institutes of Health | www.cancer.gov Epidemiology and Genomics Research In NCI's Division of Cancer Control and Population Sciences Search EGRP: Main Menu EGRP Home About the Program Mission & Vision Organizational

  18. Genetic Susceptibility to Ovarian Cancer

    Cancer.gov

    Skip to Main Content at the National Institutes of Health | www.cancer.gov Epidemiology and Genomics Research In NCI's Division of Cancer Control and Population Sciences Search EGRP: Main Menu EGRP Home About the Program Mission & Vision Organizational

  19. The mineralization phenotype in Abcc6 ( -/- ) mice is affected by Ggcx gene deficiency and genetic background--a model for pseudoxanthoma elasticum.

    PubMed

    Li, Qiaoli; Uitto, Jouni

    2010-02-01

    Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by ectopic mineralization of connective tissues and shows considerable intra- and inter-familial phenotypic variability. PXE is caused by mutations in the ABCC6 gene, and targeted ablation of Abcc6 in mouse recapitulates PXE. In this study, we examined the hypothesis that the GGCX gene encoding gamma-glutamyl carboxylase may interfere with the mineralization process in Abcc6 ( -/- ) mice. Thus, Abcc6 ( -/- ) and Ggcx (+/-) mice were generated on 129S1;C57 and 129S1;129X1;C57 genetic backgrounds, respectively, and backcrossed with C57BL/6J for five generations. Thus, these strains differ by the 129X1 contribution to the background of the mice. We then generated Abcc6 ( -/- ) ;Ggcx (+/+) and Abcc6 ( -/- ) ;Ggcx (+/-) mice by crossing Abcc6 ( -/- ) and Ggcx (+/-) mice. The degree of mineralization of connective capsule of vibrissae, a biomarker of the mineralization process in PXE, was evaluated by computerized morphometric analysis and quantified colorimetrically by calcium and phosphate levels in tissues. The mineralization of the vibrissae in Abcc6 ( -/- ) mice takes place at approximately 5-6 weeks of age and is significantly enhanced at 3 months of age in comparison to wild-type mice (>10-fold, p < 0.001). However, the onset of mineralization in Abcc6 ( -/- ) ;Ggcx (+/+) mice was delayed until between 3 and 4 months of age, suggesting that the genetic background plays a role in modifying the mineralization process. The mineralization in the Abcc6 ( -/- ) ;Ggcx (+/- ) mice was accelerated in comparison with age-matched Abcc6 ( -/- ) ;Ggcx (+/+) mice, with approximately 3-fold difference at 3, 4, and 9 months of age (p < 0.01). The mineralization process was also accelerated in these mice by a special custom-designed diet with mineral modifications. These findings suggest a role for both the GGCX gene and the genetic background as well as dietary factors in modulating the phenotypic severity of PXE caused by loss-of-function mutations in ABCC6. PMID:19784827

  20. Genetic, household and spatial clustering of leprosy on an island in Indonesia: a population-based study

    Microsoft Academic Search

    Mirjam I Bakker; Linda May; Mochammad Hatta; Agnes Kwenang; Paul R Klatser; Linda Oskam; Jeanine J Houwing-Duistermaat

    2005-01-01

    BACKGROUND: It is generally accepted that genetic factors play a role in susceptibility to both leprosy per se and leprosy type, but only few studies have tempted to quantify this. Estimating the contribution of genetic factors to clustering of leprosy within families is difficult since these persons often share the same environment. The first aim of this study was to

  1. Genetics

    NSDL National Science Digital Library

    Jennifer Doherty

    This activity helps students to understand basic principles of genetics, including relationships of genotype to phenotype, concepts of recessive and dominant alleles, and how understanding meiosis and fertilization provides the basis for understanding inheritance, as summarized in Punnett squares. The Student Handout includes an analysis of the inheritance of albinism that teaches all of these concepts, a Coin Toss Genetics activity that helps students understand the probabilistic nature of Punnett square predictions, and an analysis of the inheritance of sickle cell anemia that reinforces the basic concepts and introduces some of the complexities of genetics. The Genetics Supplement includes two additional activities, an analysis of student data on the sex makeup of sibships and pedigree analyses of recessive and dominant alleles with challenge questions that introduce the role of mutations and an evaluation of Punnett squares and pedigrees as models of inheritance.

  2. Experimental Assessment of the Susceptibility to Stress-Corrosion Cracking of Ti-6A1-4V Alloy Exposed to MON-1 Propellant Tank Environment's Background and Test Design

    NASA Astrophysics Data System (ADS)

    Bussu, G.; Stramaccioni, D.; Kaelsch, I.

    2004-10-01

    Due to the Rosetta satellite launch postponement, the possibility of subjecting the titanium propellant tanks to off-loading, decontamination and subsequent refilling was considered by the European Space Agency. In this light, it was unknown whether, during this process, alterations of chemical composition of residuals in the tanks could cause unacceptable stress- corrosion damage of the tank material. So far, the susceptibility of Ti-6Al-4V alloy to stress-corrosion cracking in MON-1 environment has been assessed in nominal conditions of stress and chemical environment which are not sufficiently representative of real cases such as the off-loading, decontamination and refilling of tanks. The test programme that will be described in the paper has the objective of assessing the possibility of stress-corrosion cracking in Ti-6Al-4V propellant tanks in the case of tank off-loading, decontamination and refilling. The assessment involves the experimental determination of crack propagation stress intensity threshold values of parent plate and weld material exposed to the propellant tank stress and chemical environment expected during off-loading and decontamination. Based on these test results, the Agency will generate requirements on the reusability of titanium propellant tanks and recommendations to future projects on how to design tanks to avoid stress- corrosion damage. Since the test activity is currently in progress, in this paper the discussion will be focused on the background and test design phase.

  3. Human histocompatibility leukocyte antigen-DQA1*0501 allele associated with genetic susceptibility of Graves disease in a Caucasian population

    SciTech Connect

    Tatsuo, Yanagawa; Ampica, Mangklakruks; Youn-Bok Chang; Yasuyuki, Okamoto; Fisfalen, M.E.; Curran, P.G.; Degroot, L.J. (Univ. of Chicago, IL (United States))

    1993-06-01

    Graves disease (GB) is an autoimmune disease of the thyroid gland. Genes of, or closely associated to, the HLA complex are assumed to contribute to the genetic predisposition to GD. The authors have previously reported an increased frequency of HLA-DR3/DQ3 in Caucasian patients with GD, and recently the importance of Dw24 encoded by DRB3 gene has been suggested. To further investigate the associations of GD and these genes, 94 unrelated patients with GD and 75 control subjects were typed for HLA-DRB3, -DRB1, and -DQA1, and -DQB1, using sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA (PCR-SSO). Three findings emerged from these studies. (1) The frequency of subjects positive for DQA1*0501 (GD, 73.4% vs. control 42.7%, P = 0.0001, RR = 3.71) was significantly increased among patients. The frequency of DR3 (GD, 34.0% vs. control 17.3%, P = 0.0146, RR = 2.46), which is in tight linkage disequilibrium with DQA1*0501, was also increased; however, it was not significant when the P value was corrected for the number of antigens tested. Neither DQB1 nor DRB3 alleles were significantly increased in frequency. (2) After exclusion of DR3-positive subjects, DQA1*0501 was still significantly increased (GD, 59.7% vs. control 30.6%, P = 0.0012, Pc < 0.01, RR = 3.35) among patients. (3) The distributions of Dw24 and Dw25,26 (Dw25 or Dw26) did not differ between patients and controls on either DR3 positive or negative groups. These findings suggest the DQA1*0501, or a closely associated unknown gene, confers susceptibility to GD, while Dw24 is not directly involved. The importance of DR3, however, remains to be elucidated, because of the fixed linkage with DQA1*0501. 34 refs., 1 fig., 5 tabs.

  4. Muscle protein turnover in cattle of differing genetic backgrounds as measured by urinary N tau-methylhistidine excretion

    SciTech Connect

    McCarthy, F.D.; Bergen, W.G.; Hawkins, D.R.

    1983-12-01

    N tau-methylhistidine (N tau MH) was used as an index for muscle protein degradation and this index was utilized to evaluate degradation rates in young growing cattle. Initially, two Charolais crossbred heifers, 12 months of age, were used to measure the recovery of radioactivity in the urine for a 120-hour period after intravenous injection of (/sup 14/C)N tau MH. Of the radioactivity injected into the animals, 89.7% was recovered after 120 hours. With rate and amount of clearance as the criteria, the excretion of N tau MH in urine appears to be a valid index of muscle protein degradation in cattle. Eight steers of two genetic types were used to evaluate the effect of frame size on turnover rates of muscle proteins with N tau MH as an index. Large frame cattle (LG) excreted more N tau MH per day throughout the trial. Total daily creatinine excretion was less for small frame (SM) cattle showing an increase with time in LG and SM cattle. N tau MH-to-creatinine ratios showed a decline with time. Fractional breakdown rates (FBR) and fractional synthesis rates (FSR) appeared to parallel each other with rates tending to decrease with age. No differences were observed between LG and SM cattle for FBR, FSR or fractional growth rate (FGR).

