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1

Genetic background affects susceptibility to tumoral stem cell reprogramming.  

PubMed

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

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

2013-07-08

2

Varying susceptibility to myocardial infarction among C57BL\\/6 mice of different genetic background  

Microsoft Academic Search

Genetically manipulated mouse lines are invaluable to investigate the effects of a single gene on sensitivity to ischemia. When choosing appropriate controls, we were concerned that intrinsic, strain-independent but colony-dependent differences may influence the susceptibility to ischemia. We, therefore, compared the infarct:risk volume ratio (I:R%) after 30-min global ischemia in Langendorff-perfused hearts from outbred C57BL\\/6 mice with that in wild-type

Diana A. Gorog; Masaya Tanno; Alamgir M. N. Kabir; Gajen S. Kanaganayagam; Rekha Bassi; Simon G. Fisher; Michael S. Marber

2003-01-01

3

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

PubMed

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

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

2013-10-15

4

Modulation of Patched-Associated Susceptibility to Radiation Induced Tumorigenesis by Genetic Background  

Microsoft Academic Search

We described previously a basal cell carcinoma (BCC) and medullo- blastoma (MB) phenotype for CD1Ptch1neo67\\/ mice exposed to ionizing radiation. Ptch1 heterozygous mice mimic the predisposition to BCC and MB development of patients affected by nevoid BCC syndrome that inherit a mutant Patched (Ptch1) allele. To examine the impact of genetic background on development of BCCs and other tumors we

Simonetta Pazzaglia; Mariateresa Mancuso; Mirella Tanori; Michael J. Atkinson; Paola Merola; Simonetta Rebessi; Vincenzo Di Majo; Vincenzo Covelli; Heidi Hahn; Anna Saran

2004-01-01

5

Loss of STAT6 promotes autoimmune disease and atopy on a susceptible genetic background.  

PubMed

Atopy and autoimmunity are usually considered opposed immunological manifestations. Lyn(-/-) mice develop lupus-like autoimmune disease yet have coexistent intrinsic allergic traits and are prone to severe, persistent asthma induced exogenously. Recently it has been proposed that the Th2 environment and IgE auto-Abs promotes autoimmune disease in Lyn(-/-) mice. To examine this apparent contradiction, we derived Lyn(-/-) mice with a null mutation in STAT6, a regulator of Th2 immunity that integrates signaling from the IL-4/IL-13 receptor complex. Atopy and spontaneous peritoneal eosinophilia, characteristic of Lyn(-/-) mice, were lost in young Lyn(-/-)STAT6(-/-) mice; however, autoimmune disease was markedly exacerbated. At a time-point where Lyn(-/-) mice showed only mild autoimmune disease, Lyn(-/-)STAT6(-/-) mice had maximal titres of IgG and IgA auto-Abs, impaired renal function, myeloid expansion and a highly activated T cell compartment. Remarkably, low level IgE auto-Abs but not IgG1 auto-Abs were a feature of some aged Lyn(-/-)STAT6(-/-) mice. Furthermore, aged Lyn(-/-)STAT6(-/-) mice showed dramatically increased levels of serum IgE but minimal IgG1, suggesting that class-switching to IgE can occur in the absence of an IgG1 intermediate. The results show that Lyn-deficient mice can overcome the effects of disabling Th2 immunity, highlighting the importance of Lyn in controlling Th2 responses. Our data also indicates that, under certain conditions, STAT6-independent factors can promote IgE class-switching. This work has important clinical implications as many experimental therapies designed for the treatment of asthma or atopy are based on targeting the STAT6 axis, which could potentially reveal life endangering autoimmunity or promote atopy in susceptible individuals. PMID:22867713

Lau, Maverick; Tsantikos, Evelyn; Maxwell, Mhairi J; Tarlinton, David M; Anderson, Gary P; Hibbs, Margaret L

2012-08-04

6

Murine adipose tissue-derived stromal cell apoptosis and susceptibility to oxidative stress in vitro are regulated by genetic background.  

PubMed

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

Pazdro, Robert; Harrison, David E

2013-04-04

7

Genetic Susceptibility to Cancer  

Cancer.gov

The Epidemiology and Genomics Research Program (EGRP) is a strong supporter of epidemiology studies investigating genetic susceptibility to cancer across all populations, including family studies, candidate gene studies, genome-wide association studies (GWAS), and use of next generation sequencing techniques to identify variants associated with specific cancers. Such studies have identified many genetic variants that may be associated with cancer.

8

Genetic diversity and disease susceptibility.  

PubMed Central

The range of genetic diversity within human populations is enormous. Genetic susceptibility to common chronic disease is a significant part of this genetic diversity, which also includes a variety of rare clear-cut inherited diseases. Modern DNA-based genomic analysis can now routinely lead to the identification of genes involved in disease susceptibility, provides the basis for genetic counselling in affected families, and more widely for a genetically targeted approach to disease prevention. This naturally raises problems concerning the use of information on an individual's decisions, but for employment, and health and life insurance.

Bodmer, W F

1997-01-01

9

PTPN2 Gene Variants Are Associated with Susceptibility to Both Crohn's Disease and Ulcerative Colitis Supporting a Common Genetic Disease Background  

Microsoft Academic Search

BackgroundGenome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants.Methodology\\/Principal FindingsGenomic DNA from 2131 individuals of Caucasian origin

Jürgen Glas; Johanna Wagner; Julia Seiderer; Torsten Olszak; Martin Wetzke; Florian Beigel; Cornelia Tillack; Johannes Stallhofer; Matthias Friedrich; Christian Steib; Burkhard Göke; Thomas Ochsenkühn; Nazanin Karbalai; Julia Diegelmann; Darina Czamara; Stephan Brand

2012-01-01

10

PTPN2 Gene Variants Are Associated with Susceptibility to Both Crohn's Disease and Ulcerative Colitis Supporting a Common Genetic Disease Background  

PubMed Central

Background Genome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants. Methodology/Principal Findings Genomic DNA from 2131 individuals of Caucasian origin (905 patients with CD, 318 patients with UC, and 908 healthy, unrelated controls) was analyzed for two SNPs in the PTPN2 region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of PTPN2 SNP rs2542151 with both susceptibility to CD (p?=?1.95×10?5; OR 1.49 [1.34–1.79]) and UC (p?=?3.87×10?2, OR 1.31 [1.02–1.68]). Moreover, PTPN2 SNP rs7234029 demonstrated a significant association with susceptibility to CD (p?=?1.30×10?3; OR 1.35 [1.13–1.62]) and a trend towards association with UC (p?=?7.53×10?2; OR 1.26 [0.98–1.62]). Genotype-phenotype analysis revealed an association of PTPN2 SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p?=?6.62×10?3). Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p?=?0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p?=?4.68×10?3) in UC. There was no evidence of epistasis between PTPN2 and NOD2 and PTPN2 and IL23R. In silico analysis revealed that the SNP rs7234029 modulates potentially the binding sites of several transcription factors involved in inflammation including GATA-3, NF-?B, C/EBP, and E4BP4. Conclusions/Significance Our data confirm the association of PTPN2 variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that PTPN2 regulates autophagosome formation in intestinal epithelial cells, the potential link between PTPN2 and ATG16L1 should be further investigated.

Seiderer, Julia; Olszak, Torsten; Wetzke, Martin; Beigel, Florian; Tillack, Cornelia; Stallhofer, Johannes; Friedrich, Matthias; Steib, Christian; Goke, Burkhard; Ochsenkuhn, Thomas; Karbalai, Nazanin; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

2012-01-01

11

Genetic susceptibility to Candida infections  

PubMed Central

Candida spp. are medically important fungi causing severe mucosal and life-threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility. On the one hand, severe fungal infections are associated with monogenic primary immunodeficiencies such as defects in STAT1, STAT3 or CARD9, recently discovered as novel clinical entities. On the other hand, more common polymorphisms in genes of the immune system have also been associated with fungal infections such as recurrent vulvovaginal candidiasis and candidemia. The discovery of the genetic susceptibility to Candida infections can lead to a better understanding of the pathogenesis of the disease, as well as to the design of novel immunotherapeutic strategies. This review is part of the review series on host-pathogen interactions. See more reviews from this series.

Smeekens, Sanne P; van de Veerdonk, Frank L; Kullberg, Bart Jan; Netea, Mihai G

2013-01-01

12

Genetic susceptibility to pancreatic cancer.  

PubMed

Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. However, it has the poorest prognosis of any major tumor type, with a 5-yr survival rate of approximately 5%. Cigarette smoking, increased body mass index, heavy alcohol consumption, and a diagnosis of diabetes mellitus have all been demonstrated to increase risk of pancreatic cancer. A family history of pancreatic cancer has also been associated with increased risk suggesting inherited genetic factors also play an important role, with approximately 5-10% of pancreatic cancer patients reporting family history of pancreatic cancer. While the genetic basis for the majority of the familial clustering of pancreatic cancer remains unclear, several important pancreatic cancer genes have been identified. These consist of high penetrance genes including BRCA2 or PALB2, to more common genetic variation associated with a modest increase risk of pancreatic cancer such as genetic variation at the ABO blood group locus. Recent advances in genotyping and genetic sequencing have accelerated the rate at which novel pancreatic cancer susceptibility genes have been identified with several genes identified within the past few years. This review addresses our current understanding of the familial aggregation of pancreatic cancer, established pancreatic cancer susceptablity genes and how this knowledge informs risk assessment and screening for high-risk families. PMID:22162228

Klein, Alison P

2012-01-01

13

Genetics of Asthma Susceptibility and Severity  

PubMed Central

The interaction of genes and environmental exposures influences the development of asthma and determines asthma severity. This review focuses on recent developments in genetic studies of asthma onset and progression. Genome-wide association studies (GWAS) are currently the most effective approach to study genetics of complex diseases. There have been two large meta-analyses of asthma susceptibility, GABRIEL and EVE, which identified the same four chromosomal regions, many of which had also been identified in previous GWAS: loci in the ORMDL3 region of 17q21, IL1RL/IL18R genes on chromosome 2q, the TSLP gene region on 5q22, and IL33 on chromosome 9p24. These regions were associated with asthma in individuals of different ethnic backgrounds. EVE also identified a novel asthma susceptibility locus, PYHIN1, in individuals of African descent. Genome-wide screens for asthma susceptibility in Asian adults and children both identified genetic variants in the major histocompatiblity complex gene region (HLA region) on chromosome 6p21 as highly associated with asthma risk. This locus was one of the first candidate genes identified for asthma and has been a significant predictor of asthma risk in several GWAS. There is also a need to understand asthma disease heterogeneity as different phenotypes may reflect several pathogenic pathways. Genes that are associated with phenotypes including lung function, biomarker levels and asthma therapeutic responses provide insight into mechanisms of asthma severity progression. For example, the HHIP gene is a significant predictor of pulmonary function changes in asthma and in the normal population. A joint model of risk variants in lung function genes were highly associated with lower FEV1 and increased asthma severity criteria. In addition, a genome-wide screen to discover pharmacogenetic associations related to response to inhaled glucocorticoids identified two correlated SNPs in the GLCCI1 gene that confer a significant lung function response to this asthma therapy. Future genetic studies for asthma susceptibility and severity will incorporate exome or whole-genome sequencing to identify common and rare genetic variants. Using these variants identified in comprehensively phenotyped asthmatics will lead to the development of personalized therapy in individuals with asthma.

Slager, Rebecca E.; Hawkins, Gregory A.; Li, Xingnan; Postma, Dirkje S.; Meyers, Deborah A.; Bleecker, Eugene R.

2012-01-01

14

Risk factors and genetic susceptibility  

Microsoft Academic Search

\\u000a Upper aerodigestive tract (oral cavity, pharyngeal, and laryngeal) cancers are sentinel diseases of exposure to tobacco and\\u000a alcohol, and thus can be considered the paradigm of environmentally induced disease. The fact that only a fraction of exposed\\u000a individuals develop these cancers suggests interindividual differences in susceptibility to these environmental insults. In\\u000a fact, heritable differences in susceptibility may be identified at

Margaret R. Spitz

15

The genetic basis of multiple sclerosis: a model for MS susceptibility  

Microsoft Academic Search

ABSTACT: BACKGROUND: MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors. METHODS: A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease

Douglas S Goodin

2010-01-01

16

Genetic susceptibility to autoimmune liver disease  

PubMed Central

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.

Mattner, Jochen

2011-01-01

17

Population screening for genetic susceptibility to disease.  

PubMed Central

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

Clarke, A.

1995-01-01

18

[Molecular and genetic background of sudden cardiac death].  

PubMed

Despite recent findings on the functional, structural and genetic background of sudden cardiac death, the incidence is still relatively high in the entire population. A thorough knowledge on susceptibility, as well as pathophysiology behind the development of malignant arrhythmias will help us to identify individuals at risk and prevent sudden cardiac death. This article presents a review of the current literature on the role of altered intracellular Ca2+ handling, acute myocardial ischaemia, cardiac autonomic innervation, renin-angiotensin-aldosterone system, monogenic and complex heritability in the pathogenesis of sudden cardiac death. PMID:23220363

Simkó, József; Szabó, Zoltán; Barta, Kitti; Ujvárosi, Dóra; Nánási, Péter; L?rincz, István

2012-12-16

19

Genetic Susceptibility to Non-Necrotizing Erysipelas/Cellulitis  

PubMed Central

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

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

2013-01-01

20

Bladder cancer epidemiology and genetic susceptibility  

PubMed Central

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

Chu, Haiyan; Wang, Meilin; Zhang, Zhengdong

2013-01-01

21

Genetic variation in Drosophila melanogaster pathogen susceptibility  

PubMed Central

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

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

2007-01-01

22

The genetics of diabetes susceptibility in mice  

Microsoft Academic Search

The factors associated with a diabetes-susceptible genotype in mice exhibiting various forms of heritable glucose intolerance syndromes are discussed. Genetic models of insulin-dependent and non-insulin-dependent diabetes in mice are described. Although single gene mutations can be defined for each model that are major contributors to diabetogenic stress, polygenic interactions are required for the expression of a diabetic phenotype, and environmental

EDWARD H. LEITER

1989-01-01

23

Genetic Susceptibility in Inflammatory Bowel Disease  

Microsoft Academic Search

The genetic susceptibility is clearly important in the complex inheritance of inflammatory bowel disease (IBD). Furthermore,\\u000a the etiologic basis of the relationship between Crohn’s disease (CD) and ulcerative colitis (UC) is as yet unexplained. The\\u000a strongest evidence supporting the contribution of inherited factors in the pathogenesis of CD and UC comes from concordance\\u000a rates in twin pairs. The development of

Jesús K. Yamamoto-Furusho

2010-01-01

24

Genetic polymorphisms linked to susceptibility to malaria  

PubMed Central

The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature. Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria.

2011-01-01

25

Genetic susceptibility to cancer. Family physicians' experience.  

PubMed Central

OBJECTIVE: To explore family physicians' experiences in dealing with genetic susceptibility to cancer. DESIGN: Qualitative study using focus groups. SETTING: Four Ontario sites: northern, rural, urban, and inner city. PARTICIPANTS: Forty rural and urban FPs participated in four focus groups: 28 were male; average age was 41. METHOD: Focus groups using a semistructured interview guide were audiotaped and transcribed. The constant comparative method of data analysis was used. Key words and concepts were identified. Data were sorted using NUD*IST software. MAIN FINDINGS: Participants realized the escalating expectations for genetic testing and its effect on family practice. They explored an expanded role for themselves in genetic testing. Possible activities included risk assessment, gatekeeping, and ordering genetic tests. They were concerned about the complexity of genetic testing, the lack of evidence regarding management, and the implications for families. CONCLUSION: We must help FPs struggling to integrate genetics into their practices, by addressing their concerns, enhancing the way they communicate information on genetics, and developing appropriate educational tools.

Carroll, June C.; Brown, Judith Belle; Blaine, Sean; Glendon, Gord; Pugh, Patricia; Medved, Wendy

2003-01-01

26

Genetic susceptibility to HIV-associated nephropathy  

PubMed Central

HIV-1–associated nephropathy (HIVAN) is a common complication of HIV-1 infection, and its skewed incidence in certain ethnic groups suggests that there is a genetic basis to HIVAN susceptibility. In their study reported in this issue of the JCI, Papeta and colleagues used a combination of gene expression profiling and linkage analysis to identify three genomic loci that regulate a network of genes expressed by podocytes — cells that are crucial to the filtration of fluid and waste by the kidney (see the related article beginning on page 1178). Surprisingly, two of these loci confer disease susceptibility in a transgenic mouse model of HIVAN. This report confirms the central role of podocytes in the pathogenesis of HIVAN and demonstrates the power of this combination of genomic analysis techniques in elucidating the pathogenesis of glomerular disease.

Quaggin, Susan E.

2009-01-01

27

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

Microsoft Academic Search

BACKGROUND: UK and US policy initiatives have suggested that, in the future, patients and clinicians in mainstream medicine could use genetic information to prevent common illnesses. There are no studies on patients' experience and understanding of the process of testing for common genetic susceptibilities in mainstream medicine. METHODS: Qualitative interviews with 42 individuals who had undergone testing for a genetic

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

2007-01-01

28

Genetic Background Influences Fluoride's Effects on Osteoclastogenesis  

PubMed Central

Excessive fluoride (F) can lead to abnormal bone biology. Numerous studies have focused on the anabolic action of F yet little is known regarding any action on osteoclastogenesis. Little is known regarding the influence of an individual’s genetic background on the responses of bone cells to F. Four-week old C57BL/6J (B6) and C3H/HeJ (C3H) female mice were treated with NaF in the drinking water (0ppm, 50ppm and 100ppm F ion) for 3 weeks. Bone marrow cells were harvested for osteoclastogenesis and hematopoietic colony-forming cell assays. Sera were analyzed for biochemical and bone markers. Femurs, tibiae and lumbar vertebrae were subjected to microCT analysis. Tibiae and femurs were subjected to histology and biomechanical testing, respectively. The results demonstrated new actions of F on osteoclastogenesis and hematopoietic cell differentiation. Strain specific responses were observed. The anabolic action of F was favored in B6 mice exhibiting dose dependent increases in serum ALP activity (p < 0.001); in proximal tibia trabecular and vertebral BMD (tibia at 50&100ppm, p = 0.001; vertebrae at 50&100ppm, p = 0.023&0.019, respectively); and decrease in intact PTH and sRANKL (p = 0.045 and p < 0.001, respectively). F treatment in B6 mice also resulted in increased numbers of CFU-GEMM colonies (p = 0.025). Strain specific accumulations in bone [F] were observed. For C3H mice, dose dependent increases were observed in osteoclast potential (p < 0.001), in situ trabecular osteoclast number (p = 0.007), hematopoietic colony forming units (CFU-GEMM: p < 0.001, CFU-GM: p = 0.006, CFU-M: p < 0.001), and serum markers for osteoclastogenesis (intact PTH: p = 0.004, RANKL: p = 0.022, TRAP5b: p < 0.001). A concordant decrease in serum OPG (p = 0.005) was also observed. Fluoride treatment had no significant effects on bone morphology, BMD and serum PYD crosslinks in C3H suggesting a lack of significant bone resorption. Mechanical properties were also unaltered in C3H. In conclusion, short term F treatment at physiological levels has strain specific effects in mice. The expected anabolic effects were observed in B6 and novel actions hallmarked by enhanced osteoclastogenesis shifts in hematopoietic cell differentiation in the C3H strain.