  5. Genetic recombination variation in wild Robertsonian mice: on the role of chromosomal fusions and Prdm9 allelic background

    PubMed Central

    Capilla, Laia; Medarde, Nuria; Alemany-Schmidt, Alexandra; Oliver-Bonet, Maria; Ventura, Jacint; Ruiz-Herrera, Aurora

    2014-01-01

    Despite the existence of formal models to explain how chromosomal rearrangements can be fixed in a population in the presence of gene flow, few empirical data are available regarding the mechanisms by which genome shuffling contributes to speciation, especially in mammals. In order to shed light on this intriguing evolutionary process, here we present a detailed empirical study that shows how Robertsonian (Rb) fusions alter the chromosomal distribution of recombination events during the formation of the germline in a Rb system of the western house mouse (Mus musculus domesticus). Our results indicate that both the total number of meiotic crossovers and the chromosomal distribution of recombination events are reduced in mice with Rb fusions and that this can be related to alterations in epigenetic signatures for heterochromatinization. Furthermore, we detected novel house mouse Prdm9 allelic variants in the Rb system. Remarkably, mean recombination rates were positively correlated with a decrease in the number of ZnF domains in the Prdm9 gene. The suggestion that recombination can be modulated by both chromosomal reorganizations and genetic determinants that control the formation of double-stranded breaks during meiosis opens new avenues for understanding the role of recombination in chromosomal speciation. PMID:24850922

  6. Susceptibility Genes in Thyroid Autoimmunity

    PubMed Central

    Ban, Yoshiyuki; Tomer, Yaron

    2005-01-01

    The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely, these loci interact and their interactions may influence disease phenotype and severity. PMID:15712599

  7. Genome Survey Sequencing and Genetic Background Characterization of Gracilariopsis lemaneiformis (Rhodophyta) Based on Next-Generation Sequencing

    PubMed Central

    Sui, Zhenghong; Fu, Feng; Wang, Jinguo; Chang, Lianpeng; Guo, Weihua; Li, Binbin

    2013-01-01

    Gracilariopsis lemaneiformis has a high economic value and is one of the most important aquaculture species in China. Despite it is economic importance, it has remained largely unstudied at the genomic level. In this study, we conducted a genome survey of Gp. lemaneiformis using next-generation sequencing (NGS) technologies. In total, 18.70 Gb of high-quality sequence data with an estimated genome size of 97 Mb were obtained by HiSeq 2000 sequencing for Gp. lemaneiformis. These reads were assembled into 160,390 contigs with a N50 length of 3.64 kb, which were further assembled into 125,685 scaffolds with a total length of 81.17 Mb. Genome analysis predicted 3490 genes and a GC% content of 48%. The identified genes have an average transcript length of 1,429 bp, an average coding sequence size of 1,369 bp, 1.36 exons per gene, exon length of 1,008 bp, and intron length of 191 bp. From the initial assembled scaffold, transposable elements constituted 54.64% (44.35 Mb) of the genome, and 7737 simple sequence repeats (SSRs) were identified. Among these SSRs, the trinucleotide repeat type was the most abundant (up to 73.20% of total SSRs), followed by the di- (17.41%), tetra- (5.49%), hexa- (2.90%), and penta- (1.00%) nucleotide repeat type. These characteristics suggest that Gp. lemaneiformis is a model organism for genetic study. This is the first report of genome-wide characterization within this taxon. PMID:23875008

  8. Genetic contribution of GADD45A to susceptibility to sporadic and non- BRCA1\\/2 familial breast cancers: a systematic evaluation in Chinese populations

    Microsoft Academic Search

    Ke-Da Yu; Gen-Hong Di; Wen-Feng Li; Nan-Yan Rao; Lei Fan; Wen-Tao Yuan; Zhen Hu; Jiong Wu; Zhen-Zhou Shen; Wei Huang; Zhi-Ming Shao

    2010-01-01

    Growth arrest and DNA damage-induced 45, alpha (GADD45A) is a candidate breast cancer susceptibility gene because its product participates in DNA repair and it is a downstream gene\\u000a of p53 and BRCA1, both of which are breast cancer susceptibility genes. We screened germline mutations of GADD45A in 185 non-BRCA1\\/2 familial breast cancer patients, but no deleterious mutation was found. Seven

  9. The Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans

    PubMed Central

    Zheng, Ming; Zhang, Haili; Dill, David L.; Clark, J. David; Tu, Susan; Yablonovitch, Arielle L.; Tan, Meng How; Zhang, Rui; Rujescu, Dan; Wu, Manhong; Tessarollo, Lino; Vieira, Wilfred; Gottesman, Michael M.; Deng, Suhua; Eberlin, Livia S.; Zare, Richard N.; Billard, Jean-Martin; Gillet, Jean-Pierre; Li, Jin Billy; Peltz, Gary

    2015-01-01

    Background We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study. Methods and Findings A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered. Conclusions ABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity. PMID:25647612

  10. Segmental Polarity in Drosophila Melanogaster: Genetic Dissection of Fused in a Suppressor of Fused Background Reveals Interaction with Costal-2

    PubMed Central

    Preat, T.; Therond, P.; Limbourg-Bouchon, B.; Pham, A.; Tricoire, H.; Busson, D.; Lamour-Isnard, C.

    1993-01-01

    fused (fu) is a segment polarity gene that encodes a putative serine/threonine kinase. A complete suppressor of the embryonic and adult phenotypes of fu mutants, Suppressor of fused (Su(fu)), was previously described. The amorphic Su(fu) mutation is viable and displays no phenotype by itself. We have used this suppressor as a tool to perform a genetic dissection of the fu gene. Analysis of the interaction between Su(fu) and 33 fu alleles shows that they belong to three different classes. Defects due to class I fu alleles are fully suppressed by Su(fu). Class II fu alleles lead to a new segment polarity phenotype in interaction with Su(fu). This phenotype corresponds to embryonic and adult anomalies similar to those displayed by the segment polarity mutant costal-2 (cos-2). Class II alleles are recessive to class I alleles in a fu[I]/fu[II];Su(fu)/Su(fu) combination. Class 0 alleles, like class I alleles, confer a normal segmentation phenotype in interaction with Su(fu). However class II alleles are dominant over class 0 alleles in a fu[0]/fu[II];Su(fu)/Su(fu) combination. Alleles of class I and II correspond to small molecular events, which may leave part of the Fu protein intact. On the contrary, class 0 alleles correspond to large deletions. Several class I and class II fu mutations have been mapped, and three mutant alleles were sequenced. These data suggest that class I mutations affect the catalytic domain of the putative Fu kinase and leave the carboxy terminal domain intact, whereas predicted class II proteins have an abnormal carboxy terminal domain. Su(fu) enhances the cos-2 phenotype and cos-2 mutations interact with fu in a way similar to Su(fu). All together these results suggest that a close relationship might exist between fu, Su(fu) and cos-2 throughout development. We thus propose a model where the Fu(+) kinase is a posterior inhibitor of Costal-2(+) while Su(fu)(+) is an activator of Costal-2(+). The expression pattern of wingless and engrailed in fu and fu;Su(fu) embryos is in accordance with this interpretation. PMID:8307322

  11. Genetics

    NSDL National Science Digital Library

    National Science Teachers Association (NSTA)

    2005-04-01

    What affects how physical characteristics are transmitted from parent to offspring? This is a question that can be answered at many levels. Molecular biologists examine the pattern of nucleotides in deoxyribonucleic acid (DNA) and the effect of mutations on the proteins produced. Classical geneticists explore the patterns by which traits are transmitted through families. Medical geneticists attempt to describe and develop treatments for diseases that have a genetic component. Genetic engineers analyze how traits can be altered in organisms through modern technology. These are only a few of the strategies that scientists employ to explain the nature of heredity. Explore historical perspectives on the study of genetics and investigate how cutting-edge technology is being used to expand our understanding of heredity.

  12. Physical Confirmation and Mapping of Overlapping Rat Mammary Carcinoma Susceptibility QTLs, Mcs2 and Mcs6

    PubMed Central

    Sanders, Jennifer; Haag, Jill D.; Samuelson, David J.

    2011-01-01

    Only a portion of the estimated heritability of breast cancer susceptibility has been explained by individual loci. Comparative genetic approaches that first use an experimental organism to map susceptibility QTLs are unbiased methods to identify human orthologs to target in human population-based genetic association studies. Here, overlapping rat mammary carcinoma susceptibility (Mcs) predicted QTLs, Mcs6 and Mcs2, were physically confirmed and mapped to identify the human orthologous region. To physically confirm Mcs6 and Mcs2, congenic lines were established using the Wistar-Furth (WF) rat strain, which is susceptible to developing mammary carcinomas, as the recipient (genetic background) and either Wistar-Kyoto (WKy, Mcs6) or Copenhagen (COP, Mcs2), which are resistant, as donor strains. By comparing Mcs phenotypes of WF.WKy congenic lines with distinct segments of WKy chromosome 7 we physically confirmed and mapped Mcs6 to ?33 Mb between markers D7Rat171 and gUwm64-3. The predicted Mcs2 QTL was also physically confirmed using segments of COP chromosome 7 introgressed into a susceptible WF background. The Mcs6 and Mcs2 overlapping genomic regions contain multiple annotated genes, but none have a clear or well established link to breast cancer susceptibility. Igf1 and Socs2 are two of multiple potential candidate genes in Mcs6. The human genomic region orthologous to rat Mcs6 is on chromosome 12 from base positions 71,270,266 to 105,502,699. This region has not shown a genome-wide significant association to breast cancer risk in pun studies of breast cancer susceptibility. PMID:21625632

  13. Mitochondrial Genetic Background Modifies the Relationship between Traffic-Related Air Pollution Exposure and Systemic Biomarkers of Inflammation

    PubMed Central

    Wittkopp, Sharine; Staimer, Norbert; Tjoa, Thomas; Gillen, Daniel; Daher, Nancy; Shafer, Martin; Schauer, James J.; Sioutas, Constantinos; Delfino, Ralph J.

    2013-01-01

    Background Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin. Objective We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations). Methods Inflammation biomarkers were measured weekly in each subject (?12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-? (TNF-?), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NOx), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (<0.25 µm, 0.25–2.5 µm, and 2.5–10 µm in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed-effects models. Results IL-6 and TNF-? were associated with traffic-related air pollutants (BC, CO, NOx and PAH), and with mass and oxidative potential of quasi-ultrafine particles <0.25 µm. These associations were stronger for haplogroup H than haplogroup U. Conclusions Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects. PMID:23717615

  14. NCI Cancer Genetics Services Directory

    Cancer.gov

    This directory lists professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, and others). Professionals must apply to be listed in this directory and must meet certain

  15. Susceptibility of Anopheles stephensi to Plasmodium gallinaceum: A Trait of the Mosquito, the Parasite, and the Environment

    PubMed Central

    Hume, Jen C. C.; Hamilton, Howard; Lee, Kevin L.; Lehmann, Tovi

    2011-01-01

    Background Vector susceptibility to Plasmodium infection is treated primarily as a vector trait, although it is a composite trait expressing the joint occurrence of the parasite and the vector with genetic contributions of both. A comprehensive approach to assess the specific contribution of genetic and environmental variation on “vector susceptibility” is lacking. Here we developed and implemented a simple scheme to assess the specific contributions of the vector, the parasite, and the environment to “vector susceptibility.” To the best of our knowledge this is the first study that employs such an approach. Methodology/Principal Findings We conducted selection experiments on the vector (while holding the parasite “constant”) and on the parasite (while holding the vector “constant”) to estimate the genetic contributions of the mosquito and the parasite to the susceptibility of Anopheles stephensi to Plasmodium gallinaceum. We separately estimated the realized heritability of (i) susceptibility to parasite infection by the mosquito vector and (ii) parasite compatibility (transmissibility) with the vector while controlling the other. The heritabilities of vector and the parasite were higher for the prevalence, i.e., fraction of infected mosquitoes, than the corresponding heritabilities of parasite load, i.e., the number of oocysts per mosquito. Conclusions The vector's genetics (heritability) comprised 67% of “vector susceptibility” measured by the prevalence of mosquitoes infected with P. gallinaceum oocysts, whereas the specific contribution of parasite genetics (heritability) to this trait was only 5%. Our parasite source might possess minimal genetic diversity, which could explain its low heritability (and the high value of the vector). Notably, the environment contributed 28%. These estimates are relevant only to the particular system under study, but this experimental design could be useful for other parasite-host systems. The prospects and limitations of the genetic manipulation of vector populations to render the vector resistant to the parasite are better considered on the basis of this framework. PMID:21694762

  16. Genetic Heterogeneity of Susceptibility Gene in Different Ethnic Populations: Refining Association Study of PTPN22 for Graves’ Disease in a Chinese Han Population

    PubMed Central

    Zhao, Shuangxia; Han, Bing; Liu, Wei; Yang, Shaoying; Yu, Shasha; Sun, Yixuan; Liang, Jun; Gao, Guanqi; Zhang, Xiaomei; Yuan, Guoyue; Li, Changgui; Du, Wenhua; Chen, Gang; Chen, Jialun; Song, Huaidong

    2013-01-01

    In our previous studies, we presumed subtypes of Graves’ disease (GD) may be caused by different major susceptibility genes or different variants of a single susceptibility gene. However, more evidence is needed to support this hypothesis. Single-nucleotide polymorphism (SNP) rs2476601 in PTPN22 is the susceptibility loci of GD in the European population. However, this polymorphism has not been found in Asian populations. Here, we investigate whether PTPN22 is the susceptibility gene for GD in Chinese population and further determine the susceptibility variant of PTPN22 in GD. We conducted an imputation analysis based on the results of our genome-wide association study (GWAS) in 1,536 GD patients and 1,516 control subjects. Imputation revealed that 255 common SNPs on a linkage disequilibrium (LD) block containing PTPN22 were associated with GD (P<0.05). Nine tagSNPs that captured the 255 common variants were selected to be further genotyped in a large cohort including 4,368 GD patients and 4,350 matched controls. There was no significant difference between the nine tagSNPs (P>0.05) in either the genotype distribution or allelic frequencies between patients and controls in the replication study. Although the combined analysis exhibited a weak association signal (Pcombined = 0.003263 for rs3811021), the false positive report probability (FPRP) analysis indicated it was most likely a false positive finding. Our study did not support an association of common SNPs in PTPN22 LD block with GD in Chinese Han population. This suggests that GD in different ethnic population is probably caused by distinct susceptibility genes. PMID:24386393

  17. Gastric Cancer Susceptibility Is Not Linked to Pro-and Anti-Inflammatory Cytokine Gene Polymorphisms in Whites: A Nationwide Multicenter Study in Spain

    Microsoft Academic Search

    María Asunción García-González; Angel Lanas; Enrique Quintero; David Nicolás; Adolfo Parra-Blanco; Mark Strunk; Rafael Benito; Miguel Angel Simón; Santos Santolaria; Federico Sopeña; Elena Piazuelo; Pilar Jiménez; Cristina Pascual; Eva Mas; Pilar Irún; Jesús Espinel; Rafael Campo; Marisa Manzano; Fernando Geijo; Maria Pellisé; Ferrán González-Huix; Miguel Nieto; Jorge Espinós; LLúcia Titó; Luis Bujanda; Manuel Zaballa

    2007-01-01

    BACKGROUND AND AIMS:Recent studies have reported an association between cytokine gene polymorphisms and GC risk. However, results are inconsistent among studies from different geographic regions and ethnic groups. Our goal was to evaluate the influence of Helicobacter pylori (H. pylori) infection and host genetic factors on GC susceptibility in a population of Spanish white GC patients.METHODS: DNA from 404 unrelated

  18. Asthma-susceptibility variants identified using probands in case-control and family-based analyses

    Microsoft Academic Search

    Blanca E Himes; Jessica Lasky-Su; Ann C Wu; Jemma B Wilk; Gary M Hunninghake; Barbara Klanderman; Amy J Murphy; Ross Lazarus; Manuel E Soto-Quiros; Lydiana Avila; Juan C Celedón; Christoph Lange; George T O'Connor; Benjamin A Raby; Edwin K Silverman; Scott T Weiss

    2010-01-01

    BACKGROUND: Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs. METHODS: We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study

  19. Individual susceptibility in occupational and environmental toxicology

    Microsoft Academic Search

    Philippe Grandjean

    1995-01-01

    By prudent interpretation of toxicological and epidemiological evidence, susceptibility could become a very useful notion, both in a scientific sense and for prevention of adverse effects. Based on presumed aetiology, susceptibility can often be separated into genetic, constitutional, and environmental categories, although some overlapping between these groups will be apparent. Inherited factors seem to be involved in determining many toxic

  20. Identification of a major susceptibility locus for lethal graft-versus-host disease in MHC-matched mice

    PubMed Central

    Cao, Thai M.; Lazzeroni, Laura C.; Tsai, Schickwann; Pang, Wendy W.; Kao, Amy; Camp, Nicola J.; Thomas, Alun; Shizuru, Judith A.