Yan, Dong; Gurumurthy, Aruna; Wright, Maggie; Pfeiler, T. Wayne; Loboa, Elizabeth G.; Everett, Eric T.

2008-01-01

29

Is there a genetic susceptibility to idiopathic parkinsonism?  

Microsoft Academic Search

The search for the etiology of idiopathic parkinsonism (IP) has been difficult and largely unsuccessful. Recently, there has been renewed interest in the possibility that there are genetic susceptibility loci for IP. Part of this interest has been spurred by recent advances in molecular genetics. This review analyzes the available genetic epidemiology and family study data (clinical and molecular genetic)

Kirk C Wilhelmsen; Zbigniew K Wszolek

1995-01-01

30

Genetic polymorphisms and associated susceptibility to asthma  

PubMed Central

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

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

2013-01-01

31

Genetic susceptibility to bladder cancer risk and outcome  

PubMed Central

Bladder cancer is an excellent model for studying genetic susceptibility and gene–environment interaction in cancer etiology. The candidate gene approach found NAT2 slow acetylator and GSTM1-null genotypes to be bladder cancer susceptibility loci and also demonstrated interactions between these two genotypes and smoking in modulating bladder cancer risk. Recent genome-wide association studies identified at least eight novel genetic susceptibility loci for bladder cancer. Genetic determinants of clinical outcomes have been inconclusive. The future directions are to identify more genetic susceptibility loci for bladder cancer risk and outcome through a genome-wide association study approach, identify the causal genes and variants, study the biological mechanisms underlying the association between the causal variants and bladder cancer risk, detect gene–environment interactions and incorporate genetic knowledge into clinically applicable risk prediction models to benefit patients and public health.

Gu, Jian; Wu, Xifeng

2011-01-01

32

Genetic Background of Celiac Disease and Its Clinical Implications  

Microsoft Academic Search

and Introduction Abstract Celiac disease (CD) is a complex genetic disorder with multiple contributing genes. Linkage studies have identified several genomic regions that probably contain CD susceptibility genes. The most important genetic factors identified are HLA-DQ2 and HLA-DQ8, which are necessary but not sufficient to predispose to CD. The associations found in non-HLA genomewide linkage and association studies are much

Victorien M. Wolters; Cisca Wijmenga

2008-01-01

33

Flanking gene and genetic background problems in genetically manipulated mice  

Microsoft Academic Search

Mice carrying engineered genetic modifications have become an indispensable tool in the study of gene functioning. The interpretation of results obtained with targeted mutants is not completely straightforward, however, because of genetic complications due to linkage and epistasis. Effects of closely linked genes flanking the targeted locus might sometimes be responsible for phenotypic changes ascribed to the null mutation. The

Wim E. Crusio

2004-01-01

34

Enteropathic spondyloarthropathy: A common genetic background with inflammatory bowel disease?  

PubMed Central

The association between spondyloarthropathy and inflammatory bowel disease (IBD) is largely established, although prevalence is variable because of different population selection and diagnostic methodologies. Most studies indicate that as many as 10%-15% of cases of IBD are complicated by ankylosing spondylitis (AS) or other forms of spondylarthritis (SpA). Of note, ileal inflammation resembling IBD has been reported in up to two thirds of cases of SpA, and it has been suggested that the presence of ileitis is associated with the chronicity of articular complications. Although this observation is of interest to unravel the pathophysiology of the disease, systematic screening of patients with SpA by ileocolonoscopy is not indicated in the absence of gut symptoms, as only a small proportion of patients with subclinical gut inflammation will develop overt IBD over time. The existence of familial clustering of both IBD and AS, the coexistence of both conditions in a patient, the evidence of an increased risk ratio among first- and second-degree relatives of affected AS or IBD patients and finally, the increased cross-risk ratios between AS and IBD, strongly suggest a shared genetic background. So far, however, IL23R is the only identified susceptibility gene shared by both IBD and AS. Although functional studies are still needed to better understand its pathogenic role, great effort is being spent therapeutically targeting this pathway that may prove effective for both disorders.

Colombo, Elisabetta; Latiano, Anna; Palmieri, Orazio; Bossa, Fabrizio; Andriulli, Angelo; Annese, Vito

2009-01-01

35

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...

36

Genetic testing in asymptomatic minors: background considerations towards ESHG Recommendations.  

PubMed

Although various guidelines and position papers have discussed, in the past, the ethical aspects of genetic testing in asymptomatic minors, the European Society of Human Genetics had not earlier endorsed any set of guidelines exclusively focused on this issue. This paper has served as a background document in preparation of the development of the policy recommendations of the Public and Professional Committee of the European Society of Human Genetics. This background paper first discusses some general considerations with regard to the provision of genetic tests to minors. It discusses the concept of best interests, participation of minors in health-care decisions, parents' responsibilities to share genetic information, the role of clinical genetics and the health-care system in communication within the family. Second, it discusses, respectively, the presymptomatic and predictive genetic testing for adult-onset disorders, childhood-onset disorders and carrier testing. PMID:19277061

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

2009-03-11

37

THE THRESHOLD OF GENETIC SUSCEPTIBILITY TO MAREK'S DISEASE  

Technology Transfer Automated Retrieval System (TEKTRAN)

The threshold of genetic susceptibility to Marek’s disease (MD) varies between lines of chickens due to genomic differences between the lines. For instance, one inbred line, 63, has a high threshold of susceptibility to MD, whereas another inbred line, 72, has a low threshold; both of the lines were...

38

The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. V. Interaction between the db gene and hepatic sex steroid sulfotransferases correlates with gender-dependent susceptibility to hyperglycemia  

Microsoft Academic Search

Steroid sulfurylation represents a potential mechanism for controlling the level of active steroids within a tissue. We have elucidated an inbred strain background-dependent interaction between the diabetes (db) mutation and steroid sulfotransferase (ST) enzymes, potentially modulating the level of active steroid hormones or their precursors in the liver. Gonadectomized mutants were analyzed to correlate how strain- and gender-dependent variation in

E. H. LEITER; H. D. CHAPMAN; D. L. COLEMAN

1989-01-01

39

Risk Communication in Genetic Testing for Cancer Susceptibility  

Microsoft Academic Search

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

Robert T. Croyle; Caryn Lerman

1999-01-01

40

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

Microsoft Academic Search

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

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

2010-01-01

41

Bovine tuberculosis: the genetic basis of host susceptibility  

PubMed Central

The prevalence of bovine tuberculosis (BTB) in the UK remains a significant economic burden and problem for the agri-food industry. Much effort has been directed towards improving diagnostics, finding vaccine candidates and assessing the usefulness of badger culling. The contribution that host genotype makes to disease outcome has, until recently, been overlooked; yet, it is biologically untenable that genetic variation does not play a role. In this review, we highlight the evidence, past and present, for a role of host genetics in determining susceptibility to BTB in livestock. We then address some of the major issues surrounding the design of future studies tasked with finding the exact causative genetic variation underpinning the TB susceptibility phenotype. Finally, we discuss some of the potential future benefits, and problems, that a knowledge of the genetic component to BTB resistance/susceptibility may bring to the agricultural industries and the wider scientific community.

Allen, A. R.; Minozzi, G.; Glass, E. J.; Skuce, R. A.; McDowell, S. W. J.; Woolliams, J. A.; Bishop, S. C.

2010-01-01

42

The effect of genetic background on the fitness of diazinon resistance genotypes of the Australian sheep blowfly, Lucilia cuprina  

Microsoft Academic Search

Laboratory and field experimentation has shown that resistant and susceptible diazinon genotypes of flies collected from the field may have similar fitness in an environment free of diazinon. If the genetic background of resistant genotypes from the field is disrupted, the fitness of the resistant genotype declines. These results, in conjunction with previous data, indicate a modification of the genetic

J A McKenzie; M J Whitten; M A Adena

1982-01-01

43

NCI Releases Preliminary Data on Genetic Susceptibility for Prostate Cancer  

Cancer.gov

The National Cancer Institute 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. This is also the first public release of a whole genome association study of cancer -- such studies examine the entire genome, with no assumptions about which genetic alterations cause cancer.

44

Genetic susceptibility to dental implant failure: a critical review.  

PubMed

The observation that clinical factors alone do not explain why some patients develop implant loss; the understanding of the osseointegrated implant failure as a complex, multifactorial process; and the observed aggregation of repetitive failure in certain individuals raise interesting questions related to host susceptibility to dental implant failure. Genetic analysis applied to dental implants began in the late 1990s, and since then, increased interest in genetic susceptibility to the phenotype has been demonstrated by several studies. These studies, however, have been based on and limited to candidate gene association analysis and were intended to find associations between specific alleles and/or genotypes of genetic markers and susceptibility to implant failure. The aim of this review is to provide a brief description of the current methodology for genetic analysis of complex traits, followed by a comprehensive review of the literature related to genetic susceptibility to dental implant failure and a discussion of different aspects of the applied methodology. Moreover, a novel approach of genome wide, case-control analysis is discussed as an alternative method to access genetic influence to dental implant failure mechanisms. Advances toward the elucidation of the genetic basis of dental implant loss may contribute to the understanding of why some patients do not respond to currently available treatments while others do and provide potential targets for effective screening, prevention, and treatment. For example, clinicians might be able to estimate, before the elective surgical procedure, the risk of a given patient to develop a negative individual host response. PMID:18700362

Alvim-Pereira, Fabino; Montes, Claudia C; Mira, Marcelo T; Trevilatto, Paula C

45

Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer's disease  

Microsoft Academic Search

Background: Genetic risk for Alzheimer's disease (AD) can be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the 4 allele increases the risk of developing late-onset AD but is not a definitive predictor of the disease, or by autosomal dominant mutations (eg, the presenilins), which almost inevitably result in early-onset familial AD. The purpose of this study was to

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

46

Molecular genetic basis of susceptibility to psoriasis  

Microsoft Academic Search

Psoriasis is one of the most common chronic inflammatory dermatosis, which is observed in 0.3–7% of the world population.\\u000a Numerous twin-, familial- and population-based studies suggest the involvement of genetic factors in the disease development.\\u000a The present review summarizes the present state of knowledge and analyzes of the most recent findings in the molecular genetics\\u000a of psoriasis.

E. S. Galimova; V. L. Akhmetova; E. K. Khusnutdinova

2008-01-01

47

Genetic background influences immune responses and disease outcome of cutaneous L. mexicana infection in mice  

Microsoft Academic Search

The experimental model of high-dose Leishmania mexicana infection is used frequently to study molecular mechanisms regulating Th2 response since most inbred mice regardless of their genetic background display Th2 cytokine-dependent susceptibility to L. mexicana unlike Leishmania major. Here, we analyzed the course of L. mexicana infection in BALB\\/c, C57BL\\/6 and CBA\\/J mouse strains using low-dose ear infection model that mimics

Lucia E. Rosas; Tracy Keiser; Joseph Barbi; Anjali A. Satoskar; Alecia Septer; Jennifer Kaczmarek; Claudio M. Lezama-Davila; Abhay R. Satoskar

2005-01-01

48

Inherited susceptibility to aminoglycoside ototoxicity: Genetic heterogeneity and clinical implications  

Microsoft Academic Search

Purpose: Aminoglycoside-induced ototoxicity appears to have a genetic susceptibility in some individuals, and theA1555G mutation in the mitochondrial 12S ribosomal RNA gene has been shown to be responsible for this susceptibility in all familial cases. An Italian family with 5 family members who became deaf after aminoglycoside exposure presented to us, and molecular analysis excluded the Al 555G mutation. The

Rosaria A. M. S. Casano; David F. Johnson; Yelena Bykhovskaya; Francesca Torricelli; Minna Bigozzi; Nathan Fischel-Ghodsian

1999-01-01

49

Genetic Susceptibility to Fungal Infections in Humans  

PubMed Central

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

Lionakis, Michail S.

2012-01-01

50

Association between adult height, genetic susceptibility and risk of glioma  

PubMed Central

Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case–control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. Results Among men, we found a positive association between height and glioma risk (?190 vs 170–174 cm, pooled OR = 1.70, 95% CI: 1.11–2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17–3.38; P-trend = 0.02). Among women, these associations were less clear (?175 vs 160–164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70–1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77–2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.

Kitahara, Cari M; Wang, Sophia S; Melin, Beatrice S; Wang, Zhaoming; Braganza, Melissa; Inskip, Peter D; Albanes, Demetrius; Andersson, Ulrika; Beane Freeman, Laura E; Buring, Julie E; Carreon, Tania; Feychting, Maria; Gapstur, Susan M; Gaziano, J Michael; Giles, Graham G; Hallmans, Goran; Hankinson, Susan E; Henriksson, Roger; Hsing, Ann W; Johansen, Christoffer; Linet, Martha S; McKean-Cowdin, Roberta; Michaud, Dominique S; Peters, Ulrike; Purdue, Mark P; Rothman, Nathaniel; Ruder, Avima M; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Stevens, Victoria L; Visvanathan, Kala; Waters, Martha A; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Hoover, Robert; Fraumeni, Joseph F; Chatterjee, Nilanjan; Yeager, Meredith; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

2012-01-01

51

Genetic susceptibility factors for Alzheimer's disease  

Microsoft Academic Search

Alzheimer's disease is the most frequent cause of dementia. Family and twin studies have suggested that genetic factors play a role in Alzheimer's disease development. Some Alzheimer's disease cases show an autosomal dominant inheritance pattern and thus allow the discovery of major disease genes. However, most Alzheimer's disease cases are sporadic. These cases are mainly due to the effects of

Florence Richard; Philippe Amouyel

2001-01-01

52

[Genetic susceptibility to herpes simplex encephalitis].  

PubMed

Herpes simplex encephalitis (HSE) is a rare but severe complication of frequent and mostly benign infection with herpes simplex virus (HSV). Although rapid and sensitive diagnosis tools and active antiviral drugs are available, HSE morbidity/mortality levels remain unsatisfactory. Molecular and cellular determinants of HSE are incompletely understood. The rarity and severity of the disease have suggested an increased susceptibility of some subjects to HSV infection. Numerous experimental studies have investigated the respective role of host and viral factors in HSE. The results of these studies have illustrated the major role of the innate immune response, in particular interferons (IFNs), in limiting access of the virus into and/or virus replication in the central nervous system (CNS). In a few children with HSE, specific defects of the immune innate response have been identified, which impair the IFN-?/? and IFN-? production of fibroblasts and/or neurons infected with HSV and render these cells more permissive to infection. The mutations affect proteins involved in the IFN pathway induced by stimulation of the TLR3 receptor. The patients' susceptibility to infection is restricted to HSV CNS invasion, underlining the major role of TLR3 in CNS protection against viral infection. The incomplete clinical penetrance of these molecular defects suggests that other factors (age, infectious dose) are involved in HSE. Whether pathogenesis of adult HSE is similar has not been investigated. PMID:23399415

Rozenberg, F

2013-02-08

53

QTL x Genetic Background Interaction: Application to Predicting Progeny Value  

Technology Transfer Automated Retrieval System (TEKTRAN)

Failures of the additive infinitesimal model continue to provide incentive to study other modes of gene action, in particular, epistasis. Epistasis can be modeled as a QTL by genetic background interaction. Association mapping models lend themselves to fitting such an interaction because they often ...

54

Genetic Background Predicts Poor Prognosis in Frontotemporal Lobar Degeneration  

Microsoft Academic Search

Background: Ruling out predictors of survival in frontotemporal lobar degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. Little is known about determinants of survival in FTLD. Objective: The aim of the present study was to identify whether genetic determinants are key, not only as risk factors but as predictors of survival in FTLD. Methods:

B. Borroni; M. Grassi; S. Archetti; A. Papetti; R. Del Bo; C. Bonvicini; G. P. Comi; M. Gennarelli; G. Bellelli; M. Di Luca; A. Padovani

2011-01-01

55

Genetic Background and Allorecognition Phenotype in Hydractinia symbiolongicarpus  

PubMed Central

The Hydractinia allorecognition complex (ARC) was initially identified as a single chromosomal interval using inbred and congenic lines. The production of defined lines necessarily homogenizes genetic background and thus may be expected to obscure the effects of unlinked allorecognition loci should they exist. Here, we report the results of crosses in which inbred lines were out-crossed to wild-type animals in an attempt to identify dominant, codominant, or incompletely dominant modifiers of allorecognition. A claim for the existence of modifiers unlinked to ARC was rejected for three different genetic backgrounds. Estimates of the genetic map distance of ARC in two wild-type haplotypes differed markedly from one another and from that measured in congenic lines. These results suggest that additional allodeterminants exist in the Hydractinia ARC.

Powell, Anahid E.; Moreno, Maria; Gloria-Soria, Andrea; Lakkis, Fadi G.; Dellaporta, Stephen L.; Buss, Leo W.

2011-01-01

56

Genetic Background and Allorecognition Phenotype in Hydractinia symbiolongicarpus.  

PubMed

The Hydractinia allorecognition complex (ARC) was initially identified as a single chromosomal interval using inbred and congenic lines. The production of defined lines necessarily homogenizes genetic background and thus may be expected to obscure the effects of unlinked allorecognition loci should they exist. Here, we report the results of crosses in which inbred lines were out-crossed to wild-type animals in an attempt to identify dominant, codominant, or incompletely dominant modifiers of allorecognition. A claim for the existence of modifiers unlinked to ARC was rejected for three different genetic backgrounds. Estimates of the genetic map distance of ARC in two wild-type haplotypes differed markedly from one another and from that measured in congenic lines. These results suggest that additional allodeterminants exist in the Hydractinia ARC. PMID:22384360

Powell, Anahid E; Moreno, Maria; Gloria-Soria, Andrea; Lakkis, Fadi G; Dellaporta, Stephen L; Buss, Leo W

2011-11-01

57

Human Papilloma Virus, Cellular Genetics and Susceptibility to Cervical Cancer  

Microsoft Academic Search

KEYWORDS Human papillmoa virus; cervical cancer; genetic susceptibility; polymorphisms ABSTRACT Research in relation to the etiology of cervical cancer has made substantial progress in the last two decades both in scientific and operational terms. In many countries, HPV is the most common sexually transmitted infection (STI) and cervical cancer remains the second most common cancer among women worldwide. Although high

Sreekala Nair; M Radhakrishna Pillai

2005-01-01

58

Mapping Genetic Modifiers of Mammary Tumor Susceptibility.  

National Technical Information Service (NTIS)

Mutations in APC/Apc predispose both humans and mice to multiple polyps of the colon and small intestine. Min/+ mice carry a mutation at Apc and are predisposed to developing spontaneous intestinal and mammary tumors. On a C57B1/6J (B6) background, Min/+ ...

A. R. Moser

2002-01-01

59

Mapping Genetic Modifiers of Mammary Tumor Susceptibility.  

National Technical Information Service (NTIS)

Mutations in APC/Apc predispose both humans and mice to multiple polyps of the colon and small intestine Min/+ mice carry a mutation at Apc and are predisposed to developing spontaneous intestinal and mammary tumors. On a C57BL/6J (B6) background Min/+ mi...

A. R. Moser

2002-01-01

60

Mapping Genetic Modifiers of Mammary Tumor Susceptibility.  

National Technical Information Service (NTIS)

Mutations in APC/Apc predispose both humans and mice to multiple polyps of the colon and small intestine. Min/+ mice carry a mutation at Apc and are predisposed to developing spontaneous intestinal and mammary tumors. On a C57BL/6J (B6) background, Min/+ ...

R. L. Williams A. Moser

2001-01-01

61

Premature birth and diseases in premature infants: common genetic background?  

PubMed

It has been proposed that during human evolution, development of obligate bipedalism, narrow birth canal cross-sectional area and the large brain have forced an adjustment in duration of pregnancy (scaling of gestational age; Plunkett 2011). Children compared to other mammals are born with proportionally small brains (compared to adult brains), suggesting shortening of pregnancy duration during recent evolution. Prevalence of both obstructed delivery and premature birth is still exceptionally high. In near term infants, functional maturity and viability is high, and gene variants predisposing to respiratory distress syndrome (RDS) are rare. Advanced antenatal and neonatal treatment practices during the new era of medicine allowed survival of also very preterm infants (gestation <32 weeks). Genetic factors may play a major role in predisposing these infants to common pulmonary (bronchopulmonary dysplasia [BPD]; RDS) and intracerebral (intraventricular hemorrhage [IVH], cerebral palsy [CP]) diseases. Fetal genes also influence the susceptibility to preterm labor and premature birth. Specific genes associating with diseases in preterm infants may also contribute to the susceptibility to preterm birth. Understanding and applying the knowledge of genetic interactions in normal and abnormal perinatal-neonatal development requires large, well-structured population cohorts, studies involving the whole genome and international interdisciplinary collaboration. PMID:22385349

Hallman, Mikko

2012-04-01

62

Chloroquine Susceptibility and Reversibility in a Plasmodium falciparum Genetic Cross  

PubMed Central

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

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

63

Genetic susceptibility in solvent induced neurobehavioral effects.  

PubMed

The aim of this investigation was to study the influence of genetic polymorphisms of biotransformation enzymes and dopamine receptors on neurobehavioral effects in referents (n = 53), solvent-workers (n = 144), and chronic toxic encephalopathy (CTE) patients (n = 33). All participants were interviewed for exposure data and confounding factors and underwent a clinical examination. Neurobehavioral complaints (neurotoxicity symptom checklist-60) and effects [simple reaction time (SRT), symbol digit substitution (SDS), hand-eye coordination (HEC), and digit span backwards (DSB)] were evaluated with a computer assisted test battery. The following genotypes were determined: GSTM1, GSTT1, GSTP1, DRD2 Taq1A, DRD2 Taq1B, and DRD2-141Cdel. Neurotoxic effects and complaints were significantly higher in CTE patients and were related to both duration and level of exposure. An equal distribution of genotypes was found between all groups. Logistic regression analysis revealed that GSTT1 was negatively associated with sleep and sensorimotor complaints. GSTM1 had a protecting influence on the relationship between logDSB and the cumulative exposure index and between logSRT and cumulative exposure index and degree of exposure, respectively. This effect was also found when correcting for age, education level, alcohol consumption, and smoking. DRD2-141Cdel polymorphisms had a negative influence on the relationship between logSDS and the total exposure time. GSTT1 might be protective against sleep and sensorimotor complaints, whereas GSTM1 seems to decrease sustained attention and short-term memory problems in relation to solvent exposure. Individuals possessing DRD2-141Cdel variant experienced more visuomotor problems. PMID:19701675

Godderis, L; Maertens, N; de Gelder, V; De Lamper, A; De Ruyck, K; Vernimmen, M; Bulterys, S; Moens, G; Thierens, H; Viaene, M K

2009-08-22

64

Human genetic susceptibility and infection with Leishmania peruviana  

SciTech Connect

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

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

1995-11-01

65

Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis  

SciTech Connect

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

Mock, B.A.; Krall, M.M.; Dosik, J.K. (National Institutes of Health, Bethesda, MD (United States))

1993-10-15

66

Impact of the Mitochondrial Genetic Background in Complex III Deficiency  

PubMed Central

Background In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities. Methodology Spectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis. Principal Findings Biochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background. Conclusions Our results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders.

Moran, Maria; Blazquez, Alberto; Pello, Rosa; Marin Buera, Lorena; Gabaldon, Toni; Garcia Penas, Juan Jose; Martin, Miguel A.; Arenas, Joaquin; Ugalde, Cristina

2010-01-01

67

The genetic background of gallstone formation: an update.  

PubMed

Gallstone disease is one of the most prevalent gastrointestinal diseases with a substantial burden to health care systems that is expected to increase in ageing populations at risk. This review summarizes recent data on the genetic background of cholesterol gallstones and the role of biliary lipid composition. Three previously unknown non-synonymous mutations in the ABCB4 gene encoding the hepatobiliary phospholipid-flippase MDR3 are presented. PMID:20494111

Marschall, Hanns-Ulrich; Katsika, Despina; Rudling, Mats; Einarsson, Curt

2010-05-21

68

The cluster structure of barley amylopectins of different genetic backgrounds.  

PubMed

The unit chains of amylopectin are organized into clusters. In this study, the cluster structure was analysed in detail in four different genotypes of barley, of which two possessed the amo1 genetic background. Amylose content of the barley starches differed from 0 to 32.6%. Isolated amylopectin was hydrolysed with ?-amylase from Bacillus subtilis into domains, defined as groups of clusters, which were size-fractionated by methanol. The domain fractions were further treated with ?-amylase to release single clusters. Amylopectin, domains and clusters were subsequently treated with phosphorylase and ?-amylase to produce ?,?-limit dextrins and the detailed internal structures of these different structure levels were investigated. Analysis was performed with gel-permeation and anion-exchange chromatography. Equal amount of A-chains were detected in all barleys, but the distribution of B-chains differed. At least two types of domain structures were identified in all four barley varieties. Large domains were built up by large clusters and small domains by small clusters. In all four barley samples the number of long chains was small suggesting that shorter chains with a degree of polymerization of 25-35 also are involved in the interconnection of clusters. The cluster structure of the amylopectin correlated with the genetic background. The two barley samples with amo1 genetic background possessed a more dense structure. Internal chain lengths in these two barleys were shorter resulting in larger domains built up by larger clusters. PMID:21704067

Bertoft, Eric; Källman, Anna; Koch, Kristine; Andersson, Roger; Aman, Per

2011-06-17

69

Genetic Epidemiology of Tuberculosis Susceptibility: Impact of Study Design  

PubMed Central

Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB.

Stein, Catherine M.

2011-01-01

70

Genetic Background of Escherichia coli and Extended-spectrum ?-Lactamase Type  

PubMed Central

To assess the implication of the genetic background of Escherichia coli strains in the emergence of extended-spectrum-?-lactamases (ESBL), 55 TEM-, 52 CTX-M-, and 22 SHV-type ESBL-producing clinical isolates involved in various extraintestinal infections or colonization were studied in terms of phylogenetic group, virulence factor (VF) content (pap, sfa/foc, hly, and aer genes), and fluoroquinolone resistance. A factorial analysis of correspondence showed that SHV type, and to a lesser extent TEM type, were preferentially observed in B2 phylogenetic group strains that exhibited numerous VFs but were fluoroquinolone-susceptible, whereas the newly emerged CTX-M type was associated with the D phylogenetic group strains that lacked VF but were fluoroquinolone-resistant. Thus, the emergence of ESBL-producing E. coli seems to be the result of complex interactions between the type of ESBL, genetic background of the strain, and selective pressures in ecologic niches.

Zamfir, Oana; Geoffroy, Sabine; Laurans, Genevieve; Arlet, Guillaume; Thien, Hoang Vu; Gouriou, Stephanie; Picard, Bertrand; Denamur, Erick

2005-01-01

71

Understanding Genetic and Environmental Risk Factors in Susceptible Persons  

PubMed Central

Most major chronic diseases probably result from environmental factors accumulating over time in genetically susceptible persons. A detailed family history assessment can help identify the subset of the general population with a strong predisposition to certain major diseases. An understanding of the environmental factors promoting disease development will facilitate more effective prevention or delay disease in a targeted susceptible population. To effectively use this growing knowledge in genetics and epidemiology, health professionals need to motivate people to follow sound recommendations for preventing and delaying disease. To increase the efficiency and effectiveness of strategies for health promotion and disease prevention, family history data can help determine those diseases for which persons have the greatest risk. They can then concentrate their primary efforts on those preventive measures that will most likely benefit them.

Williams, Roger R.

1984-01-01

72

Integrating genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility  

PubMed Central

Background Predicting susceptibility to multiple sclerosis may have important clinical applications either as part of a diagnostic algorithm or as a tool with which to identify high-risk individuals for prospective studies. Here, we examine the utility of an aggregate measure of risk of multiple sclerosis (MS) based on genetic susceptibility loci. Secondarily, we assess the added effect of environmental risk factors that have been associated with susceptibility for MS. Methods We created a weighted genetic risk score (wGRS) that includes 16 MS susceptibility loci. We tested our model using data from (1) 2215 MS cases and 2189 controls (derivation samples), (2) a validation set of 1340 cases and 1109 controls taken from several MS therapeutic trials (TT samples), and (3) a second validation set of 143 cases and 281 controls from the U.S. Nurses’ Health Studies I and II (NHS) for whom we also have information regarding exposure to smoking and Epstein-Barr Virus (EBV). Findings . Patients with wGRS > 1.25 standard deviations from the mean had a significantly higher odds ratio for MS in all datasets. The area under the curve for a purely genetic model was 0.70 and for a gender + genetic model was 0.74 in the derivation samples (P <0.0001), 0.64 and 0.72 in the TT cohort (P <0.0001). Similarly, consideration of smoking and immune response to EBV enhanced the AUC of 0.64 for the genetic model to 0.68 in the NHS cohort (P =0.02). The wGRS does not appear to be correlated with conversion of a clinically isolated syndrome to MS. Interpretation The current combination of 16 susceptibility alleles into a wGRS modestly predicts MS risk and shows consistent discriminatory ability in independent subject samples and is enhanced by considering non-genetic risk factors.

De Jager, Philip L.; Chibnik, Lori B.; Cui, Jing; Reischl, Joachim; Lehr, Stephan; Simon, K. Claire; Aubin, Cristin; Bauer, David; Heubach, Jurgen F.; Sandbrink, Rupert; Tyblova, Michaela; Lelkova, Petra; Havrdova, Eva; Pohl, Christoph; Horakova, Dana; Ascherio, Alberto; Hafler, David A.; Karlson, Elizabeth W.

2011-01-01

73

Genetic susceptibility to malignant diseases--ethical issues. Minireview.  

PubMed

Ethical problems connected with genetic testing with the intention of the measurement of the susceptibility or predisposition to malignant tumors are presented (respect for autonomy, beneficence, nonmaleficence, confidentiality, privacy, veracity and truth-telling, informed consent, right to know, right not to know, informational self-determination, etc.). Various aspects dealing with ethics of screening and research projects involving human subjects are discussed as well. PMID:12044052

Munzarová, M

2002-01-01

74

Folate pathway genetic polymorphisms and susceptibility of central nervous system tumors in Thai children  

Microsoft Academic Search

Background: Folate is an important micronutrient molecule participating in DNA synthesis, methylation and repair mechanisms. Genetic polymorphisms in folate pathway related enzymes including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, thymidylate synthase (TS) 28-bp tandem repeat, and reduced folate carrier (RFC) G80A have been shown to be associated with increased susceptibility for several cancers. The aim of

Nongnuch Sirachainan; Siranee Wongruangsri; Saowanee Kajanachumpol; Samart Pakakasama; Anannit Visudtibhan; Issarang Nuchprayoon; Apasri Lusawat; Suchart Phudhicharoenrat; Shanop Shuangshoti; Suradej Hongeng

2008-01-01

75

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

SciTech Connect

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.

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

76

Population genetic analyses of susceptibility to increased body weight  

PubMed Central

Introduction Obesity is a complex condition with multifactorial origin. Assuming that such a state is genetically controlled, the aim of our study was to evaluate the degree of genetic homozygosity among overweight and obese individuals by the homozygously recessive characteristics (HRC) test. Material and methods We analysed the presence, distribution and individual combination of 15 selected genetically controlled recessive phenotype traits in a sample of 140 individuals with increased body mass index (overweight individuals n = 100 and obese individuals n = 40) and a control group of normal weight individuals (n = 300). Results Obese individuals have significantly higher mean values for genetic homozygosity than those with normal weight (normal weight: 3.61 ±1.48; obese: 4.13 ±1.47, p < 0.05) and difference in the presence of certain individual combinations of evaluated phenotype traits (??2 = 76.9; p < 0.01). There was no difference in average homozygosity of such genetic markers between groups of normal weight and overweight individuals (normal weight: 3.61 ±1.48; overweight: 3.93 ±1.51, p > 0.05) and between groups of overweight and obese individuals (overweight: 3.93 ±1.51; obese: 4.13 ±1.47, p > 0.05). There is no difference in the presence of certain individual combinations of evaluated phenotype traits between overweight and obese individuals (??2 = 20.6; p > 0.05). Conclusions There is a populational genetic difference in the degree of genetic homozygosity and variability between the group of normal weight and group of obese individuals, indicating a possible genetic component. Overweight and obese individuals have a genetic predisposition, but different expression of genetic loads could be one of the possible explanations for different susceptibility to increase of fat mass and body mass index.

Cvjeticanin, Suzana; Petronic, Ivana; Milincic, Zeljka; Brdar, Radivoj; Karan, Radmila; Konstantinovic, Ljubica; Dragin, Aleksandra; Cutovic, Milisav

2012-01-01

77

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

PubMed Central

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

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

2012-01-01

78

Identification of multiple genetic susceptibility Loci in takayasu arteritis.  

PubMed

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

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

2013-07-03

79

Host Genetic Variation in Susceptibility to Punta Toro Virus  

PubMed Central

SUMMARY Infection of small laboratory animals by Punta Toro virus (PTV), family Bunyaviridae, genus Phlebovirus, is a model for the study of the human pathogen Rift Valley fever virus (RVFV). We have identified inbred mouse strains with significant differences in host response to the Adames strain of PTV. Nine inbred strains of mice representing major branches in the Mus musculus phylogeny were inoculated subcutaneously with a high dose of PTV in survival experiments. Two inbred strains of mice, NZW/LacJ and 129S1/SvImJ, died ~4 days after PTV infection, whereas 7 other strains survived the challenge and showed no clinical signs of disease. Histologically, 129S1/SvImJ mice showed massive hepatocellular necrosis and had additional lesions in lung, brain, and spleen, whereas NZW/LacJ mice had mild piecemeal hepatocellular necrosis. PTV viral loads in the livers of infected mice were determined by reverse transcriptase quantitative PCR. Inbred mice from strains that showed clinical signs and succumbed to PTV infection had higher liver viral loads than did mice of resistant strains. Hybrid F1 mice were generated by crossing susceptible 129S1 and resistant FVB/N mice and tested for susceptibility. The hybrid F1 mice showed significantly higher viral loads in the liver than the resistant parental FVB/N mice, suggesting that susceptibility is dominant. These findings will enable an unbiased genetic approach to identify host genes mediating susceptibility to PTV.

Ashley, Shanna L.; Ameres, Stefanie M.; Gerrard, Sonja R.; Foreman, Oded; Eaton, Kathryn A.; Weinberg, Jason B.; Spindler, Katherine R.

2013-01-01

80

Knowledge Gaining by Human Genetic Studies on Tuberculosis Susceptibility  

PubMed Central

Tuberculosis (TB) is a serious health issue in the developing world. Lack of knowledge on the etiological mechanisms of TB hinders the development of effective strategies for the treatment or prevention of TB disease. Human genetic study is an indispensable approach to understand the molecular basis of common diseases. Numerous efforts were made to screen the human genome for TB susceptibility by linkage mapping. A large number of candidate-based association studies of TB were performed to examine the association of predicted functional DNA variations in candidate genes. Recently, the first genome-wide association study (GWAS) on TB was reported. The GWAS is a proof-of-principle evidence which justifies the genetic approach to understand TB. Further hypothesis-free efforts on TB research may renovate the traditional idea of TB genetic susceptibility as none of the candidate genes with important roles in containing Mycobacterium tuberculosis (MTB) infection was identified of association with active TB, while the TB-associated loci in the GWAS harbors no gene with function in MTB infection.