    2009-01-01

    Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. While it is understood that susceptibility results from interacting polymorphisms of genes encoding histocompatibility antigens and immune regulatory molecules, a detailed and integrative understanding of the genetic background underlying GVHD remains lacking. To gain insight regarding these issues, we performed a forward genetic study. A MHC-matched mouse model was utilized in which irradiated recipient BALB.K and B10.BR mice demonstrate differential susceptibility to lethal GHVD when transplanted using AKR/J donors. Assessment of GVHD in (B10.BR x BALB.K)F1 mice revealed that susceptibility is a dominant trait and conferred by deleterious alleles from the BALB.K strain. In order to identify the alleles responsible GVHD susceptibility, a genome scanning approach was taken using (B10.BR x BALB.K)F1 × B10.BR backcross mice as recipients. A major susceptibility locus, termed the Gvh1 locus, was identified on chromosome 16 using linkage analysis (LOD = 9.1). A second locus was found on chromosome 13, named Gvh2, which had additive but protective effects. Further identification of Gvh genes by positional cloning may yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy. PMID:19525392

  1. Highly-efficient, fluorescent, locus directed cre and FlpO deleter mice on a pure C57BL/6N genetic background.

    PubMed

    Birling, Marie-Christine; Dierich, Andrée; Jacquot, Sylvie; Hérault, Yann; Pavlovic, Guillaume

    2012-06-01

    To facilitate the use of the new mutant resource developed in the mouse, we have generated Cre and FlpO deleter mice on a pure inbred C57BL/6N background. The new transgenic constructs were designed to drive either the Cre or FlpO recombinase, fused to a specific fluorescent marker, respectively the eGFP or the eYFP, and were inserted by homologous recombination in the neutral Rosa26 locus. They allow a rapid, cost-effective, and efficient identification of the carrier individuals through the coexpression of the fluorescent marker. The recombination efficiency of the two deleter lines, Gt(ROSA)26S or < tm1(ACTB-cre,-EGFP)Ics> and Gt(ROSA) 26S or < tm2(CAG-flpo, EYFP)Ics>, was carefully evaluated using five loxP-flanked or four FRT-flanked alleles located at different positions in the mouse genome. For each tested locus, we observed a 100% excision rate. The transgenic mice are easily distinguishable from wild type animals by their bright fluorescence that remains easily detectable until 10 days after birth. In the adult, fluorescence can still be detected in the unpigmented paws. Furthermore, they both display accumulation of the specific recombinase during oogenesis. These fluorescent 'Cre- and Flp- deleter' transgenic lines are valuable tools for the scientific community by their high and stable recombination efficiency, the simplicity of genotype identification and the maintenance of a pure genetic background when used to remove specific selection cassette or to induce complete loss-of-function allele. PMID:22121025

  2. [Genetic background of bronchial asthma].

    PubMed

    Kawakami, Y

    1992-12-01

    Familial aggregations and genes for atopy, airway hyperresponsiveness, and serum IgE were studied in 69 members of five atopic asthmatic families spanning three generations. Atopy was found in 68%, bronchial asthma in 26%, airway hyperresponsiveness in 45%, and positive mite allergen in 59%. Both atopy and airway hyperresponsiveness were inherited in an autosomal dominant fashion, but were not related to each other. No linkage was found of HLA with atopy and mite positivity. T cell gamma receptor gene (7p15), IL-3, IL-4, and IL-5 genes (5q23), and postulated atopic gene (11q13) were all not linked to atopy. However, alle 2.5 kb of 11q13 showed an association with serum IgE level. The beta 2 adrenergic receptor gene (5q31-32) was linked to airway responsiveness to inhaled beta 2 adrenergic agonist, and was associated with the occurrence of bronchial asthma. PMID:1306210

  3. Genetics of obesity and overgrowth syndromes.

    PubMed

    Sabin, Matthew A; Werther, George A; Kiess, Wieland

    2011-02-01

    Childhood overweight and obesity is highly prevalent within society. In the majority of individuals, weight gain is the result of exposure to an 'obesogenic' environment, superimposed on a background of genetic susceptibility brought about by evolutionary adaptation. These individuals tend to be tall in childhood with a normal final adult height, as opposed to those who have an underlying monogenic cause where short stature is more common (although not universal). Identifying genetic causes of weight gain, or tall stature and overgrowth, within this setting can be extremely problematic and yet it is imperative that clinicians remain alert, as identification of a genetic diagnosis has major implications for the individual, family and potential offspring. Alongside this, the recognition of new genetic mutations in this area is furthering our knowledge on the important mechanisms that regulate childhood growth and body composition. This review describes the genetic syndromes associated with obesity and overgrowth. PMID:21396586

  4. Transfer of innate resistance and susceptibility to Leishmania donovani infection in mouse radiation bone marrow chimaeras.

    PubMed

    Crocker, P R; Blackwell, J M; Bradley, D J

    1984-07-01

    Reciprocal radiation bone marrow chimaeras were made between H-2-compatible strains of mice innately resistant or susceptible to visceral leishmaniasis. In initial experiments, susceptibility but not resistance to Leishmania donovani could be transferred with donor bone marrow into irradiated recipients. In subsequent experiments it was possible to transfer both resistance and susceptibility. This was achieved either by selecting more radiosensitive mouse strains as susceptible recipients, or alternatively by increasing the irradiation dose for the susceptible recipients used in the initial experiments. Using the higher irradiation dose, successful transfer of resistance and susceptibility between congenic mice carrying the Lshr and Lshs alleles on the more radioresistant B10 genetic background provided firm evidence that the results obtained in this study were specifically related to expression of the Lsh gene. We conclude that Lsh gene-controlled resistance and susceptibility to L. donovani is determined by bone marrow-derived cells. The cell type(s) involved is likely to be of the macrophage lineage. PMID:6378765

  5. Transfer of innate resistance and susceptibility to Leishmania donovani infection in mouse radiation bone marrow chimaeras.

    PubMed Central

    Crocker, P R; Blackwell, J M; Bradley, D J

    1984-01-01

    Reciprocal radiation bone marrow chimaeras were made between H-2-compatible strains of mice innately resistant or susceptible to visceral leishmaniasis. In initial experiments, susceptibility but not resistance to Leishmania donovani could be transferred with donor bone marrow into irradiated recipients. In subsequent experiments it was possible to transfer both resistance and susceptibility. This was achieved either by selecting more radiosensitive mouse strains as susceptible recipients, or alternatively by increasing the irradiation dose for the susceptible recipients used in the initial experiments. Using the higher irradiation dose, successful transfer of resistance and susceptibility between congenic mice carrying the Lshr and Lshs alleles on the more radioresistant B10 genetic background provided firm evidence that the results obtained in this study were specifically related to expression of the Lsh gene. We conclude that Lsh gene-controlled resistance and susceptibility to L. donovani is determined by bone marrow-derived cells. The cell type(s) involved is likely to be of the macrophage lineage. PMID:6378765

  6. Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 × Brown Norway hybrid rats

    PubMed Central

    Sheridan, Kevin M.; Ferguson, Michael J.; Distasi, Matthew R.; Witzmann, Frank A.; Dalsing, Michael C.; Miller, Steven J.; Unthank, Joseph L.

    2010-01-01

    Available studies indicate that both genetic background and aging influence collateral growth capacity, but it is not known how their combination affects collateral growth. We evaluated collateral growth induced by ileal artery ligation in Fischer 344 (F344), Brown Norway (BN), and the first generation hybrid of F344 × BN (F1) rats available for aging research from the National Institute on Aging. Collateral growth was determined by paired diameter measurements in anesthetized rats immediately and 7 days postligation. In 3-mo-old rats, significant collateral growth occurred only in BN (35% ± 11%, P < 0.001). The endothelial cell number in arterial cross sections was also determined, since this precedes shear-mediated luminal expansion. When compared with the same animal controls, the intimal cell number was increased only in BN rats (92% ± 21%, P < 0.001). The increase in intimal cell number and the degree of collateral luminal expansion in BN rats was not affected by age from 3 to 24 mo. Immunohistochemical studies demonstrated that intimal cell proliferation was much greater in the collaterals of BN than of F1 rats. The remarkable difference between these three strains of rats used in aging research and the lack of an age-related impairment in the BN rats are novel observations. These rat strains mimic clinical observations of interindividual variation in collateral growth capacity and the impact of age on arteriogenesis and should be useful models to investigate the molecular mechanisms responsible for such differences. PMID:17906115

  7. Differential Proinflammatory and Oxidative Stress Response and Vulnerability to Metabolic Syndrome in Habitual High-Fat Young Male Consumers Putatively Predisposed by Their Genetic Background