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

2011-01-01

81

TGF-? Mediates Genetic Susceptibility to Chronic Kidney Disease  

PubMed Central

The mechanisms of progression of chronic kidney disease (CKD) are poorly understood. Epidemiologic studies suggest a strong genetic component, but the genes that contribute to the onset and progression of CKD are largely unknown. Here, we applied an experimental model of CKD (75% excision of total renal mass) to six different strains of mice and found that only the FVB/N strain developed renal lesions. We performed a genome-scan analysis in mice generated by back-crossing resistant and sensitive strains; we identified a major susceptibility locus (Ckdp1) on chromosome 6, which corresponds to regions on human chromosome 2 and 3 that link with CKD progression. In silico analysis revealed that the locus includes the gene encoding the EGF receptor (EGFR) ligand TGF-?. TGF-? protein levels markedly increased after nephron reduction exclusively in FVB/N mice, and this increase preceded the development of renal lesions. Furthermore, pharmacologic inhibition of EGFR prevented the development of renal lesions in the sensitive FVB/N strain. These data suggest that variable TGF-? expression may explain, in part, the genetic susceptibility to CKD progression. EGFR inhibition may be a therapeutic strategy to counteract the genetic predisposition to CKD.

Laouari, Denise; Burtin, Martine; Phelep, Aurelie; Martino, Carla; Pillebout, Evangeline; Montagutelli, Xavier; Friedlander, Gerard

2011-01-01

82

Genetic susceptibility to obesity and metabolic syndrome in childhood.  

PubMed

Obesity is one of the major public health problems worldwide. It is a chronic, complex, and multifactorial origin disease characterised by body fat excess mainly due to an imbalance between dietary intake and energy expenditure. One of the major complications of obesity is metabolic syndrome, which comprises anthropometrical, clinical, and metabolic dysfunctions that predispose the affected individual to the development of type 2 diabetes mellitus and cardiovascular diseases. It is hypothesised that the variability in the susceptibility to obesity-mediated metabolic complications involves both environmental and genetic factors. Whereas advances in the knowledge of the variations in the human genome have led to the identification of susceptibility genes that contribute to obesity and related disorders, relatively few studies have specifically focused on the interactions between obesity and genetic polymorphisms and the development of metabolic complications. Despite these limited efforts, an increasing amount of evidence suggests that the effects of some gene variants on metabolic traits are modified by or present only in the setting of obesity. Furthermore, some of these loci may have larger effects on metabolic phenotypes in the presence of certain dietary or lifestyle factors. In the present manuscript, we reviewed the genes and their variants that have been evidenced to play a role in obesity-associated metabolic complications through genetic association studies, including candidate gene and genome-wide association approaches in adults and children. PMID:24010743

Aguilera, Concepción M; Olza, Josune; Gil, Angel

2013-09-01

83

Genetic Control of Bordetella pertussis Infection: Identification of Susceptibility Loci Using Recombinant Congenic Strains of Mice  

Microsoft Academic Search

Susceptibility to and severity of Bordetella pertussis infection in infants and children vary widely. The spectrum of clinical symptoms ranges from subclinical infection to mild disease, severe whooping cough, and death. The aims of this study were to examine genetic susceptibilities of mice to B. pertussis and to identify genetic loci in the mouse genome that are involved in susceptibility

H. A. Banus; H. J. van Kranen; F. R. Mooi; B. Hoebee; N. J. Nagelkerke; P. Demant; T. G. Kimman

2005-01-01

84

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

PubMed Central

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

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

2007-01-01

85

‘A Low Risk Is Still a Risk’: Exploring Women’s Attitudes towards Genetic Testing for Breast Cancer Susceptibility in Order to Target Disease Prevention  

Microsoft Academic Search

Background: Population breast cancer screening programs by mammography are offered to women based on age. It has been suggested that a screening program based on genetic risk profile could be more effective by targeting interventions at those at higher genetic risk. This study explores women’s attitudes towards genetic testing for breast cancer susceptibility in order to target breast cancer prevention.

L. Henneman; D. R. Timmermans; C. M. Bouwman; M. C. Cornel; H. Meijers-Heijboer

2011-01-01

86

Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise  

PubMed Central

Purpose of review In this review, we summarize the basic principles governing rare variant interpretation in the heritable cardiac arrhythmia syndromes, focusing on recent advances that have led to disease-specific approaches to the interpretation of positive genetic testing results. Recent findings Elucidation of the genetic substrates underlying heritable cardiac arrhythmia syndromes has unearthed new arrhythmogenic mechanisms and given rise to a number of clinically meaningful genotype–phenotype correlations. As such, genetic testing for these disorders now carries important diagnostic, prognostic, and therapeutic implications. Recent large-scale systematic studies designed to explore the background genetic ‘noise’ rate associated with these genetic tests have provided important insights and enhanced how positive genetic testing results are interpreted for these potentially lethal, yet highly treatable, cardiovascular disorders. Summary Clinically available genetic tests for heritable cardiac arrhythmia syndromes allow the identification of potentially at-risk family members and contribute to the risk-stratification and selection of therapeutic interventions in affected individuals. The systematic evaluation of the ‘signal-to-noise’ ratio associated with these genetic tests has proven critical and essential to assessing the probability that a given variant represents a rare pathogenic mutation or an equally rare, yet innocuous, genetic bystander.

Giudicessi, John R.; Ackerman, Michael J.

2013-01-01

87

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

PubMed Central

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

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

2013-01-01

88

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

PubMed Central

Background Few genetic factors predisposing to the sporadic form of amyotrophic lateral sclerosis (ALS) have been identified, but the pathology itself seems to be a true multifactorial disease in which complex interactions between environmental and genetic susceptibility factors take place. The purpose of this study was to approach genetic data with an innovative statistical method such as artificial neural networks to identify a possible genetic background predisposing to the disease. A DNA multiarray panel was applied to genotype more than 60 polymorphisms within 35 genes selected from pathways of lipid and homocysteine metabolism, regulation of blood pressure, coagulation, inflammation, cellular adhesion and matrix integrity, in 54 sporadic ALS patients and 208 controls. Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis Results Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis. An unexpected discovery of a strong genetic background in sporadic ALS using a DNA multiarray panel and analytical processing of the data with advanced artificial neural networks was found. The predictive accuracy obtained with Linear Discriminant Analysis and Standard Artificial Neural Networks ranged from 70% to 79% (average 75.31%) and from 69.1 to 86.2% (average 76.6%) respectively. The corresponding value obtained with Advanced Intelligent Systems reached an average of 96.0% (range 94.4 to 97.6%). This latter approach allowed the identification of seven genetic variants essential to differentiate cases from controls: apolipoprotein E arg158cys; hepatic lipase -480 C/T; endothelial nitric oxide synthase 690 C/T and glu298asp; vitamin K-dependent coagulation factor seven arg353glu, glycoprotein Ia/IIa 873 G/A and E-selectin ser128arg. Conclusion This study provides an alternative and reliable method to approach complex diseases. Indeed, the application of a novel artificial intelligence-based method offers a new insight into genetic markers of sporadic ALS pointing out the existence of a strong genetic background.

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

2008-01-01

89

Genetic susceptibility loci, pesticide exposure and prostate cancer risk.  

PubMed

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

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

2013-04-04

90

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

SciTech Connect

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

Zhang Peng; Lau, Y. Y.; Franzi, Matthew; Gilgenbach, R. M. [Department of Nuclear Engineering and Radiological Sciences, University of Michigan, Ann Arbor, Michigan 48109-2104 (United States)

2011-05-15

91

Genetic susceptibility variants associated with colorectal cancer prognosis.  

PubMed

Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.45-0.93, P = 0.0179; GG/GA genotypes, dominant model: HR = 0.66, 95% CI 0.47-0.94, P = 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR = 0.73, 95% CI 0.53-1.01, P = 0.0570; GA genotype, genotypic model: HR = 0.66, 95% CI 0.47-0.92, P = 0.0137; GG/GA genotypes, dominant model: HR = 0.68, 95% CI 0.50-0.94, P = 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patient's survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers. PMID:23712746

Abulí, Anna; Lozano, Juan José; Rodríguez-Soler, María; Jover, Rodrigo; Bessa, Xavier; Muñoz, Jenifer; Esteban-Jurado, Clara; Fernández-Rozadilla, Ceres; Carracedo, Angel; Ruiz-Ponte, Clara; Cubiella, Joaquín; Balaguer, Francesc; Bujanda, Luis; Reñé, Josep M; Clofent, Juan; Morillas, Juan Diego; Nicolás-Pérez, David; Xicola, Rosa M; Llor, Xavier; Piqué, Josep M; Andreu, Montserrat; Castells, Antoni; Castellví-Bel, Sergi

2013-05-27

92

Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus  

PubMed Central

Objective Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. Materials and methods 4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Results Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0×10?6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing. Conclusion Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

Sanchez, Elena; Nadig, Ajay; Richardson, Bruce C; Freedman, Barry I; Kaufman, Kenneth M; Kelly, Jennifer A; Niewold, Timothy B; Kamen, Diane L; Gilkeson, Gary S; Ziegler, Julie T; Langefeld, Carl D; Alarcon, Graciela S; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Brown, Elizabeth E; Kimberly, Robert P; Reveille, John D; Vila, Luis M; Merrill, Joan T; Anaya, Juan-Manuel; James, Judith A; Pons-Estel, Bernardo A; Martin, Javier; Park, So-Yeon; Bang, So-Young; Bae, Sang-Cheol; Moser, Kathy L; Vyse, Timothy J; Criswell, Lindsey A; Gaffney, Patrick M; Tsao, Betty P; Jacob, Chaim O; Harley, John B; Alarcon-Riquelme, Marta E; Sawalha, Amr H

2011-01-01

93

Independent genetic susceptibility to cardiac hypertrophy in inherited hypertension.  

PubMed

Cardiac hypertrophy is a common but not inevitable complication of hypertension. Variation in heart size in hypertensives may reflect independent genetic susceptibility to cardiac hypertrophy. Using an experimental genetic model, we determined the location of quantitative trait loci responsible for cardiac hypertrophy and/or hypertension. We studied 182 F2 male animals derived from a cross of the spontaneously hypertensive rat and normotensive Donryu rats. Direct mean arterial pressure (MAP) and left ventricular (LV) mass were measured at 20 weeks of age, and DNA was obtained for linkage analysis. The estimated heritability of MAP was 62% and for LV mass expressed per unit of body weight (relative LV mass) was 76%. We used 185 polymorphic markers, with an average intermarker distance of 12.3 centimorgans for a genome-wide scan in a representative subgroup of 46 animals to identify preliminary quantitative trait loci, which were then mapped in all 182 male F2 rats. Two loci showed logarithm of the odds scores of > 4.0. One on chromosome 2, Lvm-1, was linked to relative LV mass but showed no evidence of linkage to MAP. Another locus on chromosome 1, Map-1, was linked to MAP. In the same region, a locus Lvm-2 was linked with relative LV mass. These data indicate the existence of a genetic locus on chromosome 2 of the spontaneously hypertensive rat that affects relative LV mass independently of blood pressure. PMID:9495256

Innes, B A; McLaughlin, M G; Kapuscinski, M K; Jacob, H J; Harrap, S B

1998-03-01

94

Genetic Background Affects Properties of Satellite Cells and mdx Phenotypes  

PubMed Central

Duchenne muscular dystrophy (DMD) is the most common lethal genetic disorder of children. The mdx (C57BL/10 background, C57BL/10-mdx) mouse is a widely used model of DMD, but the histopathological hallmarks of DMD, such as the smaller number of myofibers, accumulation of fat and fibrosis, and insufficient regeneration of myofibers, are not observed in adult C57BL/10-mdx except for in the diaphragm. In this study, we showed that DBA/2 mice exhibited decreased muscle weight, as well as lower myofiber numbers after repeated degeneration–regeneration cycles. Furthermore, the self-renewal efficiency of satellite cells of DBA/2 is lower than that of C57BL/6. Therefore, we produced a DBA/2-mdx strain by crossing DBA/2 and C57BL/10-mdx. The hind limb muscles of DBA/2-mdx mice exhibited lower muscle weight, fewer myofibers, and increased fat and fibrosis, in comparison with C57BL/10-mdx. Moreover, remarkable muscle weakness was observed in DBA/2-mdx. These results indicate that the DBA/2-mdx mouse is a more suitable model for DMD studies, and the efficient satellite cell self-renewal ability of C57BL/10-mdx might explain the difference in pathologies between humans and mice.

Fukada, So-ichiro; Morikawa, Daisuke; Yamamoto, Yukiko; Yoshida, Tokuyuki; Sumie, Noriaki; Yamaguchi, Masahiko; Ito, Takahito; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi; Tsujikawa, Kazutake; Yamamoto, Hiroshi

2010-01-01

95

Mammographic texture synthesis using genetic programming and clustered lumpy background  

NASA Astrophysics Data System (ADS)

In this work we investigated the digital synthesis of images which mimic real textures observed in mammograms. Such images could be produced in an unlimited number with tunable statistical properties in order to study human performance and model observer performance in perception experiments. We used the previously developed clustered lumpy background (CLB) technique and optimized its parameters with a genetic algorithm (GA). In order to maximize the realism of the textures, we combined the GA objective approach with psychophysical experiments involving the judgments of radiologists. Thirty-six statistical features were computed and averaged, over 1000 real mammograms regions of interest. The same features were measured for the synthetic textures, and the Mahalanobis distance was used to quantify the similarity of the features between the real and synthetic textures. The similarity, as measured by the Mahalanobis distance, was used as GA fitness function for evolving the free CLB parameters. In the psychophysical approach, experienced radiologists were asked to qualify the realism of synthetic images by considering typical structures that are expected to be found on real mammograms: glandular and fatty areas, and fiber crossings. Results show that CLB images found via optimization with GA are significantly closer to real mammograms than previously published images. Moreover, the psychophysical experiments confirm that all the above mentioned structures are reproduced well on the generated images. This means that we can generate an arbitrary large database of textures mimicking mammograms with traceable statistical properties.

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

2006-03-01

96

Is Genetic Background Important in Lung Cancer Survival?  

PubMed Central

Background In lung cancer, a patient's survival is poor with a wide variation in survival within the stage of disease. The aim of this study was to investigate the familial concordance in lung cancer survival by means of analyses of pairs with different degrees of familial relationships. Methods Our population-based Swedish family database included three million families and over 58 100 lung cancer patients. We modelled the proband (parent, sibling, spouse) survival utilizing a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. Subsequently, the survival in proband's relative (child, sibling, spouse) was analysed with a Cox model. Findings By use of Cox modelling with 5 years follow-up, we noted a decreased hazard ratio for death in children with good parental survival (Hazard Ratio [HR]?=?0.71, 95% CI?=?0.51 to 0.99), compared to those with poor parental survival. Also for siblings, a very strong protective effect was seen (HR?=?0.14, 95% CI?=?0.030 to 0.65). Finally, in spouses no correlation in survival was found. Interpretation Our findings suggest that genetic factors are important in lung cancer survival. In a clinical setting, information on prognosis in a relative may be vital in foreseeing the survival in an individual newly diagnosed with lung cancer. Future molecular studies enhancing the understanding of the underlying mechanisms and pathways are needed.

Lindstrom, Linda S.; Hall, Per; Hartman, Mikael; Wiklund, Fredrik; Czene, Kamila

2009-01-01

97

[Genetic susceptibility to virus associated encephalitis or encephalopathy].  

PubMed

There has been rapid progress in the understanding of the protective mechanism against infection during the past decade. We reviewed the genetic susceptibility in familial or recurrent encephalitis/encephalopathy and subacute sclerosing panencephalitis (SSPE). Recessive mutation of UNC-93B1 and dominant mutation of TLR3 were associated with herpes simplex encephalitis (HSE). Those mutations impair the dsRNA-induced IFN-alpha/beta and IFN-lambda production and predispose to HSE. Dominant mutation of RANBP2 (encoding a nuclear pore protein) was detected in familial or recurrent patients with acute necrotizing encephalopathy. Polymorphisms of MxA, IL-4, IRF1, TLR3, PD1 and TLR3 are probably associated with the development of SSPE. Identification of causing or predisposing genes would enable the early diagnosis and the establishment of effective protection or treatment. PMID:21400855

Nakamura, Kazuyuki; Hayasaka, Kiyoshi

2011-03-01

98

Genetic susceptibility to lead poisoning-A case report.  

PubMed

Lead poisoning is well documented in persons occupationally exposed to lead. What is less known is, that even in persons working in lead based industries, the effect of lead and the appearance of signs and symptoms of lead poisoning is genetically determined. Three genes related to lead metabolism, exhibiting polymorphism have already been demonstrated-?ALA-dehydratase, Vitamin D receptor gene and Hemochromatosis gene. These alleles determine the susceptibility of the individuals to lead. We present here a case of a lead acid battery worker, who presented without any signs and symptoms of lead poisoning except for a very high level of blood lead (82.8?g/dl and 47.5?g/dl 9 months later). PMID:23105707

Bijoor, Anita R; Venkatesh, T

2007-09-01

99

Breast cancer susceptibility: current knowledge and implications for genetic counselling  

PubMed Central

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.

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

2009-01-01

100

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

PubMed Central

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

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

2012-01-01

101

Genetic susceptibility to lung cancer and co-morbidities  

PubMed Central

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

Holloway, John W.; Fong, Kwun M.

2013-01-01

102

Genetic susceptibility to end-stage renal disease.  