    PubMed Central

    González-Muniesa, Pedro; Marrades, María Pilar; Martínez, José Alfredo; Moreno-Aliaga, María Jesús

    2013-01-01

    The current nutritional habits and lifestyles of modern societies favor energy overloads and a diminished physical activity, which may produce serious clinical disturbances and excessive weight gain. In order to investigate the mechanisms by which the environmental factors interact with molecular mechanisms in obesity, a pathway analysis was performed to identify genes differentially expressed in subcutaneous abdominal adipose tissue (SCAAT) from obese compared to lean male (21–35 year-old) subjects living in similar obesogenic conditions: habitual high fat dietary intake and moderate physical activity. Genes involved in inflammation (ALCAM, CTSB, C1S, YKL-40, MIF, SAA2), extracellular matrix remodeling (MMP9, PALLD), angiogenesis (EGFL6, leptin) and oxidative stress (AKR1C3, UCHL1, HSPB7 and NQO1) were upregulated; whereas apoptosis, signal transcription (CITED 2 and NR3C1), cell control and cell cycle-related genes were downregulated. Interestingly, the expression of some of these genes (C1S, SAA2, ALCAM, CTSB, YKL-40 and tenomodulin) was found to be associated with some relevant metabolic syndrome features. The obese group showed a general upregulation in the expression of inflammatory, oxidative stress, extracellular remodeling and angiogenic genes compared to lean subjects, suggesting that a given genetic background in an obesogenic environment could underlie the resistance to gaining weight and obesity-associated manifestations. PMID:23975165

  8. Polymorphism of Plasmodium falciparum Na + \\/H + exchanger is indicative of a low in vitro quinine susceptibility in isolates from Viet Nam

    Microsoft Academic Search

    Véronique Sinou; Le Hong Quang; Stéphane Pelleau; Vu Nhu Huong; Nguyen Thu Huong; Le Minh Tai; Lionel Bertaux; Marc Desbordes; Christine Latour; Lai Quang Long; Nguyen Xuan Thanh; Daniel Parzy

    2011-01-01

    Background  The Plasmodium falciparum NA+\\/H+ exchanger (pfnhe1, gene PF13_0019) has recently been proposed to influence quinine (QN) susceptibility. However, its contribution to QN resistance\\u000a seems to vary geographically depending on the genetic background of the parasites. Here, the role of this gene was investigated\\u000a in in vitro QN susceptibility of isolates from Viet Nam.\\u000a \\u000a \\u000a \\u000a \\u000a Method  Ninety-eight isolates were obtained from three different

  9. Genetic variability at promoters of IL-18 (pro-) and IL-10 (anti-) inflammatory gene affects susceptibility and their circulating serum levels: An explorative study of prostate cancer patients in North Indian populations.

    PubMed

    Dwivedi, Shailendra; Goel, Apul; Khattri, Sanjay; Mandhani, Anil; Sharma, Praveen; Misra, Sanjeev; Pant, Kamlesh Kumar

    2015-07-01

    Inflammation is an important hallmark of all types of cancers with a well-established role in carcinogenesis. The net inflammatory response is determined by the balance between pro- and anti-inflammatory cytokines, the levels of which may be affected by the genetic make-up. Interleukin (IL)-18, a pro-inflammatory cytokine expressed by various cells including those of the prostate, is a key mediator of anti-cancer immune response. IL-10, an anti-inflammatory cytokine associated with tumour malignancy, causes escape from immune surveillance. This study hypothesizes that genetic variants of IL-18 (-607 C/A and -137 G/T) and IL-10 (-819 C/T and -592 C/A) may influence the circulating levels of these interleukins, thereby generating susceptibility risk to prostate cancer. The study was conducted on 676 subjects (controls and patients of prostate cancer (PCa): 291 each; and 94 patients with benign prostate hypertrophy (BPH)). Genotyping was performed by PCR-RFLP and Real-Time PCR probe-based method. Circulating interleukin levels were obtained by ELISA. Circulating IL-18 levels were significantly elevated in cancer and BPH patients carrying GG genotypes for -137 of IL-18. The trend of circulating IL-18 levels was GG>GC>CC, observed in all groups. The -137 genetic variants of IL-18 significantly associated with PCa risk were GC, CC, and GC+CC, compared to GG (OR: 1.71, 95% CI: 1.20-2.46; OR: 3.35, 95% CI: 2.03-5.53; and OR: 2.05, 95% CI: 1.46-2.87, respectively). A significant association of AA and CA+AA against CC genotype was observed at -607 locus of IL-18 (OR: 0.46, 95%CI: 0.29-0.72; OR: 0.61, 95% CI: 0.41-0.90, respectively). Significantly elevated levels of IL-10 were observed with TT (wild) genotype at -819 of IL-10, compared to the CC (homozygous mutant) genotype in all three groups of subjects. However, no significant association was found between IL-10 promoter genotypes and PCa risk. We conclude that genetic variants of IL-18 and IL-10 promoters influence the circulating levels of these interleukins. Variations at -137 and -607 loci of IL-18 are associated with susceptibility to PCa. PMID:25892571

  10. Transcriptional Responses of Resistant and Susceptible Fish Clones to the Bacterial Pathogen Flavobacterium psychrophilum

    PubMed Central

    Martin, Samuel A. M.; Jouneau, Luc; Bernardet, Jean-Francois; Houel, Armel; Lunazzi, Aurélie; Duchaud, Eric; Michel, Christian; Quillet, Edwige; Boudinot, Pierre

    2012-01-01

    Flavobacterium psychrophilum is a bacterial species that represents one of the most important pathogens for aquaculture worldwide, especially for salmonids. To gain insights into the genetic basis of the natural resistance to F. psychrophilum, we selected homozygous clones of rainbow trout with contrasted susceptibility to the infection. We compared the transcriptional response to the bacteria in the pronephros of a susceptible and a resistant line by micro-array analysis five days after infection. While the basal transcriptome of healthy fish was significantly different in the resistant and susceptible lines, the transcriptome modifications induced by the bacteria involved essentially the same genes and pathways. The response to F. psychrophilum involved antimicrobial peptides, complement, and a number of enzymes and chemokines. The matrix metalloproteases mmp9 and mmp13 were among the most highly induced genes in both genetic backgrounds. Key genes of both pro- and anti-inflammatory response such as IL1 and IL10, were up-regulated with a greater magnitude in susceptible animals where the bacterial load was also much higher. While higher resistance to F. psychrophilum does not seem to be based on extensive differences in the orientation of the immune response, several genes including complement C3 showed stronger induction in the resistant fish. They may be important for the variation of susceptibility to the infection. PMID:22720048

  11. Transcriptional responses of resistant and susceptible fish clones to the bacterial pathogen Flavobacterium psychrophilum.

    PubMed

    Langevin, Christelle; Blanco, Mar; Martin, Samuel A M; Jouneau, Luc; Bernardet, Jean-Francois; Houel, Armel; Lunazzi, Aurélie; Duchaud, Eric; Michel, Christian; Quillet, Edwige; Boudinot, Pierre

    2012-01-01

    Flavobacterium psychrophilum is a bacterial species that represents one of the most important pathogens for aquaculture worldwide, especially for salmonids. To gain insights into the genetic basis of the natural resistance to F. psychrophilum, we selected homozygous clones of rainbow trout with contrasted susceptibility to the infection. We compared the transcriptional response to the bacteria in the pronephros of a susceptible and a resistant line by micro-array analysis five days after infection. While the basal transcriptome of healthy fish was significantly different in the resistant and susceptible lines, the transcriptome modifications induced by the bacteria involved essentially the same genes and pathways. The response to F. psychrophilum involved antimicrobial peptides, complement, and a number of enzymes and chemokines. The matrix metalloproteases mmp9 and mmp13 were among the most highly induced genes in both genetic backgrounds. Key genes of both pro- and anti-inflammatory response such as IL1 and IL10, were up-regulated with a greater magnitude in susceptible animals where the bacterial load was also much higher. While higher resistance to F. psychrophilum does not seem to be based on extensive differences in the orientation of the immune response, several genes including complement C3 showed stronger induction in the resistant fish. They may be important for the variation of susceptibility to the infection. PMID:22720048

  12. Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration

    PubMed Central

    Chen, Wei; Stambolian, Dwight; Edwards, Albert O.; Branham, Kari E.; Othman, Mohammad; Jakobsdottir, Johanna; Tosakulwong, Nirubol; Pericak-Vance, Margaret A.; Campochiaro, Peter A.; Klein, Michael L.; Tan, Perciliz L.; Conley, Yvette P.; Kanda, Atsuhiro; Kopplin, Laura; Li, Yanming; Augustaitis, Katherine J.; Karoukis, Athanasios J.; Scott, William K.; Agarwal, Anita; Kovach, Jaclyn L.; Schwartz, Stephen G.; Postel, Eric A.; Brooks, Matthew; Baratz, Keith H.; Brown, William L.; Brucker, Alexander J.; Orlin, Anton; Brown, Gary; Ho, Allen; Regillo, Carl; Donoso, Larry; Tian, Lifeng; Kaderli, Brian; Hadley, Dexter; Hagstrom, Stephanie A.; Peachey, Neal S.; Klein, Ronald; Klein, Barbara E. K.; Gotoh, Norimoto; Yamashiro, Kenji; Ferris, Frederick; Fagerness, Jesen A.; Reynolds, Robyn; Farrer, Lindsay A.; Kim, Ivana K.; Miller, Joan W.; Cortón, Marta; Carracedo, Angel; Sanchez-Salorio, Manuel; Pugh, Elizabeth W.; Doheny, Kimberly F.; Brion, Maria; DeAngelis, Margaret M.; Weeks, Daniel E.; Zack, Donald J.; Chew, Emily Y.; Heckenlively, John R.; Yoshimura, Nagahisa; Iyengar, Sudha K.; Francis, Peter J.; Katsanis, Nicholas; Seddon, Johanna M.; Haines, Jonathan L.; Gorin, Michael B.; Abecasis, Gonçalo R.; Swaroop, Anand; Johnson, Robert N.; Ai, Everett; McDonald, H. Richard; Stolarczuk, Margaret; Pavan, Peter Reed; Billiris, Karina K.; Iyer, Mohan; Menosky, Matthew M.; Pautler, Scott E.; Millard, Sharon M.; Hubbard, Baker; Aaberg, Thomas; DuBois, Lindy; Lyon, Alice; Anderson-Nelson, Susan; Jampol, Lee M.; Weinberg, David V.; Muñana, Annie; Rozenbajgier, Zuzanna; Orth, David; Cohen, Jack; MacCumber, Matthew; MacCumber, Matthew; Figliulo, Celeste; Porcz, Liz; Folk, James; Boldt, H. Culver; Russell, Stephen R.; Ivins, Rachel; Hinz, Connie J.; Barr, Charles C.; Bloom, Steve; Jaegers, Ken; Kritchman, Brian; Whittington, Greg; Heier, Jeffrey; Frederick, Albert R.; Morley, Michael G.; Topping, Trexler; Davis, Heather L.; Bressler, Susan B.; Bressler, Neil M.; Doll, Warren; Trese, Michael; Capone, Antonio; Garretson, Bruce R.; Hassan, Tarek S.; Ruby, Alan J.; Osentoski, Tammy; McCannel, Colin A.; Ruszczyk, Margaret J.; Grand, Gilbert; Blinder, Kevin; Holekamp, Nancy M.; Joseph, Daniel P.; Shah, Gaurav; Nobel, Ginny S.; Antoszyk, Andrew N.; Browning, David J.; Stallings, Alison H; Singerman, Lawrence J.; Miller, David; Novak, Michael; Pendergast, Scott; Zegarra, Hernando; Schura, Stephanie A.; Smith-Brewer, Sheila; Davidorf, Frederick H.; Chambers, Robert; Chorich, Louis; Salerno, Jill; Dreyer, Richard F.; Ma, Colin; Kopfer, Marcia R.; Klein, Michael L.; Wilson, David J.; Nolte, Susan K.; Grunwald, Juan E.; Brucker, Alexander J.; Dunaief, Josh; Fine, Stuart L.; Maguire, Albert M.; Stoltz, Robert A.; McRay, Monique N.; Fish, Gary Edd; Anand, Rajiv; Spencer, Rand; Arnwine, Jean; Chandra, Suresh R.; Altaweel, Michael; Blodi, Barbara; Gottlieb, Justin; Ip, Michael; Nork, T. Michael; Perry-Raymond, Jennie; Fine, Stuart L.; Maguire, Maureen G.; Brightwell-Arnold, Mary; Harkins, Sandra; Peskin, Ellen; Ying, Gui-Shuang; Kurinij, Natalie

    2010-01-01

    We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10?75), ARMS2 (P < 10?59), C2/CFB (P < 10?20), C3 (P < 10?9), and CFI (P < 10?6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10?11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 × 10?7; CETP, P = 7.4 × 10?7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL (P = 3.0 × 10?3) and ABCA1 (P = 5.6 × 10?4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. PMID:20385819

  13. Streptococcus gallolyticus subsp. gallolyticus from human and animal origins: genetic diversity, antimicrobial susceptibility, and characterization of a vancomycin-resistant calf isolate carrying a vanA-Tn1546-like element.

    PubMed

    Romero-Hernández, Beatriz; Tedim, Ana P; Sánchez-Herrero, José Francisco; Librado, Pablo; Rozas, Julio; Muñoz, Gloria; Baquero, Fernando; Cantón, Rafael; Del Campo, Rosa

    2015-04-01

    The aim of this work was to characterize the antibiotic susceptibility and genetic diversity of 41 Streptococcus gallolyticus subsp. gallolyticus isolates: 18 isolates obtained from animals and 23 human clinical isolates. Antibiotic susceptibility was determined by the semiautomatic Wider system and genetic diversity by pulsed-field gel electrophoresis (PFGE) with SmaI. Animal isolates grouped separately in the PFGE analysis, but no statistical differences in antimicrobial resistance were found between the two groups. The LMG 17956 sequence type 28 (ST28) strain recovered from the feces of a calf exhibited high levels of resistance to vancomycin and teicoplanin (MIC, ?256 mg/liter). Its glycopeptide resistance mechanism was characterized by Southern blot hybridization and a primer-walking strategy, and finally its genome, determined by whole-genome sequencing, was compared with four closely related S. gallolyticus subsp. gallolyticus genomes. Hybridization experiments demonstrated that a Tn1546-like element was integrated into the bacterial chromosome. In agreement with this finding, whole-genome sequencing confirmed a partial deletion of the vanY-vanZ region and partial duplication of the vanH gene. The comparative genomic analyses revealed that the LMG 17956 ST28 strain had acquired an unusually high number of transposable elements and had experienced extensive chromosomal rearrangements, as well as gene gain and loss events. In conclusion, S. gallolyticus subsp. gallolyticus isolates from animals seem to belong to lineages separate from those infecting humans. In addition, we report a glycopeptide-resistant isolate from a calf carrying a Tn1546-like element integrated into its chromosome. PMID:25605355

  14. 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

    PubMed Central

    2010-01-01

    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 menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. Results These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. Conclusions The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified. PMID:21194473

  15. A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p

    Microsoft Academic Search

    Sreekumar G Pillai; Mathias N Chiano; Nicola J White; Marcy Speer; Kathleen C Barnes; Karin Carlsen; Jorrit Gerritsen; Peter Helms; Warren Lenney; Michael Silverman; Peter Sly; John Sundy; John Tsanakas; Andrea von Berg; Moira Whyte; Shela Varsani; Paul Skelding; Michael Hauser; Jeffery Vance; Margaret Pericak-Vance; Daniel K Burns; Lefkos T Middleton; Shyama R Brewster; Wayne H Anderson; John H Riley

    2006-01-01

    Asthma is a complex disease and the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Families with at least two siblings with asthma were collected from Europe, Australia and the US. A genome scan using a set of 364 families with a panel of 396 microsatellite markers was conducted. Nonparametric linkage analyses were conducted

  16. The trajectory of psychological impact in BRCA1\\/2 genetic testing: does time heal?

    Microsoft Academic Search

    Tammy M. Beran; Annette L. Stanton; Lorna Kwan; Joyce Seldon; Julienne E. Bower; Andrea Vodermaier; Patricia A. Ganz

    2008-01-01

    BACKGROUND: Most research on adjustment of women undergoing genetic testing for breast cancer susceptibility has not followed women for more than 6 months after result receipt and has not evaluated curvilinear patterns in general and cancer-specific adjustment. PURPOSE: This study's primary goal was to examine the trajectory of psychological status in women at risk for breast and ovarian cancer prior

  17. Shared Genetic Influences on ADHD Symptoms and Very Low-Frequency EEG Activity: A Twin Study

    ERIC Educational Resources Information Center

    Tye, Charlotte; Rijsdijk, Fruhling; Greven, Corina U.; Kuntsi, Jonna; Asherson, Philip; McLoughlin, Grainne

    2012-01-01

    Background: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex aetiology. The identification of candidate intermediate phenotypes that are both heritable and genetically linked to ADHD may facilitate the detection of susceptibility genes and elucidate aetiological pathways.…

  18. Genetic counseling

    E-print Network

    Stough, Laura

    2014-01-01

    syndrome or spina bifida, while postnatal testing may reveal phenylke- tonuria or hypothyroidism. Most disorders occur when one or both of the parents pass on their genes. Couples who are carriers may choose to have their DNA tested before conception... and susceptibility genes brought forth by the sequencing of the human genome has brought challenges to the field of genetic counseling. The traditional role of genetic counseling has significantly widened to address a diversity of developing needs, ranging from...