PubMed

New methods have been developed to uncover the genotypes that result in complex diseases. End-stage renal disease is a complex disease, without a simple correspondence between genotype and phenotype. Both population-based and family-based epidemiological studies and analysis of model organisms suggest that the pathogenesis of end-stage renal disease may have a genetic component. A number of studies have analyzed candidate nephropathy genes with little success, but recently several well-designed studies of multiplex families with diabetic nephropathy have identified candidate nephropathy susceptibility loci. To date, kidney disease-oriented research has focused on effector mechanisms responsible for the initiation and progression of chronic renal disease. However, because end-stage renal disease is a complex disease, interruption of a single effector pathway is unlikely to result in significant therapeutic benefit. Further understanding of the pathogenesis of kidney disease and the development of new kidney disease therapies will require continued application of genetic and genomic tools to kidney disease research. PMID:10491742

Schelling, J R; Zarif, L; Sehgal, A; Iyengar, S; Sedor, J R

1999-07-01

103

A Strong Impact of Genetic Background on Gut Microflora in Mice.  

PubMed

Genetic background affects susceptibility to ileocolitis in mice deficient in two intracellular glutathione peroxidases, GPx1 and GPx2. The C57BL/6 (B6) GPx1/2 double-knockout (DKO) mice have mild ileocolitis, and 129S1/Sv (129) DKO mice have severe inflammation. We used diet to modulate ileocolitis; a casein-based defined diet with AIN76A micronutrients (AIN) attenuates inflammation compared to conventional LabDiets. Because luminal microbiota induce DKO ileocolitis, we assessed bacterial composition with automated ribosomal intergenic-spacer analysis (ARISA) on cecal DNA. We found that mouse strain had the strongest impact on the composition of microbiota than diet and GPx genotypes. In comparing AIN and LabDiet, DKO mice were more resistant to change than the non-DKO or WT mice. However, supplementing yeast and inulin to AIN diet greatly altered microflora profiles in the DKO mice. From 129 DKO strictly, we found overgrowth of Escherichia coli. We conclude that genetic background predisposes mice to colonization of potentially pathogenic E. coli. PMID:20976020

Esworthy, R Steven; Smith, David D; Chu, Fong-Fong

2010-06-01

104

Genetic susceptibility to non-polyposis colorectal cancer  

PubMed Central

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

Lynch, H.; de la Chapelle, A.

1999-01-01

105

Genetic dissection of MHC-associated susceptibility to Lepeophtheirus salmonis in Atlantic salmon  

PubMed Central

Background Genetic variation has been shown to play a significant role in determining susceptibility to the salmon louse, Lepeophtheirus salmonis. However, the mechanisms involved in differential response to infection remain poorly understood. Recent findings in Atlantic salmon (Salmo salar) have provided evidence for a potential link between marker variation at the major histocompatibility complex (MHC) and differences in lice abundance among infected siblings, suggesting that MHC genes can modulate susceptibility to the parasite. In this study, we used quantitative trait locus (QTL) analysis to test the effect of genomic regions linked to MHC class I and II on linkage groups (LG) 15 and 6, respectively. Results Significant QTL effects were detected on both LG 6 and LG 15 in sire-based analysis but the QTL regions remained unresolved due to a lack of recombination between markers. In dam-based analysis, a significant QTL was identified on LG 6, which accounted for 12.9% of within-family variance in lice abundance. However, the QTL was located at the opposite end of DAA, with no significant overlap with the MHC class II region. Interestingly, QTL modelling also revealed evidence of sex-linked differences in lice abundance, indicating that males and females may have different susceptibility to infection. Conclusion Overall, QTL analysis provided relatively weak support for a proximal effect of classical MHC regions on lice abundance, which can partly be explained by linkage to other genes controlling susceptibility to L. salmonis on the same chromosome.

Gharbi, Karim; Glover, Kevin A; Stone, Louise C; MacDonald, Elizabeth S; Matthews, Louise; Grimholt, Unni; Stear, Michael J

2009-01-01

106

Susceptibility genetic variants associated with early-onset colorectal cancer.  

PubMed

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

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

2012-01-10

107

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

Microsoft Academic Search

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 with autism, but most discoveries either fail to be replicated or account for a small effect. Thus, in most cases the underlying causative genetic mechanisms are not fully understood. In

Gregory Matuszek; Zohreh Talebizadeh

2009-01-01

108

The genetic architecture of rheumatoid arthritis: from susceptibility to clinical subphenotype associations.  

PubMed

Rheumatoid Arthritis (RA) is the most common chronic inflammatory disease of the joints and is characterized by a complex genetic architecture. In recent years, a substantial advance has been performed in the identification of the genes that increase the risk to develop RA. Genome-Wide Association Studies (GWAS) have allowed the characterization of more than 40 new susceptibility genes and the confirmation of a marked differential genetic background between patients expressing anti-cyclic citrullinated peptide antibodies (ACPA, approximately 80% of all RA patients) and ACPA negative RA patients. GWAS have also confirmed the existence of a common genetic basis between RA and other autoimmune diseases and the overrepresentation of specific biological pathways like antigen presentation and TNF signaling. Dense genotyping analysis has also allowed the detailed characterization of the different association signals within the HLA region, the strongest risk locus for RA. In the present manuscript, we also review the most recent advances in the genetics of clinically relevant subphenotypes in RA which are the response to treatment and the severity of the disease. In the next years the increasing ability to characterize the DNA variation and the availability of well characterized patient cohorts will be critical to translate genetic information into the much awaited personalized medicine in RA. PMID:23574521

Julià, Antonio; Marsal, Sara

2013-01-01

109

PKC? overexpression, irrespective of genetic background, sensitizes skin to ultraviolet radiation-induced development of squamous cell carcinomas  

PubMed Central

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

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

2009-01-01

110

A murine model of genetic susceptibility to lead bioaccumulation.  

PubMed

Previous reports have shown that blood lead levels in humans are associated with a polymorphic form of delta-aminolevulinate dehydratase (ALAD), an enzyme of heme biosynthesis that binds and is inhibited by lead. We hypothesized that ALAD levels may influence the distribution and accumulation of lead in the blood and target organs. To assess this, we studied strains of mice that differ in the numbers of copies of the ALAD gene. Our findings showed that mice with a duplication of the ALAD gene (DBA) accumulated twice the amount of lead in their blood and had higher lead levels in kidney and liver than mice with a single copy of the gene (C57) exposed to the same oral doses of lead during adulthood. Hybrid animals showed intermediate blood lead levels. Levels of blood zinc protoporphyrin (ZPP) increased with lead exposure in C57 animals while they were not affected in DBA mice, suggesting protection from production of this abnormal enzyme in mice with a duplication of the gene. Except for these protective effects in the formation of ZPP in DBA animals, duplication of the ALAD gene was found to increase lead accumulation. We conclude that although these mouse strains do not precisely replicate the polymorphism observed in humans, they may be used as a model to study genetic influences in lead bioaccumulation. Understanding genetic factors that affect susceptibility to lead-induced intoxication could have important implications for public health and intervention initiatives. These mouse strains may represent a useful model for future study of the role of ALAD in lead intoxication. PMID:9024676

Claudio, L; Lee, T; Wolff, M S; Wetmur, J G

1997-01-01

111

Genetic risk profiles for cancer susceptibility and therapy response.  

PubMed

Cells in the body are permanently attacked by DNA-reactive species, both from intracellular and environmental sources. Inherited and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and DNA repair enzymes) can modify cancer susceptibility as well as therapy response. Genetic profiles should help to identify high-risk individuals who subsequently can be enrolled in preventive measures or treated by tailored therapy regimens. Some of our attempts to define such risk profiles are presented. Cancer susceptibility: Single nucleotide polymorphisms (SNPs) in metabolic and repair genes were investigated in a hospital-based lung cancer case-control study. When evaluating the risk associated with different genotypes for N-acetyltransferases (Wikman et al. 2001) and glutathione-S-transferases (Risch et al. 2001), it is mandatory to distinguish between the three major histological subtypes of lung tumors. A promoter polymorphism of the myeloperoxidase gene MPO was shown to decrease lung cancer susceptibility mainly in small cell lung cancer (SCLC) (Dally et al. 2002). The CYP3A4*1B allele was also linked to an increased SCLC risk and in smoking women increased the risk of lung cancer eightfold (Dally et al. 2003b). Polymorphisms in DNA repair genes were shown to modulate lung cancer risk in smokers, and reduced DNA repair capacity elevated the disease risk (Rajaee-Behbahani et al. 2001). Investigations of several DNA repair gene variants revealed that lung cancer risk was only moderately affected by a single variant but was enhanced up to approximately threefold by specific risk allele combinations (Popanda et al. 2004). Therapy response: Inter-individual differences in therapy response are consistently observed with cancer chemotherapeutic agents. Initial results from ongoing studies showed that certain polymorphisms in drug transporter genes (ABCB1) differentially affect response outcome in histological subgroups of lung cancer. Stronger beneficial effects were seen in non-small cell lung cancer (NSCLC) patients following gemcitabine and in SCLC patients following etoposide-based treatment. Several DNA repair parameters (polymorphisms, RNA expression, and DNA repair capacity) were measured in vitro in lymphocytes of patients before radiotherapy and correlated with the occurrence of acute side effects (radio-hypersensitivity). Our initial analysis of several repair gene variants in breast cancer patients (n = 446) who received radiotherapy revealed no association of single polymorphisms and the development of side effects (moist desquamation of the irradiated normal skin). The risk for this side effect was, however, strongly reduced in normal weight women carrying a combination of XRCC1 399Gln and APE1 148Glu alleles, indicating that these variants afford some protection against radio-hypersensitivity (Chang-Claude et al. 2005). Based on these data we conclude that specific metabolic and DNA repair gene variants can affect cancer risk and therapy outcome. Predisposition to hereditary cancer syndromes is dominated by the strong effects of some high-penetrance tumor susceptibility genes, while predisposition to sporadic cancer is influenced by the combination of multiple low-penetrance genes, of which as a major challenge, many disease-relevant combinations remain to be identified. Before translating these findings into clinical use and application for public health measures, large population-based studies and validation of the results will be required. PMID:17302182

Bartsch, Helmut; Dally, Heike; Popanda, Odilia; Risch, Angela; Schmezer, Peter

2007-01-01

112

Genetic susceptibility: radiation effects relevant to space travel.  

PubMed

Genetic variation in the capacity to repair radiation damage is an important factor influencing both cellular and tissue radiosensitivity variation among individuals as well as dose rate effects associated with such damage. This paper consists of two parts. The first part reviews some of the available data relating to genetic components governing such variability among individuals in susceptibility to radiation damage relevant for radiation protection and discusses the possibility and extent to which these may also apply for space radiations. The second part focuses on the importance of dose rate effects and genetic-based variations that influence them. Very few dose rate effect studies have been carried out for the kinds of radiations encountered in space. The authors present here new data on the production of chromosomal aberrations in noncycling low passage human ATM+/+ or ATM+/- cells following irradiations with protons (50 MeV or 1 GeV), 1 GeV(-1) n iron ions and gamma rays, where doses were delivered at a high dose rate of 700 mGy(-1) min, or a lower dose rate of 5 mGy min(-1). Dose responses were essentially linear over the dose ranges tested and not significantly different for the two cell strains. Values of the dose rate effectiveness factor (DREF) were expressed as the ratio of the slopes of the dose-response curves for the high versus the lower (5 mGy min(-1)) dose rate exposures. The authors refer to this as the DREF5. For the gamma ray standard, DREF5 values of approximately two were observed. Similar dose rate effects were seen for both energies of protons (DREF5 ? 2.2 in both cases). For 1 GeV(-1) n iron ions [linear energy transfer (LET) ? 150 keV ?(-1)], the DREF5 was not 1 as might have been expected on the basis of LET alone but was approximately 1.3. From these results and conditions, the authors estimate that the relative biological effectiveness for 1 GeV(-1) n iron ions for high and low dose rates, respectively, were about 10 and 15 rather than around 20 for low dose rates, as has been assumed by most recommendations from radiation protection organizations for charged particles of this LET. The authors suggest that similar studies using appropriate animal models of carcinogenesis would be valuable. PMID:23032891

Peng, Yuanlin; Nagasawa, Hatsumi; Warner, Christy; Bedford, Joel S

2012-11-01

113

Consumers' Use of Web-Based Information and Their Decisions About Multiplex Genetic Susceptibility Testing  

PubMed Central

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.

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

2010-01-01

114

Transfer of the Rf-1 region from FHH onto the ACI background increases susceptibility to renal impairment.  

PubMed

The genetically hypertensive fawn-hooded (FHH/Eur) rat is characterized by the early presence of systolic and glomerular hypertension, progressive proteinuria (UPV), and albuminuria (UAV), and focal glomerulosclerosis, resulting in premature death from renal failure. Previous studies showed that at least five genetic loci (Rf-1 to Rf-5) were linked to the development of renal impairment. Of these five, Rf-1 appears to play a major role. To study the impact of Rf-1 in the absence of the other loci, we transferred the Rf-1 region of chromosome 1, between the markers D1Mit34 and D1Rat156, Rf-1B for short, onto the genomic background of the normotensive August x Copenhagen Irish (ACI) rat. In this congenic strain, named ACI.FHH-D1Mit34/Rat156 or ACI.FHH-Rf1B, we challenged the renal hemodynamic function of these animals by studying the effects of unilateral nephrectomy (UNX) alone, or combined with N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Following UNX, the congenic strain developed significantly more UPV and UAV than the ACI progenitor. The differences were even more pronounced when UNX was combined with an L-NAME-induced rise in systolic blood pressure to about 150 mmHg, i.e., the level of hypertension present in the parental FHH strain. These findings indicate that the Rf-1B region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increase in blood pressure. PMID:11875190

Provoost, Abraham P; Shiozawa, Masahide; Van Dokkum, Richard P E; Jacob, Howard J

2002-02-28

115

Susceptibility of Common and Rare Plant Species to the Genetic Consequences of Habitat Fragmentation  

Microsoft Academic Search

Small plant populations are more prone to extinction due to the loss of genetic variation through random genetic drift, increased selfing, and mating among related individuals. To date, most researchers deal- ing with genetic erosion in fragmented plant populations have focused on threatened or rare species. We raise the question whether common plant species are as susceptible to habitat fragmentation

OLIVIER HONNAY; HANS JACQUEMYN

2007-01-01

116

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

Microsoft Academic Search

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

Linda D. Cameron; Jeanne Reeve

2006-01-01

117

A quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury  

Microsoft Academic Search

INTRODUCTION: Clinical observations and animal models provide evidence that the development of acute lung injury (ALI), a phenomenon of acute diffuse lung inflammation in critically ill patients, is influenced by genetic factors. Association studies are the main tool for exploring common genetic variations underlying ALI susceptibility and\\/or outcome. We aimed to assess the quality of positive genetic association studies with

Carlos Flores; Maria del Mar Pino-Yanes; Jesús Villar

2008-01-01

118

Novel genetic mutation in the background of Carney complex.  

PubMed

Carney complex is a rare disease inherited in an autosomal dominant manner. It is mostly caused by inactivating mutations of the subunit of protein kinase A. Carney complex is associated with atrial myxoma, nevi or myxomas of the skin, breast tumor and endocrine overactivity. Primary pigmented nodular adrenocortical disease is the specific endocrine manifestation. The authors present the history of a 53-year-old female patient who had undergone surgery for atrial myxomas, thyroid tumor and breast cancer. She was also operated for an adrenal adenoma causing Cushing’s syndrome. Genetic study revealed a novel mutation in the regulatory subunit of protein kinase A (ivs2-1G>A splice mutation in intron 2). Her heterozygous twins were also genetically screened and one of them carried the same mutation. The authors emphasize that despite the absence of specific treatment for patients with Carney complex, confirmation of the diagnosis by genetic studies is important for the close follow-up of the patient and early identification of novel manifestations. PMID:22297707

Halászlaki, Csaba; Takács, István; Butz, Henriett; Patócs, Attila; Lakatos, Péter

2012-04-01

119

Identifying Predictors of Activity Based Anorexia Susceptibility in Diverse Genetic Rodent Populations  

PubMed Central

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

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

2012-01-01

120

Systems genetics of susceptibility to obesity-induced diabetes in mice  

PubMed Central

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.

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

2012-01-01

121

An updated systematic review of the role of host genetics in susceptibility to influenza.  

PubMed

The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted in June 2011 to summarise the evidence on the role of host genetics in susceptibility to influenza, and this report updates that previously published review. Animal studies suggest that genetic control of susceptibility to severe influenza in mice is complex and not controlled by a single locus, but there is encouraging evidence that some of the host genetic determinants of susceptibility to severe disease may be common across influenza subtypes. Although a number of studies on genetic susceptibility to influenza in humans have been published recently, all are underpowered and unreplicated, so do not provide robust statistical evidence of an association between the identified genetic loci and susceptibility. One study does however present convincing functional evidence for an important role for IFITM3 in susceptibility to severe influenza in mice, and some evidence that this may also be important in human A/H1N1/pdm2009 infection. PMID:24034482

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

2013-09-01

122

HLA Class I and Genetic Susceptibility to Type 1 Diabetes  

PubMed Central

OBJECTIVE We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study. RESEARCH DESIGN AND METHODS Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients. RESULTS Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes–associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10?11) and B*3906 (10.31; P = 4 × 10?10). Other significantly type 1 diabetes–associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403). CONCLUSIONS These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.

Noble, Janelle A.; Valdes, Ana Maria; Varney, Michael D.; Carlson, Joyce A.; Moonsamy, Priscilla; Fear, Anna Lisa; Lane, Julie A.; Lavant, Eva; Rappner, Rebecca; Louey, Anthony; Concannon, Patrick; Mychaleckyj, Josyf C.; Erlich, Henry A.

2010-01-01

123

Pheochromocytoma and Paraganglioma: Understanding the Complexities of the Genetic Background  

PubMed Central

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.

Fishbein, Lauren; Nathanson, Katherine L.

2012-01-01

124

Research Review: genetic vulnerability or differential susceptibility in child development: the case of attachment.  