  19. Development of a Mesoamerican intra-genepool genetic map for quantitative trait loci detection in a drought tolerant × susceptible common bean ( Phaseolus vulgaris L.) cross

    Microsoft Academic Search

    Matthew W. BlairCarlos; Carlos H. Galeano; Eduardo Tovar; Monica C. Muñoz Torres; Alejandro Velasco Castrillón; Steve E. Beebe; Idupulapati M. Rao

    Drought is a major constraint to common bean (Phaseolus vulgaris L.) production, especially in developing countries where irrigation for the crop is infrequent. The Mesoamerican genepool\\u000a is the most widely grown subdivision of common beans that include small red, small cream and black seeded varieties. The objective\\u000a of this study was to develop a reliable genetic map for a Mesoamerican × Mesoamerican

  20. Genetic study of two single nucleotide polymorphisms within corresponding microRNAs and susceptibility to tuberculosis in a Chinese Tibetan and Han population

    Microsoft Academic Search

    Dingdong Li; Tingting Wang; Xingbo Song; MeiLang Qucuo; Bin Yang; Junlong Zhang; Jun Wang; Binwu Ying; Chuanmin Tao; Lanlan Wang

    2011-01-01

    MicroRNAs (miRNA) are thought to play important roles in the pathogenesis of diseases. Single nucleotide polymorphisms (SNPs) within miRNAs can change their characteristics via altering their target selection and\\/or expression, resulting in functional and\\/or phenotypic changes. We decided to investigate the genetic association with pulmonary tuberculosis with 2 nucleotide variations within corresponding microRNAs regulating the Toll-like receptor (TLR)–mediating signal pathway.

  1. Differences in mtDNA haplogroup distribution among 3 Jewish populations alter susceptibility to T2DM complications

    PubMed Central

    Feder, Jeanette; Blech, Ilana; Ovadia, Ofer; Amar, Shirly; Wainstein, Julio; Raz, Itamar; Dadon, Sarah; Arking, Dan E; Glaser, Benjamin; Mishmar, Dan

    2008-01-01

    Background Recent genome-wide association studies searching for candidate susceptibility loci for common complex diseases such as type 2 diabetes mellitus (T2DM) and its common complications have uncovered novel disease-associated genes. Nevertheless these large-scale population screens often overlook the tremendous variation in the mitochondrial genome (mtDNA) and its involvement in complex disorders. Results We have analyzed the mitochondrial DNA (mtDNA) genetic variability in Ashkenazi (Ash), Sephardic (Seph) and North African (NAF) Jewish populations (total n = 1179). Our analysis showed significant differences (p < 0.001) in the distribution of mtDNA genetic backgrounds (haplogroups) among the studied populations. To test whether these differences alter the pattern of disease susceptibility, we have screened our three Jewish populations for an association of mtDNA genetic haplogroups with T2DM complications. Our results identified population-specific susceptibility factors of which the best example is the Ashkenazi Jewish specific haplogroup N1b1, having an apparent protective effect against T2DM complications in Ash (p = 0.006), being absent in the NAF population and under-represented in the Seph population. We have generated and analyzed whole mtDNA sequences from the disease associated haplogroups revealing mutations in highly conserved positions that are good candidates to explain the phenotypic effect of these genetic backgrounds. Conclusion Our findings support the possibility that recent bottleneck events leading to over-representation of minor mtDNA alleles in specific genetic isolates, could result in population-specific susceptibility loci to complex disorders. PMID:18445251

  2. Factors influencing susceptibility to metals.

    PubMed Central

    Gochfeld, M

    1997-01-01

    Although the long-neglected field of human susceptibility to environmental toxicants is currently receiving renewed attention, there is only scant literature on factors influencing susceptibility to heavy metals. Genetic factors may influence the availability of sulfhydryl-containing compounds such as glutathione and metallothionein, which modify the distribution and toxicity of certain metals. Age and gender play a role in modifying uptake and distribution, although the mechanisms are often obscure. Concurrent exposure to divalent cations may enhance or reduce the toxicity of certain metals through competition for receptor-mediated transport or targets. Increasing use of biomarkers of exposure should greatly increase our understanding of the underlying distribution of susceptibility to various environmental agents. PMID:9255566

  3. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

    PubMed

    Steffens, Michael; Leu, Costin; Ruppert, Ann-Kathrin; Zara, Federico; Striano, Pasquale; Robbiano, Angela; Capovilla, Giuseppe; Tinuper, Paolo; Gambardella, Antonio; Bianchi, Amedeo; La Neve, Angela; Crichiutti, Giovanni; de Kovel, Carolien G F; Kasteleijn-Nolst Trenité, Dorothée; de Haan, Gerrit-Jan; Lindhout, Dick; Gaus, Verena; Schmitz, Bettina; Janz, Dieter; Weber, Yvonne G; Becker, Felicitas; Lerche, Holger; Steinhoff, Bernhard J; Kleefuß-Lie, Ailing A; Kunz, Wolfram S; Surges, Rainer; Elger, Christian E; Muhle, Hiltrud; von Spiczak, Sarah; Ostertag, Philipp; Helbig, Ingo; Stephani, Ulrich; Møller, Rikke S; Hjalgrim, Helle; Dibbens, Leanne M; Bellows, Susannah; Oliver, Karen; Mullen, Saul; Scheffer, Ingrid E; Berkovic, Samuel F; Everett, Kate V; Gardiner, Mark R; Marini, Carla; Guerrini, Renzo; Lehesjoki, Anna-Elina; Siren, Auli; Guipponi, Michel; Malafosse, Alain; Thomas, Pierre; Nabbout, Rima; Baulac, Stephanie; Leguern, Eric; Guerrero, Rosa; Serratosa, Jose M; Reif, Philipp S; Rosenow, Felix; Mörzinger, Martina; Feucht, Martha; Zimprich, Fritz; Kapser, Claudia; Schankin, Christoph J; Suls, Arvid; Smets, Katrin; De Jonghe, Peter; Jordanova, Albena; Caglayan, Hande; Yapici, Zuhal; Yalcin, Destina A; Baykan, Betul; Bebek, Nerses; Ozbek, Ugur; Gieger, Christian; Wichmann, Heinz-Erich; Balschun, Tobias; Ellinghaus, David; Franke, Andre; Meesters, Christian; Becker, Tim; Wienker, Thomas F; Hempelmann, Anne; Schulz, Herbert; Rüschendorf, Franz; Leber, Markus; Pauck, Steffen M; Trucks, Holger; Toliat, Mohammad R; Nürnberg, Peter; Avanzini, Giuliano; Koeleman, Bobby P C; Sander, Thomas

    2012-12-15

    Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes. PMID:22949513

  4. Common genetic variants on 3q28 contribute to non-small cell lung cancer susceptibility: evidence from 10 case-control studies.

    PubMed

    Jin, Yu-xing; Jiang, Ge-ning; Zheng, Hui; Duan, Liang; Ding, Jia-an

    2015-04-01

    The association between common variations (rs10937405, rs4488809) on 3q28 and lung cancer has been widely evaluated in various ethnic groups, since it was first identified through genome-wide association approach. However, the results have been inconclusive. To derive a more precise estimation of the relationship and the effect of factors that might modify the risk, we performed this meta-analysis. The random-effects model was applied, addressing heterogeneity and publication bias. A total of 10 articles involving 36,221 cases and 58,108 controls were included. Overall, the summary per-allele OR of 1.19 (95 % CI 1.14-1.25, P < 10(-5)) and 1.17 (95 % CI 1.10-1.23, P < 10(-5)) was found for the rs10937405 and rs4488809 polymorphisms, respectively. Significant results were also observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. Significant results were found in East Asians when stratified by ethnicity, whereas no significant associations were found among Caucasians. After stratifying by sample size, study design, control source and sex, significant associations were also obtained. In addition, our data indicate that these polymorphisms are involved in lung cancer susceptibility and confer its effect primarily in lung adenocarcinoma when stratified by histological subtype. Furthermore, significant associations were also detected both never-smokers and smokers for these polymorphisms. In conclusion, this meta-analysis demonstrated that rs10937405 and rs4488809 are a risk factor associated with increased non-small cell lung cancer susceptibility, particularly for East Asian populations. PMID:25344291

  5. NCI Cancer Genetics Services Directory: Search Results

    Cancer.gov

    This directory lists professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, and others). Professionals must apply to be listed in this directory and must meet certain

  6. Genome-Wide Transcriptome Directed Pathway Analysis of Maternal Pre-Eclampsia Susceptibility Genes

    PubMed Central

    Yong, Hannah E. J.; Melton, Phillip E.; Johnson, Matthew P.; Freed, Katy A.; Kalionis, Bill; Murthi, Padma; Brennecke, Shaun P.; Keogh, Rosemary J.; Moses, Eric K.