PubMed

Gene-environment interactions interpreted in terms of differential susceptibility may play a large part in the explanation of individual differences in human development. Reviewing studies on the behavioral and molecular genetics of attachment, we present evidence for interactions between genetic and environmental factors explaining individual differences in attachment security and disorganization. In particular, the DRD4 7-repeat polymorphism seems associated with an increased risk for disorganized attachment, but only when combined with environmental risk. Gene-environment (G x E) interactions may be interpreted as genetic vulnerability or differential susceptibility. We found support for the differential susceptibility hypothesis predicting not only more negative outcomes for susceptible children in unfavorable environments, but also positive outcomes for susceptible children in favorable environments. PMID:18093021

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

2007-12-01

125

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

Microsoft Academic Search

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

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

2010-01-01

126

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

PubMed Central

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

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

2013-01-01

127

Genetic susceptibility to post-thymectomy autoimmune diseases in mice  

Microsoft Academic Search

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

Akinori Kojima; Richmond T. Prehn

1981-01-01

128

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

Microsoft Academic Search

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

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

129

Genetic susceptibility of intervertebral disc degeneration among young Finnish adults  

PubMed Central

Background Disc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD. Methods We investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging. Results Of the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of IL6 was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, SKT rs16924573 (OR 0.27 95% CI 0.07-0.96) and CILP rs2073711 in women (OR 2.04, 95% CI 1.07-3.89). Conclusion Our results indicate that IL6, SKT and CILP are involved in the etiology of DD among young adults.

2011-01-01

130

Genetic Variation in 15-Hydroxyprostaglandin Dehydrogenase and Colon Cancer Susceptibility  

PubMed Central

Background 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a metabolic antagonist of COX-2, catalyzing the degradation of inflammation mediator prostaglandin E2 (PGE2) and other prostanoids. Recent studies have established the 15-PGDH gene as a colon cancer suppressor. Methods We evaluated 15-PDGH as a colon cancer susceptibility locus in a three-stage design. We first genotyped 102 single-nucleotide polymorphisms (SNPs) in the 15-PGDH gene, spanning ?50 kb up and down-stream of the coding region, in 464 colon cancer cases and 393 population controls. We then genotyped the same SNPs, and also assayed the expression levels of 15-PGDH in colon tissues from 69 independent patients for whom colon tissue and paired germline DNA samples were available. In the final stage 3, we genotyped the 9 most promising SNPs from stages 1 and 2 in an independent sample of 525 cases and 816 controls (stage 3). Results In the first two stages, three SNPs (rs1365611, rs6844282 and rs2332897) were statistically significant (p<0.05) in combined analysis of association with risk of colon cancer and of association with 15-PGDH expression, after adjustment for multiple testing. For one additional SNP, rs2555639, the T allele showed increased cancer risk and decreased 15-PGDH expression, but just missed statistical significance (p-adjusted?=?0.063). In stage 3, rs2555639 alone showed evidence of association with an odds ratio (TT compared to CC) of 1.50 (95% CI?=?1.05–2.15, p?=?0.026). Conclusions Our data suggest that the rs2555639 T allele is associated with increased risk of colon cancer, and that carriers of this risk allele exhibit decreased expression of 15-PGDH in the colon.

Lutterbaugh, James D.; Elston, Robert C.; Veigl, Martina L.; Markowitz, Sanford D.; Li, Li

2013-01-01

131

Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better?  

PubMed

Genetic epidemiology, including twin studies, provides robust evidence that genetic variation in human populations contributes to susceptibility to infectious disease. One of the major limitations of studies that attempt to identify the genes and mechanisms that underlie this susceptibility has been lack of power caused by small sample size. With the development of novel technologies, burgeoning information on the human genome, the HapMap project, and human genetic diversity, we are at the beginning of a new era in the study of the genetics of complex diseases. This review looks afresh at the epidemiological evidence that supports a role for genetics in susceptibility to infectious disease, examines the somewhat limited achievements to date, and discusses current advances in methodology and technology that will potentially lead to translational data in the future. PMID:17008174

Burgner, David; Jamieson, Sarra E; Blackwell, Jenefer M

2006-10-01

132

Genetic testing for cancer susceptibility: the promise and the pitfalls  

Microsoft Academic Search

Genetic testing for hereditary cancer risk is now available and has the potential to reduce cancer mortality through the targeting of preventive therapies and by motivating behavioural change. However, generating and communicating genetic information can have psychological and social consequences. As testing extends from identifying rare hereditary cancers to testing for common genetic variants that are associated with cancer risk,

Alexandra E. Shields; Caryn Lerman

2004-01-01

133

Genetic Background Affects Human Glial Fibrillary Acidic Protein Promoter Activity  

PubMed Central

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

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

2013-01-01

134

Effects of genetic background on response to selection in experimental populations of Arabidopsis thaliana.  

PubMed Central

The extent to which genetic background can influence allelic fitness is poorly understood, despite having important evolutionary consequences. Using experimental populations of Arabidopsis thaliana and map-based population genetic data, we examined a multigeneration response to selection in populations with differentiated genetic backgrounds. Replicated experimental populations of A. thaliana with genetic backgrounds derived from ecotypes Landsberg and Niederzenz were subjected to strong viability and fertility selection by growing individuals from each population at high density for three generations in a growth chamber. Patterns of genome-wide selection were evaluated by examining deviations from expected frequencies of mapped molecular markers. Estimates of selection coefficients for individual genomic regions ranged from near 0 to 0.685. Genomic regions demonstrating the strongest response to selection most often were selected similarly in both genetic backgrounds. The selection response of several weakly selected regions, however, appeared to be sensitive to genetic background, but only one region showed evidence of positive selection in one background and negative selection in another. These results are most consistent with models of adaptive evolution in which allelic fitnesses are not strongly influenced by genetic background and only infrequently change in sign due to variation at other loci.

Ungerer, Mark C; Linder, C Randal; Rieseberg, Loren H

2003-01-01

135

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

Microsoft Academic Search

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

David Quigley; Allan Balmain

2009-01-01

136

Genetic and Environmental Susceptibility to Non-Alcoholic Fatty Liver Disease  

Microsoft Academic Search

While the majority of those with non-alcoholic fatty liver disease (NAFLD) will have simple hepatic steatosis, a minority will develop progressive steatohepatitis. Family studies and inter-ethnic variations in susceptibility suggest that genetic factors may be important in determining disease risk. Although no genetic associations with advanced NAFLD have been replicated in large studies, preliminary data suggest that polymorphisms in genes

Christopher Paul Day

2010-01-01

137

Genetic susceptibility to systemic lupus erythematosus in the genomic era  

Microsoft Academic Search

Our understanding of the genetic basis of systemic lupus erythematosus (SLE) has been rapidly advanced using large-scale, case–control, candidate gene studies as well as genome-wide association studies during the past 3 years. These techniques have identified more than 30 robust genetic associations with SLE including genetic variants of HLA and Fc? receptor genes, IRF5, STAT4, PTPN22, TNFAIP3, BLK, BANK1, TNFSF4

Yun Deng; Betty P. Tsao

2010-01-01

138

Experimental Ocular Toxoplasmosis in Genetically Susceptible and Resistant Mice  

Microsoft Academic Search

Genetic factors determining the pathogenesis and course of ocular toxoplasmosis are poorly understood. In this study, we explored the development of experimental ocular pathogenesis in genetically dissimilar mice infected with either the RH strain, the PLK strain, or the immunodominant surface antigen 1 (SAG1 (P30))- deficient mutant of the RH strain of Toxoplasma gondii. At 11 days postinfection, ocular infection

Fangli Lu; Shiguang Huang; Mark S. Hu; Lloyd H. Kasper

2005-01-01

139

Recent advances in the genetics of RA susceptibility  

Microsoft Academic Search

RA is a common autoimmune disease with a complex aetiology in which genetic and environmental factors contribute to disease. The genetic component of RA is largely undefined and, up until very recently, there were only two reproducible associations. The strongest of these associations is of genes within the HLA region, particularly the HLA-DRB1 gene. A second, more modest, association identified

J. Bowes; A. Barton

2008-01-01

140

The Obesity Epidemic: Metabolic Imprinting on Genetically Susceptible Neural Circuits  

Microsoft Academic Search

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

Barry E. Levin

2000-01-01

141

Genetic analysis of susceptibility to Type 1 diabetes  

Microsoft Academic Search

Allelic sequencing combined with comparative analyses of population-specific haplotypes have provided persuasive evidence that the Type 1 diabetes susceptibility determinants associated and linked to the MHC class II region are partly due to DQ allelic polymorphism. A central role for an immune response molecule in this disease is consistent with many of the features of Type 1 diabetes. Identification of

J. A. Todd

1992-01-01

142

Gender Differences in Learned Helplessness Behavior Are Influenced by Genetic Background  

Microsoft Academic Search

Learned helplessness behavior was examined in female and male C57BL\\/6J (B6), 129\\/J (129) and (B6 × 129)F1 mice, common genetic backgrounds for the generation of knockout models, as well as in mice of a mixed genetic background (outbred mice). Both genotype and gender differences were observed in learned helplessness. Outbred males showed increased shuttle escape latencies following 60, 120, or

Barbara J Caldarone; Tony P George; Venetia Zachariou; Marina R Picciotto

2000-01-01

143

Network Launched to Support Studies of Genetic Susceptibility to Cancer  

Cancer.gov

The National Cancer Institute announced today it has awarded cooperative agreements for the new Cancer Genetics Network, a major research initiative to create a national network of centers specializing in the study of inherited predisposition to cancer.

144

Genetic Background Specific Hypoxia Resistance in Rat is Correlated with Balanced Activation of a Cross-Chromosomal Genetic Network Centering on Physiological Homeostasis  

PubMed Central

Genetic background of an individual can drastically influence an organism’s response upon environmental stress and pathological stimulus. Previous studies in inbred rats showed that compared to Brown Norway (BN), Dahl salt-sensitive (SS) rat exerts strong hypoxia susceptibility. However, despite extensive narrow-down approaches via the chromosome substitution methodology, this genome-based physiological predisposition could not be traced back to distinct quantitative trait loci. Upon the completion and public data availability of PhysGen SS-BN consomic (CS) rat platform, I employed systems biology approach attempting to further our understanding of the molecular basis of genetic background effect in light of hypoxia response. I analyzed the physiological screening data of 22 CS rat strains under normoxia and 2-weeks of hypoxia, and cross-compared them to the parental strains. The analyses showed that SS-9BN and SS-18BN represent the most hypoxia-resistant CS strains with phenotype similar to BN, whereas SS-6BN and SS-YBN segregated to the direction of SS. A meta-analysis on the transcriptomic profiles of these CS rat strains under hypoxia treatment showed that although polymorphisms on the substituted BN chromosomes could be directly involved in hypoxia resistance, this seems to be embedded in a more complex trans-chromosomal genetic regulatory network. Via information theory based modeling approach, this hypoxia relevant core genetic network was reverse engineered. Network analyses showed that the protective effects of BN chromosome 9 and 18 were reflected by a balanced activation of this core network centering on physiological homeostasis. Presumably, it is the system robustness constituted on such differential network activation that acts as hypoxia response modifier. Understanding of the intrinsic link between the individual genetic background and the network robustness will set a basis in the current scientific efforts toward personalized medicine.

Mao, Lei

2012-01-01

145

Genetic Polymorphisms and Drug Susceptibility in Four Isolates of Leishmania tropica Obtained from Canadian Soldiers Returning from Afghanistan  

PubMed Central

Background Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease characterized by the presence of one or more lesions on the skin that usually heal spontaneously after a few months. Most cases of CL worldwide occur in Southwest Asia, Africa and South America, and a number of cases have been reported among troops deployed to Afghanistan. No vaccines are available against this disease, and its treatment relies on chemotherapy. The aim of this study was to characterize parasites isolated from Canadian soldiers at the molecular level and to determine their susceptibility profile against a panel of antileishmanials to identify appropriate therapies. Methodology/Principal Findings Parasites were isolated from skin lesions and characterized as Leishmania tropica based on their pulsed field gel electrophoresis profiles and pteridine reductase 1 (PTR1) sequences. Unusually high allelic polymorphisms were observed at several genetic loci for the L. tropica isolates that were characterized. The drug susceptibility profile of intracellular amastigote parasites was determined using an established macrophage assay. All isolates were sensitive to miltefosine, amphotericin B, sodium stibogluconate (Pentostam) and paromomycin, but were not susceptible to fluconazole. Variable levels of susceptibility were observed for the antimalarial agent atovaquone/proguanil (Malarone). Three Canadian soldiers from this study were successfully treated with miltefosine. Conclusions/Significance This study shows high heterogeneity between the two L. tropica allelic versions of a gene but despite this, L. tropica isolated from Afghanistan are susceptible to several of the antileishmanial drugs available.

Plourde, Marie; Coelho, Adriano; Keynan, Yoav; Larios, Oscar E.; Ndao, Momar; Ruest, Annie; Roy, Gaetan; Rubinstein, Ethan; Ouellette, Marc

2012-01-01

146

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

Microsoft Academic Search

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

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

1994-01-01

147

No Influence of Indy on Lifespan in Drosophila after Correction for Genetic and Cytoplasmic Background Effects  

PubMed Central

To investigate whether alterations in mitochondrial metabolism affect longevity in Drosophila melanogaster, we studied lifespan in various single gene mutants, using inbred and outbred genetic backgrounds. As positive controls we included the two most intensively studied mutants of Indy, which encodes a Drosophila Krebs cycle intermediate transporter. It has been reported that flies heterozygous for these Indy mutations, which lie outside the coding region, show almost a doubling of lifespan. We report that only one of the two mutants lowers mRNA levels, implying that the lifespan extension observed is not attributable to the Indy mutations themselves. Moreover, neither Indy mutation extended lifespan in female flies in any genetic background tested. In the original genetic background, only the Indy mutation associated with altered RNA expression extended lifespan in male flies. However, this effect was abolished by backcrossing into standard outbred genetic backgrounds, and was associated with an unidentified locus on the X chromosome. The original Indy line with long-lived males is infected by the cytoplasmic symbiont Wolbachia, and the longevity of Indy males disappeared after tetracycline clearance of this endosymbiont. These findings underscore the critical importance of standardisation of genetic background and of cytoplasm in genetic studies of lifespan, and show that the lifespan extension previously claimed for Indy mutants was entirely attributable to confounding variation from these two sources. In addition, we saw no effects on lifespan of expression knockdown of the Indy orthologues nac-2 and nac-3 in the nematode Caenorhabditis elegans.

Toivonen, Janne M; Walker, Glenda A; Martinez-Diaz, Pedro; Bjedov, Ivana; Driege, Yasmine; Jacobs, Howard T; Gems, David; Partridge, Linda

2007-01-01

148

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

PubMed Central

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.

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

2011-01-01

149

Genetic risk prediction: individualized variability in susceptibility to toxicants.  

PubMed

Genetic risk prediction uses genetic data to individualize prediction of outcome or effect from a known harmful toxicant. Several examples of toxicogenetics (usually binary traits) are discussed, reflecting largely Mendelian traits before the Human Genome Project began in 1990. Numerous complexities of the genome and what constitutes "a gene" have emerged during these past two decades. Examples of toxicogenomics (continuous outcomes, gradients) are examined. Most xenobiotic-induced environmental diseases resemble human complex diseases or other multifactorial traits such as height; these traits result from hundreds of low-effect genes. Consequently, uncovering an association between a trait and a genetic variant in a large cohort can provide important information about underlying biology; however, screening for a specific variant in an individual worker or patient has poor predictive value and little clinical utility. Individualized risk assessment for toxicants that cause environmental diseases, although a lofty goal, remains to be achieved. PMID:23294311

Nebert, Daniel W; Zhang, Ge; Vesell, Elliot S

2013-01-01

150

Food makes you a target: disentangling genetic, physiological, and behavioral effects determining susceptibility to infection.  

PubMed

Genetics, physiology, and behavior are all expected to influence the susceptibility of hosts to parasites. Furthermore, interactions between genetic and other factors are suggested to contribute to the maintenance of genetic polymorphism in resistance when the relative susceptibility of host genotypes is context dependent. We used a maternal sibship design and long- and short-term food deprivation treatments to test the role of family-level genetic variation, body condition, physiological state, and foraging behavior on the susceptibility of Lymnaea stagnalis snails to infection by a trematode parasite that uses chemical cues to locate its hosts. In experimental exposures, we found that snails in the long-term food deprivation treatment contracted fewer parasites than snails that were continuously well-fed, possibly because well-fed snails grew larger and attracted more transmission stages. When we kept the long-term feeding rates the same, but manipulated the physiological state and foraging behavior of the snails with short-term food deprivation treatment, we found that snails that were fed before the exposure contracted more parasites than snails that were fed during the exposure. This suggests that direct physiological effects of food processing, but not foraging behavior, predisposed snails to infection. Feeding treatments also affected the family-level variation in snail susceptibility, suggesting that the relative susceptibility of host genotypes was context dependent. PMID:21121912

Seppälä, Otto; Karvonen, Anssi; Haataja, Maarit; Kuosa, Marja; Jokela, Jukka

2010-12-24

151

Hunt for genetic susceptibility in a complex disease  

Microsoft Academic Search

One of the most frequent spine abnormality in early adulthud is adolescent idiopathic scoliosis. It has great significance, since it represents 80% of all types of scoliosis. It is ten times more frequent in girls, than in boys. The mode of inheritance is contraversial, there were data for autosomal dominant, X-linked dominant, or non-mendelian inheritance. So far no candidate genetic

Ágnes Czibula; Mónika Mórocz; Csanád Z. Bachrati; Ágnes Csiszár; László Szappanos; Erika B. Szabó; Ferenc Szeszák; Éva Morava; Tamás Illés; István Raskó

2003-01-01

152

The obesity epidemic: metabolic imprinting on genetically susceptible neural circuits.  

PubMed

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 density and quantity are raised. Once obesity is fully developed, these abnormalities largely disappear. This suggests that obesity might be the normal state for such individuals. Formation of new neural circuits involved in energy homeostasis might underlie the near permanence of the obese body weight. Such neural plasticity can occur during both nervous system development and in adult life. Maternal diabetes, obesity, and undernutrition have all been associated with obesity in the offspring of such mothers, especially in genetically predisposed individuals. Altered brain neural circuitry and function often accompanies such obesity. This enhanced obesity may then be passed on to subsequent generations in a feed-forward, upward spiral of increasing body weight across generations. Such findings suggest a form of "metabolic imprinting" upon genetically predisposed neural circuits involved in energy homeostasis. Centrally acting drugs used for obesity treatment lower the defended body weight and alter the function of neural pathways involved in energy homeostasis. But they generally have no permanent effect on body weight or neural function. Thus, early identification of obesity-prone mothers, infants, and adults and treatment of early obesity may be the only way to prevent the formation of permanent neural connections that promote and perpetuate obesity in genetically predisposed individuals. PMID:10933311

Levin, B E

2000-07-01

153

Genetics of Allergic Disease: Evidence for Organ-Specific Susceptibility Genes  

Microsoft Academic Search

Background: While previous studies have probed the genetics of asthma and serum IgE levels, there have been no studies on the genetics of allergic conjunctivitis. This paper describes the initial phase of a genetic study of allergic conjunctivitis. Methods: Approximately 117 families with probands with allergic conjunctivitis were recruited generating 245 affected sib pairs. Each family member completed a detailed

Akio Nishimura; Robert Scott Campbell-Meltzer; Kathy Chute; Jeff Orrell; Santa Jeremy Ono

2001-01-01

154

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

PubMed

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

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

2013-01-14

155

A framework for detecting and characterizing genetic background-dependent imprinting effects  

PubMed Central

Genomic imprinting, where the effects of alleles depend on their parent-of-origin, can be an important component of the genetic architecture of complex traits. Although there has been a rapidly increasing number of studies of genetic architecture that have examined imprinting effects, none have examined whether imprinting effects depend on genetic background. Such effects are critical for the evolution of genomic imprinting because they allow the imprinting state of a locus to evolve as a function of genetic background. Here we develop a two-locus model of epistasis that includes epistatic interactions involving imprinting effects and apply this model to scan the mouse genome for loci that modulate the imprinting effects of quantitative trait loci (QTL). The inclusion of imprinting leads to nine orthogonal forms of epistasis, five of which do not appear in the usual two-locus decomposition of epistasis. Each form represents a change in the imprinting status of one locus across different classes of genotypes at the other locus. Our genome scan identified two different locus pairs that show complex patterns of epistasis, where the imprinting effect at one locus changes across genetic backgrounds at the other locus. Thus, our model provides a framework for the detection of genetic background-dependent imprinting effects that should provide insights into the background dependence and evolution of genomic imprinting. Our application of the model to a genome scan supports this assertion by identifying pairs of loci that show reciprocal changes in their imprinting status as the background provided by the other locus changes.

Cheverud, James M.

2010-01-01

156

Differential effects of genetic susceptibility factors in males and females with multiple sclerosis.  

PubMed

Multiple sclerosis (MS), a putative autoimmune disease, has a well documented female preponderance among patients. However, this is not the only sex effect observed in the disease. Unaffected mothers appear to be at a higher risk to transmit susceptibility (genetic, environmental or interactions thereof) compared to unaffected fathers. This maternal effect can range from intrauterine exposures to transmission of genotypes and epigenetics. PMID:23796437

Sadovnick, A Dessa

2013-05-11

157

The genetics of infectious disease susceptibility: has the evidence for epistasis been overestimated?  

PubMed

Interactions amongst genes, known as epistasis, are assumed to make a substantial contribution to the genetic variation in infectious disease susceptibility, but this claim is controversial. Here, we focus on the debate surrounding the evolutionary importance of interactions between resistance loci and argue that its role in explaining overall variance in disease outcomes may have been overestimated. PMID:23855805

Hall, Matthew D; Ebert, Dieter

2013-07-15

158

The genetics of infectious disease susceptibility: has the evidence for epistasis been overestimated?  

PubMed Central

Interactions amongst genes, known as epistasis, are assumed to make a substantial contribution to the genetic variation in infectious disease susceptibility, but this claim is controversial. Here, we focus on the debate surrounding the evolutionary importance of interactions between resistance loci and argue that its role in explaining overall variance in disease outcomes may have been overestimated.

2013-01-01

159

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

Microsoft Academic Search

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

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

2011-01-01

160

Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus  

Microsoft Academic Search

Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus. Nephropathia epidemica (NE) caused by Puumala hantavirus is one type of hemorrhagic fever with renal syndrome (HFRS). There is considerable variability in the clinical severity of NE. Many infections are subclinical but the disease can even be fatal. We questioned whether the wide spectrum in the outcome of

Jukka Mustonen; Jukka Partanen; Mari Kanerva; Kari Pietilä; Olli Vapalahti; Amos Pasternack; Antti Vaheri

1996-01-01

161

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

Microsoft Academic Search

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

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

2005-01-01

162

Mechanisms of Disease: genetic susceptibility and environmental triggers in the development of rheumatoid arthritis  

Microsoft Academic Search

Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that influence susceptibility. This interaction triggers immunologic events that eventually result in the clinical signs of arthritis. Knowledge of the chain of etiological events that lead to the development of RA is incomplete. In this review, we describe the experimental approaches that

Leonid Padyukov; Johnny Lorentzen; Lars Alfredsson; Lars Klareskog

2006-01-01

163

IL6 and IL10 are genetic susceptibility factors of periodontal disease  

PubMed Central

Background: Periodontitis is a disease mainly caused by a chronic infection of tissues that support the teeth. Several factors, such as diabetes, smoking and oral care, as well as genetic susceptibility can influence both the risk to develop periodontitis and its progression. The aim of the investigation was to test whether alleles of candidate genes were associated with periodontitis. Materials and Methods: A case control study was performed with a cohort of 184 patients with chronic periodontitis and 231 healthy controls from the Italian population. A total of six single nucleotide polymorphisms from five candidate genes, i.e., IL1A, IL1B, IL6, IL10 and vitamin D receptor, were investigated. Results: Evidence of association were obtained for rs1800795 mapping in IL6 (P value = 0.01) as well as for the rs1800872 mapping in IL10 (P = 0.04). The rarer variant allele lowered the risk to develop periodontitis at IL6 (Odds Ratio [OR] = 0.69 [95% confidence interval {CI} 0.51-0.93]) and increased the risk at IL10 (OR = 1.38 [95% CI 1.01-1.86]). Conclusions: The present investigation indicated that polymorphisms of IL6 and IL10 constitute risk factors for chronic periodontitis, while there was no evidence implicating a specific IL1A or IL1B genotype.

Scapoli, Luca; Girardi, Ambra; Palmieri, Annalisa; Carinci, Francesco; Testori, Tiziano; Zuffetti, Francesco; Monguzzi, Riccardo; Lauritano, Dorina

2012-01-01

164

DCDC2 Genetic Variants and Susceptibility to Developmental Dyslexia  

PubMed Central

Objective(s) Developmental Dyslexia is a heritable condition, with genetic factors accounting for 44%–75% of the variance in performance tests of reading component subphenotypes. Compelling genetic linkage and association evidence supports a quantitative trait locus in the 6p21.3 region, which encodes a gene called DCDC2. In the present study, we explored the contribution of two DCDC2 markers to dyslexia, related reading and memory phenotypes in nuclear families of Italian origin. Methods 303 nuclear families recruited on the basis of having a proband with Developmental Dyslexia have been studied with 6p21.3 markers, BV677278 and rs793862. Marker-trait association was investigated by the quantitative transmission disequilibrium test (QTDT, version 2.5.1) as modelled by Abecasis et al. (2000), which allows for the analyses of quantitative traits. Seven phenotypes were used in association analyses, i.e. word and non-word reading, word and non-word spelling, orthographic choice, memory and the affected status based on inclusion criteria. Results QTDT analyses yielded evidence for association between reading skills and the BV677278 deletion (empirical p-values= .025–.029) and between memory and BV677278 allele 10 (empirical p-value= .0001). Conclusions Our result adds further evidence in support of DCDC2 contributing to the deficits in Developmental Dyslexia. More specifically, our data support the view that DCDC2 influences both reading and memory impairments thus shedding further light into the etiologic basis and the phenotypic complexity of Developmental Dyslexia.

Marino, Cecilia; Meng, Haiying; Mascheretti, Sara; Rusconi, Marianna; Cope, Natalie; Giorda, Roberto; Molteni, Massimo; Gruen, Jeffrey R

2011-01-01

165

Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block.  

PubMed

Genetic and population studies suggest that onset, progression and ultimate outcome of infection with Mycobacteria, including the agent of tuberculosis Mycobacterium tuberculosis, are strongly influenced by genetic factors. Family-based and case-control linkage and association studies have suggested a complex genetic component for susceptibility to tuberculosis. On the other hand, patients with inborn errors in the IL12/IFN? circuit may develop disseminated mycobacterial infections following perinatal BCG vaccination. The study of such MSMD (Mendelian Susceptibility to Mycobacterial Diseases) patients has provided much insight into innate and acquired immune defenses against mycobacteria. Parallel genetic analyses in mouse models of mycobacterial infections have also indicated complex genetic control, and have provided candidate genes for parallel testing in humans. Recently, mutations in human IRF8 were discovered and shown to cause two distinct forms of a novel primary immunodeficiency and associated susceptibility to mycobacteria. Autosomal recessive IRF8 deficiency is caused by mutation K108E and associated with severe disease with complete depletion of monocytes and dendritic cells. Mutation T80A causes autosomal dominant IRF8 deficiency and a milder form of the disease with selective loss of a subset of dendritic cells. These findings have established that IRF8 is required for ontogeny of the myeloid lineage and for host response to mycobacteria. The ongoing study of the IRF8 transcriptome has shown promise for the identification of IRF8 dependent pathways that play a critical role in host defense against mycobacteria in particular, and against intracellular pathogens in general. PMID:23468103

Salem, S; Gros, P

2013-01-01

166

Familial Abdominal Aortic Aneurysm: a Systematic Review of a Genetic Background  

Microsoft Academic Search

Background: familial clustering of the abdominal aortic aneurysm (AAA) is clear, 12–19% of AAA patients have one or more first-degree relatives with an aneurysm and 4–19% is detected with ultrasound screening.Objectives: to review the genetic background of AAA.Design, methods and materials: computer searches of the MEDLINE, EMBASE, SUMsearch database and the Cochrane Library and searched reference lists of English language

C. J. van Vlijmen-van Keulen; G. Pals; J. A. Rauwerda

2002-01-01

167

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

PubMed Central

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

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

2009-01-01

168

The Requirement of WHIRLY1 for Embryogenesis Is Dependent on Genetic Background in Maize  

PubMed Central

Plastid gene expression is essential to embryogenesis in higher plants, but the underlying mechanism is obscure. Through molecular characterization of an embryo defective 16 (emb16) locus, here we report that the requirement of plastid translation for embryogenesis is dependent on the genetic background in maize (Zea mays). The emb16 mutation arrests embryogenesis at transition stage and allows the endosperm to develop largely normally. Molecular cloning reveals that Emb16 encodes WHIRLY1 (WHY1), a DNA/RNA binding protein that is required for genome stability and ribosome formation in plastids. Interestingly, the previous why1 mutant alleles (why1-1 and why1-2) do not affect embryogenesis, only conditions albino seedlings. The emb16 allele of why1 mutation is in the W22 genetic background. Crosses between emb16 and why1-1 heterozygotes resulted in both defective embryos and albino seedlings in the F1 progeny. Introgression of the emb16 allele from W22 into A188, B73, Mo17, Oh51a and the why1-1 genetic backgrounds yielded both defective embryos and albino seedlings. Similar results were obtained with two other emb mutants (emb12 and emb14) that are impaired in plastid protein translation process. These results indicate that the requirement of plastid translation for embryogenesis is dependent on genetic backgrounds, implying a mechanism of embryo lethality suppression in maize.

Zhang, Ya-Feng; Hou, Ming-Ming; Tan, Bao-Cai

2013-01-01

169

The requirement of WHIRLY1 for embryogenesis is dependent on genetic background in maize.  

PubMed

Plastid gene expression is essential to embryogenesis in higher plants, but the underlying mechanism is obscure. Through molecular characterization of an embryo defective 16 (emb16) locus, here we report that the requirement of plastid translation for embryogenesis is dependent on the genetic background in maize (Zea mays). The emb16 mutation arrests embryogenesis at transition stage and allows the endosperm to develop largely normally. Molecular cloning reveals that Emb16 encodes WHIRLY1 (WHY1), a DNA/RNA binding protein that is required for genome stability and ribosome formation in plastids. Interestingly, the previous why1 mutant alleles (why1-1 and why1-2) do not affect embryogenesis, only conditions albino seedlings. The emb16 allele of why1 mutation is in the W22 genetic background. Crosses between emb16 and why1-1 heterozygotes resulted in both defective embryos and albino seedlings in the F1 progeny. Introgression of the emb16 allele from W22 into A188, B73, Mo17, Oh51a and the why1-1 genetic backgrounds yielded both defective embryos and albino seedlings. Similar results were obtained with two other emb mutants (emb12 and emb14) that are impaired in plastid protein translation process. These results indicate that the requirement of plastid translation for embryogenesis is dependent on genetic backgrounds, implying a mechanism of embryo lethality suppression in maize. PMID:23840682

Zhang, Ya-Feng; Hou, Ming-Ming; Tan, Bao-Cai

2013-06-28

170

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...

171

Stress reactions at slaughter and meat quality in pigs: genetic background and prior experience  

Microsoft Academic Search

Stress reactions to the slaughter procedure influence ante- and post-mortem muscle metabolism and, consequently, the rate and extent of glycogen breakdown and pH decline, colour and drip loss. Effects are principally due to variations in ATPase activity and muscle glycogen reserves. Behavioural, physiological and metabolic responses to aversive situations depend on genetic background and prior experience of the animals. For

Claudia Terlouw

2005-01-01

172

Genetic analysis of the influence of pertussis toxin on experimental allergic encephalomyelitis susceptibility: an environmental agent can override genetic checkpoints.  

PubMed

Pertussis toxin (PTX) is a potent ancillary adjuvant used to elicit several different autoimmune diseases, including experimental allergic encephalomyelitis (EAE). To delineate the genetics of PTX effect in EAE, we mapped EAE-modifying (eae-m) loci in cohorts of backcross mice immunized with and without PTX. In this study, we analyzed the genetic basis of EAE susceptibility and severity and the intermediate phenotypes of mononuclear cell infiltration, suppuration, and demyelination. In animals immunized with PTX, one major locus, eae9, controls disease susceptibility and severity. Eae9 also regulates the extent of mononuclear cell infiltration of the spinal cord in male mice. Without PTX, five eae-m loci were noted, including three new loci in intervals on chromosomes 8 (eae14), 10 (eae17), and 18 (eae18). Taken together, these results suggest that eae9 controls the effects of PTX in EAE susceptibility, and is capable of overriding the other genetic checkpoints in the pathogenesis of this disease. PMID:10706738

Blankenhorn, E P; Butterfield, R J; Rigby, R; Cort, L; Giambrone, D; McDermott, P; McEntee, K; Solowski, N; Meeker, N D; Zachary, J F; Doerge, R W; Teuscher, C

2000-03-15

173

Fetal Radiation Exposure Induces Testicular Cancer in Genetically Susceptible Mice  

PubMed Central

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5–6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis.

Shetty, Gunapala; Comish, Paul B.; Weng, Connie C. Y.; Matin, Angabin; Meistrich, Marvin L.

2012-01-01

174

Identification of susceptibility genes and genetic modifiers of human diseases  

NASA Astrophysics Data System (ADS)

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.

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

2005-03-01

175

Fetal radiation exposure induces testicular cancer in genetically susceptible mice.  

PubMed

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis. PMID:22348147

Shetty, Gunapala; Comish, Paul B; Weng, Connie C Y; Matin, Angabin; Meistrich, Marvin L

2012-02-13

176

XCIND as a genetic disease of X-irradiation hypersensitivity and cancer susceptibility.  

PubMed

The XCIND syndrome is named after distinct hypersensitivity to ionizing (X-ray) irradiation, cancer susceptibility, immunodeficiency, neurological abnormality, and double-strand DNA breakage. The disorders comprising XCIND syndrome are usually inherited in an autosomal recessive manner. Ataxia telangiectasia (A-T) is one such disease, and is caused by biallelic germline mutation of the Ataxia telangiectasia mutated (ATM) gene. Heterozygous carriers of the ATM mutation, who do not show A-T-like clinical symptoms, are estimated to comprise 1 % of the population. Thus, understanding the biological basis of XCIND, including A-T, should help shed light on the pathogenesis of genetic diseases with cancer susceptibility. PMID:23266960

Mizutani, Shuki; Takagi, Masatoshi

2012-12-25

177

Evolution, revolution and heresy in the genetics of infectious disease susceptibility  

PubMed Central

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.

Hill, Adrian V. S.

2012-01-01

178

The impact of the genetic background on the genome make-up of tumor cells.  

PubMed

Endometrial adenocarcinoma (EAC) is the most common form of malignancy in the female genital tract, ranking as the fourth leading form of invasive tumors that affect women. The BDII inbred rat strain has been used as a powerful tumor model in studies of the genetic background of EAC. Females from the BDII strain are prone to develop tumors with an incidence of more than 90%. Development of EAC in BDII female rats has similarities in pathogenesis, histopathological, and molecular properties to that of human, and thus represents a unique model for analysis of EAC tumorigenesis and for comparative studies in human EACs. In a previous study, a set of rat EAC cell lines derived from tumors developed in female crossprogenies between BDII and nonsusceptible rat strains were analyzed by spectral karyotyping (SKY). Here we present an analysis with specific focus on the impact of different genetic backgrounds on the rate and occurrence of genetic aberrations in experimental tumors using data presented in the previous report. We could reveal that the ploidy state, and the abundance and type of structural as well as numerical change differed between the two genetic setups. We have also identified chromosomes harboring aberrations independent of genetic input from the nonsusceptible strains, which provide valuable information for the identification of the genes involved in the development of EAC in the BDII model as well as in human endometrial tumors. PMID:22250046

Falck, Eva; Behboudi, Afrouz; Klinga-Levan, Karin

2012-01-17

179

Expression variation of the porcine ADRB2 has a complex genetic background.  