    2015-01-01

    Background Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant genetic component. Numerous genetic studies, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling of tissues at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between these two approaches, although genes identified in both approaches are significantly associated with PE. We have thus taken a novel integrative bioinformatics approach of analysing pathways common to the susceptibility genes and the PE transcriptome. Methods Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n = 65 normotensive and n = 60 PE decidua basalis tissues collected at delivery. The R software package libraries lumi and limma were used to preprocess transcript data for pathway analysis. Pathways were analysed and constructed using Pathway Studio. We examined ten candidate genes, which are from these functional groups: activin/inhibin signalling—ACVR1, ACVR1C, ACVR2A, INHA, INHBB; structural components—COL4A1, COL4A2 and M1 family aminopeptidases—ERAP1, ERAP2 and LNPEP. Results/Conclusion Major common regulators/targets of these susceptibility genes identified were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA. The top two categories of pathways associated with the susceptibility genes, which were significantly altered in the PE decidual transcriptome, were apoptosis and cell signaling (p < 0.001). Thus, susceptibility genes from distinct functional groups share similar downstream pathways through common regulators/targets, some of which are altered in PE. This study contributes to a better understanding of how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their contributions to the pathogenesis and severity of PE. PMID:26010865

  7. Effects of genetic background and null mutation of 5HT 1A receptors on basal and stress-induced body temperature: Modulation by serotonergic and GABA A-ergic drugs

    Microsoft Academic Search

    M. J. V. van Bogaert; Ronald Oosting; Miklos Toth; Lucianne Groenink; Ruud van Oorschot; Berend Olivier

    2006-01-01

    The stress-induced hyperthermia procedure, in which effects of drugs on basal (T1) and stress-induced body temperature (T2) are measured, predicts anxiolytic drug effect. Serotonergic drugs alter these responses and here, we studied the role of 5-HT1A receptors in stress-induced hyperthermia by using 5-HT1A receptor knockout mice. Three strains (129\\/Sv, Swiss Webster and C57Bl6) were used because genetic background can significantly

  8. Genetic Susceptibility for Individual Cooperation Preferences: The Role of Monoamine Oxidase A Gene (MAOA) in the Voluntary Provision of Public Goods

    PubMed Central

    Mertins, Vanessa; Schote, Andrea B.; Hoffeld, Wolfgang; Griessmair, Michele; Meyer, Jobst

    2011-01-01

    In the context of social dilemmas, previous research has shown that human cooperation is mainly based on the social norm of conditional cooperation. While in most cases individuals behave according to such a norm, deviant behavior is no exception. Recent research further suggests that heterogeneity in social behavior might be associated with varying genetic predispositions. In this study, we investigated the relationship between individuals' behavior in a public goods experiment and the promoter-region functional repeat polymorphism in the monoamine oxidase A gene (MAOA). In a dynamic setting of increasing information about others' contributions, we analyzed differences in two main components of conditional cooperation, namely the players' own contribution and their beliefs regarding the contribution of other players. We showed that there is a significant association between individuals' behavior in a repeated public goods game and MAOA. Our results suggest that male carriers of the low activity alleles cooperate significantly less than those carrying the high activity alleles given a situation where subjects had to rely on their innate beliefs about others' contributions. With increasing information about the others' cooperativeness, the genetic effect diminishes. Furthermore, significant opposing effects for female subjects carrying two low activity alleles were observed. PMID:21698196

  9. Genetic susceptibility for individual cooperation preferences: the role of monoamine oxidase A gene (MAOA) in the voluntary provision of public goods.

    PubMed

    Mertins, Vanessa; Schote, Andrea B; Hoffeld, Wolfgang; Griessmair, Michele; Meyer, Jobst

    2011-01-01

    In the context of social dilemmas, previous research has shown that human cooperation is mainly based on the social norm of conditional cooperation. While in most cases individuals behave according to such a norm, deviant behavior is no exception. Recent research further suggests that heterogeneity in social behavior might be associated with varying genetic predispositions. In this study, we investigated the relationship between individuals' behavior in a public goods experiment and the promoter-region functional repeat polymorphism in the monoamine oxidase A gene (MAOA). In a dynamic setting of increasing information about others' contributions, we analyzed differences in two main components of conditional cooperation, namely the players' own contribution and their beliefs regarding the contribution of other players. We showed that there is a significant association between individuals' behavior in a repeated public goods game and MAOA. Our results suggest that male carriers of the low activity alleles cooperate significantly less than those carrying the high activity alleles given a situation where subjects had to rely on their innate beliefs about others' contributions. With increasing information about the others' cooperativeness, the genetic effect diminishes. Furthermore, significant opposing effects for female subjects carrying two low activity alleles were observed. PMID:21698196

  10. Molecular epidemiology and in-vitro antifungal susceptibility of Aspergillus terreus species complex isolates in Delhi, India: evidence of genetic diversity by amplified fragment length polymorphism and microsatellite typing.

    PubMed

    Kathuria, Shallu; Sharma, Cheshta; Singh, Pradeep Kumar; Agarwal, Puneet; Agarwal, Kshitij; Hagen, Ferry; Meis, Jacques F; Chowdhary, Anuradha

    2015-01-01

    Aspergillus terreus is emerging as an etiologic agent of invasive aspergillosis in immunocompromised individuals in several medical centers in the world. Infections due to A. terreus are of concern due to its resistance to amphotericin B, in vivo and in vitro, resulting in poor response to antifungal therapy and high mortality. Herein we examined a large collection of molecularly characterized, geographically diverse A. terreus isolates (n = 140) from clinical and environmental sources in India for the occurrence of cryptic A. terreus species. The population structure of the Indian A. terreus isolates and their association with those outside India was determined using microsatellite based typing (STR) technique and Amplified Fragment Length Polymorphism analysis (AFLP). Additionally, in vitro antifungal susceptibility of A. terreus isolates was determined against 7 antifungals. Sequence analyses of the calmodulin locus identified the recently described cryptic species A. hortai, comprising 1.4% of Aspergillus section Terrei isolates cultured from cases of aspergilloma and probable invasive aspergillosis not reported previously. All the nine markers used for STR typing of A. terreus species complex proved to be highly polymorphic. The presence of high genetic diversity revealing 75 distinct genotypes among 101 Indian A. terreus isolates was similar to the marked heterogeneity noticed in the 47 global A. terreus population exhibiting 38 unique genotypes mainly among isolates from North America and Europe. Also, AFLP analysis showed distinct banding patterns for genotypically diverse A. terreus isolates. Furthermore, no correlation between a particular genotype and amphotericin B susceptibility was observed. Overall, 8% of the A. terreus isolates exhibited low MICs of amphotericin B. All the echinocandins and azoles (voriconazole, posaconazole and isavuconazole) demonstrated high potency against all the isolates. The study emphasizes the need of molecular characterization of A. terreus species complex isolates to better understand the ecology, acquisition and transmission of this species. PMID:25781896

  11. Mapping of a quantitative trait locus controlling susceptibility to Coxsackievirus B3-induced viral hepatitis.

    PubMed

    Wiltshire, S A; Marton, J; Leiva-Torres, G A; Vidal, S M

    2015-06-01

    The pathogenesis of coxsackieviral infection is a multifactorial process involving host genetics, viral genetics and the environment in which they interact. We have used a mouse model of Coxsackievirus B3 infection to characterize the contribution of host genetics to infection survival and to viral hepatitis. Twenty-five AcB/BcA recombinant congenic mouse strains were screened. One, BcA86, was found to be particularly susceptible to early mortality; 100% of BcA86 mice died by day 6 compared with 0% of B6 mice (P=0.0012). This increased mortality was accompanied by an increased hepatic necrosis as measured by serum alanine aminotransferase (ALT) levels (19547±10556 vs 769±109, P=0.0055). This occurred despite a predominantly resistant (C57BL/6) genetic background. Linkage analysis in a cohort (n=210) of (BcA86x C56Bl/10)F2 animals revealed a new locus on chromosome 13 (peak linkage 101.2?Mbp, lod 4.50 and P=0.003). This locus controlled serum ALT levels as early as 48?h following the infection, and led to an elevated expression of type I interferon. Another locus on chromosome 17 (peak linkage 57.2?Mbp) was significantly linked to heart viral titer (lod 3.4 and P=0.046). These