PubMed

Porcine adrenergic receptor beta 2 (ADRB2) gene exhibits differential allelic expression in skeletal muscle, and its genetic variation has been associated with muscle pH. Exploring the molecular-genetic background of expression variation for porcine ADRB2 will provide insight into the mechanisms driving its regulatory divergence and may also contribute to unraveling the genetic basis of muscle-related traits in pigs. In the present study, we therefore examined haplotype effects on the expression of porcine ADRB2 in four tissues: longissimus dorsi muscle, liver, subcutaneous fat, and spleen. The diversity and structure of haplotypes of the proximal gene region segregating in German commercial breeds were characterized. Seven haplotypes falling into three clades were identified. Two clades including five haplotypes most likely originated from introgression of Asian genetics during formation of modern breeds. Expression analyses revealed that the Asian-derived haplotypes increase expression of the porcine ADRB2 compared to the major, wild-type haplotype independently of tissue type. In addition, several tissue-specific differences in the expression of the Asian-derived haplotypes were found. Inspection of haplotype sequences showed that differentially expressed haplotypes exhibit polymorphisms in a polyguanine tract located in the core promoter region. These findings demonstrate that expression variation of the porcine ADRB2 has a complex genetic basis and suggest that the promoter polyguanine tract is causally involved. This study highlights the challenges of finding causal genetic variants underlying complex traits. PMID:23996144

Murani, Eduard; Ponsuksili, Siriluck; Reyer, Henry; Wittenburg, Dörte; Wimmers, Klaus

2013-08-31

180

Are Adolescents with ADHD Interested in Genetic Testing for Nicotine Addiction Susceptibility?  

PubMed Central

It has been well-established that some adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for cigarette smoking. Current research on the genetic basis of this association could ultimately translate into genetic tests capable of identifying smoking-prone adolescents with ADHD. In this study we examined 81 ADHD affected adolescents’ (age 13–21) interest in genetic testing for nicotine addiction susceptibility. Fifty-seven percent of adolescents indicated a fair amount of interest or more in testing. Most adolescents indicated that the personal information revealed from testing would be either useful (29%) or interesting (37%). Implications for genetically-informed smoking prevention and cessation interventions in high risk adolescents with ADHD are discussed.

Herbert, Linda J.; Walker, Leslie R.; Sharff, McKane E.; Abraham, Anisha A.; Tercyak, Kenneth P.

2010-01-01

181

Are adolescents with ADHD interested in genetic testing for nicotine addiction susceptibility?  

PubMed

It has been well-established that some adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for cigarette smoking. Current research on the genetic basis of this association could ultimately translate into genetic tests capable of identifying smoking-prone adolescents with ADHD. In this study we examined 81 ADHD affected adolescents' (age 13-21) interest in genetic testing for nicotine addiction susceptibility. Fifty-seven percent of adolescents indicated a fair amount of interest or more in testing. Most adolescents indicated that the personal information revealed from testing would be either useful (29%) or interesting (37%). Implications for genetically-informed smoking prevention and cessation interventions in high risk adolescents with ADHD are discussed. PMID:20617054

Herbert, Linda J; Walker, Leslie R; Sharff, McKane E; Abraham, Anisha A; Tercyak, Kenneth P

2010-04-14

182

The Jewish people: their ethnic history, genetic disorders and specific cancer susceptibility.  

PubMed

The Jews are an ancient and unique group of people linked by language, religion and customs in spite of their major geographical shifts, expulsions, forced conversions and massacres throughout their entire history. As a result of these historical events that led to repeated migration, the Jewish people became dispersed into various ethnic sub-groups. Between these ethnic groups exists heterogeneity, as well as some similarities, to the populations amongst whom they lived. Rare genetic diseases have been reported to be prevalent among the different groups of Jews, which for the most part can be explained by random genetic drift together with intra-familial marriages. In this publication, we will briefly discuss the origin of the various ethnic groups and some of the genetic diseases commonly found in them, with emphasis on the Ashkenazim, their prevalent genetic diseases and cancer susceptibility. PMID:15516841

Kedar-Barnes, Inbal; Rozen, Paul

2004-01-01

183

Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep.  

PubMed

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

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

2013-02-11

184

Genetic susceptibility to the delayed sequelae of neonatal respiratory syncytial virus infection is MHC dependent.  

PubMed

Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H-2(k), C3H/HeN) and sensitive (H-2(b), BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC-dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection. PMID:20921522

Tregoning, John S; Yamaguchi, Yuko; Wang, Belinda; Mihm, Dagmar; Harker, James A; Bushell, Ellen S C; Zheng, Ming; Liao, Guochun; Peltz, Gary; Openshaw, Peter J M

2010-10-04

185

[Genetic susceptibility to infectious diseases: immunogenetical approaches to mycobacterial infections and subacute sclerosing panencephalitis].  

PubMed

Genetic susceptibility to infectious diseases can be explained by nucleotide alteration (mutation, polymorphism, etc.) of genes encoding molecules involved in the entry of or the immune response to microorganisms. We have conducted studies on host genetic factors for the development of mycobacterial infections and subacute sclerosing panencephalitis (SSPE) in the past decade. First, we identified autosomal dominant IFN-gamma receptor deficiency as a predominant genetic basis of patients with bacille Calmette-Guérin osteomyelitis in Japan. Second, by gene-based association analysis of 21 candidate genes, it was suggested that genetic variants of IL-12 receptor beta1 gene (IL12RB1) confer genetic susceptibility to tuberculosis, and are associated with the progression of the disease in Japanese. Third, we demonstrated that variants of several genes encoding molecules associated with innate immunity (MxA and TLR3 genes) and acquired immunity (IL4 and programmed cell death 1 [PD1] genes) were associated with the development of SSPE. Immunogenetical approaches to infectious diseases would help us to evaluate the risk for disease development and progression, individualize prevention and treatment strategies, and create new therapies. PMID:20549906

Kusuhara, Koichi

2010-06-01

186

Gene expression profiling of Naïve sheep genetically resistant and susceptible to gastrointestinal nematodes  

Microsoft Academic Search

BACKGROUND: Gastrointestinal nematodes constitute a major cause of morbidity and mortality in grazing ruminants. Individual animals or breeds, however, are known to differ in their resistance to infection. Gene expression profiling allows us to examine large numbers of transcripts simultaneously in order to identify those transcripts that contribute to an animal's susceptibility or resistance. RESULTS: With the goal of identifying

Orla M Keane; Amonida Zadissa; Theresa Wilson; Dianne L Hyndman; Gordon J Greer; David B Baird; Alan F McCulloch; Allan M Crawford; John C McEwan

2006-01-01

187

Association between N142D genetic polymorphism of GSTO2 and susceptibility to colorectal cancer  

Microsoft Academic Search

Expression pattern analysis has been revealed that glutathione S-transferase omega 2 (GSTO2, a member of class omega) is ubiquitously expressed. Over expression of GSTO2 induced apoptosis.\\u000a The gene encoding GSTO2 was localized to human chromosome 10q24.3, a region that may harbor gene(s) involved in the developing of colorectal cancer.\\u000a To investigate the association between GSTO2 N142D genetic polymorphism and susceptibility

Mohammad Masoudi; Iraj Saadat; Shahpour Omidvari; Mostafa Saadat

188

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...

189

American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.  

PubMed

As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster expanded access to, and continued advances in, medical care provided to patients and families affected by hereditary cancer syndromes. The 1996 ASCO Statement on Genetic Testing for Cancer Susceptibility set forth specific recommendations relating to clinical practice, research needs, educational opportunities, requirement for informed consent, indications for genetic testing, regulation of laboratories, and protection from discrimination, as well as access to and reimbursement for cancer genetics services. In updating this Statement, ASCO endorses the following principles: Indications for Genetic Testing: ASCO recommends that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer. ASCO recommends that genetic testing only be done in the setting of pre- and post-test counseling, which should include discussion of possible risks and benefits of cancer early detection and prevention modalities. Special Issues in Testing Children for Cancer Susceptibility: ASCO recommends that the decision to offer testing to potentially affected children should take into account the availability of evidence-based risk-reduction strategies and the probability of developing a malignancy during childhood. Where risk-reduction strategies are available or cancer predominantly develops in childhood, ASCO believes that the scope of parental authority encompasses the right to decide for or against testing. In the absence of increased risk of a childhood malignancy, ASCO recommends delaying genetic testing until an individual is of sufficient age to make an informed decision regarding such tests. As in other areas of pediatric care, the clinical cancer genetics professional should be an advocate for the best interests of the child. Counseling About Medical Management After Testing: ASCO recommends that oncologists include in pre- and post-test counseling the discussion of possible risks and benefits of cancer early-detection and prevention modalities, some of which have presumed but unproven efficacy for individuals at increased hereditary risk of cancer. Regulation of Genetic Testing: ASCO recommends strengthening regulatory oversight of laboratories that provide clinical cancer predisposition tests. These quality assurance mechanisms should include oversight of the reagents used in genetic testing, interlaboratory comparisons of reference samples, standardization of laboratory genetic test reports, and proficiency testing. Protection From Insurance and Employment Discrimination: ASCO supports establishing a federal law to prohibit discrimination by health insurance providers and employers on the basis of an individual's inherited susceptibility to cancer. Protections against genetic discrimination should apply to those with group coverage, those with individual health insurance policies, and the uninsured. Coverage of Services: ASCO supports efforts to ensure that all individuals at significantly increased risk of hereditary cancer have access to appropriate genetic counseling, testing, screening, surveillance, and all related medical and surgical interventions, which should be covered without penalty by public and private third-party payers. Confidentiality and Communication of Familial Risk: ASCO recommends that providers make concerted efforts to protect the confidentiality of genetic information. However, they should remind patients of the importance of communicating test

2003-04-11

190

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

PubMed

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

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

2011-12-06

191

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

PubMed Central

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

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

2010-01-01

192

Genetic Susceptibility to Type 2 Diabetes and Breast Cancer Risk in Women of European and African Ancestry  

PubMed Central

Background Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight. Methods We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2651 breast cancer cases and 2520 controls of African or European ancestry that were pooled from seven studies. Results We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk. Conclusion The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist. Impact The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk.

Hou, Ningqi; Zheng, Yonglan; Gamazon, Eric R.; Ogundiran, Temidayo O.; Adebamowo, Clement; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Simon, Michael S.; John, Esther M.; Hennis, Anselm; Nemesure, Barbara; Wu, Suh-Yuh; Leske, M. Cristina; Ambs, Stefan; Niu, Qun; Zhang, Jing; Pierce, Brandon; Cox, Nancy J.; Olopade, Olufunmilayo I.; Huo, Dezheng

2012-01-01

193

Genetic Polymorphisms of a Novel Vascular Susceptibility Gene, Ninjurin2 (NINJ2), Are Associated with a Decreased Risk of Alzheimer's Disease  

Microsoft Academic Search

BackgroundAccumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously.MethodsA total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD)

Kun-Pei Lin; Shih-Yuan Chen; Liang-Chuan Lai; Yi-Ling Huang; Jen-Hau Chen; Ta-Fu Chen; Yu Sun; Li-Li Wen; Ping-Keung Yip; Yi-Min Chu; Wei J. Chen; Yen-Ching Chen

2011-01-01

194

[Interaction between environment and genetic background in type 2 diabetes: lessons from animal models].  

PubMed

The respective roles of predisposing genetic factors and environmental factors in the development of type 2 diabetes (T2D) in obese subjects is poorly documented. Rodent models have been set up in an attempt to better understand of the differential effect of a prolonged metabolic stress induced by a high fat diet on glycaemic control according to the genetic background. In utero growth retardation resulting from a hypocaloric diet in pregnant rats induces a dramatic alteration of the development of islet cells leading to diabetes and insulin secretory defects in adult age. Experimentally induced diabetes in rodents results in hyperglycaemia and hyperinsulinemia in the fetus related to accelerated endocrine pancreas maturation responsible for the onset of diabetes in the adult. Deranged metabolic environment during fetal life may therefore further contribute to the onset of diabetes in the adult. Normal mouse strains with different genetic backgrounds show a wide range of responses to a high fat diet, with strains resistant to the diet and other more or less sensitive to the diet, the most sensitive exhibiting obesity diabetes and, insulin deficiency. The inability of the ? cell to respond to the increased insulin demand related to insulin resistance seems to be pivotal in the pathophysiologic process and a new notion is emerging: "nutritional genetics" which studies the influence of nutrients on gene expression. PMID:24005636

Bernard, Catherine; Della Zuana, Odile; Ktorza, Alain

2013-09-05

195

Effect of the Genetic Background on the Reproduction of Leptin-Deficient Obese Mice  

Microsoft Academic Search

Obesity is often associated with an impairment of the hypotha- lamic-pituitary-gonadal axis. The leptin-deficient ob\\/ob mouse model is characterized by a morbid obesity with a sterility in males and females that is corrected by continuous leptin treatment. Since ob\\/ob mice are maintained on the C57BL\\/6J inbred genetic background, we sought to determine whether their infertility can be corrected without leptin

AMANDA EWART-TOLAND; KHALID MOUNZIH; JUN QIU; FARID F. CHEHAB

1999-01-01

196

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

Microsoft Academic Search

Major thrombophilic mutations have been identified as risk factors for nontraumatic osteonecrosis of the femoral head (ONFH)\\u000a in Caucasians. We asked whether the genetic background of patients with ONFH in the Korean population was similar. We analyzed\\u000a factor V G1691A mutation (factor V Leiden), prothrombin G20210A mutation, and methylenetetrahydrofolate reductase C677T and\\u000a A1298C polymorphisms in 71 patients (53 men, 18

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

2008-01-01

197

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

PubMed Central

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.

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

198

The Joint Effects of Background Selection and Genetic Recombination on Local Gene Genealogies  

PubMed Central

Background selection, the effects of the continual removal of deleterious mutations by natural selection on variability at linked sites, is potentially a major determinant of DNA sequence variability. However, the joint effects of background selection and genetic recombination on the shape of the neutral gene genealogy have proved hard to study analytically. The only existing formula concerns the mean coalescent time for a pair of alleles, making it difficult to assess the importance of background selection from genome-wide data on sequence polymorphism. Here we develop a structured coalescent model of background selection with recombination and implement it in a computer program that efficiently generates neutral gene genealogies for an arbitrary sample size. We check the validity of the structured coalescent model against forward-in-time simulations and show that it accurately captures the effects of background selection. The model produces more accurate predictions of the mean coalescent time than the existing formula and supports the conclusion that the effect of background selection is greater in the interior of a deleterious region than at its boundaries. The level of linkage disequilibrium between sites is elevated by background selection, to an extent that is well summarized by a change in effective population size. The structured coalescent model is readily extendable to more realistic situations and should prove useful for analyzing genome-wide polymorphism data.

Zeng, Kai; Charlesworth, Brian

2011-01-01

199

The joint effects of background selection and genetic recombination on local gene genealogies.  

PubMed

Background selection, the effects of the continual removal of deleterious mutations by natural selection on variability at linked sites, is potentially a major determinant of DNA sequence variability. However, the joint effects of background selection and genetic recombination on the shape of the neutral gene genealogy have proved hard to study analytically. The only existing formula concerns the mean coalescent time for a pair of alleles, making it difficult to assess the importance of background selection from genome-wide data on sequence polymorphism. Here we develop a structured coalescent model of background selection with recombination and implement it in a computer program that efficiently generates neutral gene genealogies for an arbitrary sample size. We check the validity of the structured coalescent model against forward-in-time simulations and show that it accurately captures the effects of background selection. The model produces more accurate predictions of the mean coalescent time than the existing formula and supports the conclusion that the effect of background selection is greater in the interior of a deleterious region than at its boundaries. The level of linkage disequilibrium between sites is elevated by background selection, to an extent that is well summarized by a change in effective population size. The structured coalescent model is readily extendable to more realistic situations and should prove useful for analyzing genome-wide polymorphism data. PMID:21705759

Zeng, Kai; Charlesworth, Brian

2011-07-29

200

Genetic variations in CHRNA7 or CHRFAM7 and susceptibility to dementia.  

PubMed

The presence of memory impairment and cognitive deficits in the Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Pick's disease (PiD) has been associated to dysfunction of cholinergic transmission, possibly due to the loss of cholinergic neurons and to the elimination of nAChR in dementia patients. Alternative hypotheses take into account molecular interactions of the ?-amyloid peptide A? with nAChR, which may lead to deregulation of the receptor function. Genetic polymorphisms of CHRNA7 and CHRFAM7A, a fusion gene containing a partial CHRNA7 duplication, have been investigated as possible susceptibility traits to dementia, potentially useful either to identify high risk individuals or as therapeutic targets. To summarize the existing evidence, a systematic re-evaluation of published papers has been performed (PubMed database, no language restriction, updated to 1st August 2011). Eleven articles reporting data on genetic variations in CHRNA7 or CHRFAM7 and risk of dementia fulfilled selection criteria and were evaluated. Published evidence on the association between variations in CHRNA7 or CHRFAM7A and the risk of dementia is still sparse and inconclusive. Further studies are needed to establish whether some polymorphisms may really affect the probability of developing AD or other forms of dementia. Additional and more conclusive results may come from the ongoing GWAS studies investigating high numbers of genetic variants in large samples, that have the potential to assess the role of genetic susceptibility in dementia. PMID:22300029

Neri, Monica; Bonassi, Stefano; Russo, Patrizia

2012-05-01

201

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...

202

Genetic Control of Susceptibility to Infection with Candida albicans in Mice  

PubMed Central

Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value?=?2.43×10?11) and a novel effect on distal chromosome 11 (P value?=?7.63×10?9). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFN?. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n?=?158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD?=?4.59), and a chromosome 8 locus (Carg3; LOD?=?3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner.

Radovanovic, Irena; Mullick, Alaka; Gros, Philippe

2011-01-01

203

Genetic control of suceptibility to Candida albicans in susceptible A\\/J and resistant C57BL\\/6J mice  

Microsoft Academic Search

The importance of host factors in determining susceptibility to systemic Candida albicans infections is evident in both humans and mice. We have used a mouse model to study the genetic basis of susceptibility, using the inbred strains A\\/J and C57BL\\/6J, which are susceptible and resistant, respectively, based on different parameters of the response to infection. To identify genes responsible for

A Tuite; M Elias; S Picard; A Mullick; P Gros

2005-01-01

204

Riding the wave of ependymal cilia: genetic susceptibility to hydrocephalus in primary ciliary dyskinesia.  

PubMed

Congenital hydrocephalus is a relatively common and debilitating birth defect with several known physiological causes. Dysfunction of motile cilia on the ependymal cells that line the ventricular surface of the brain can result in hydrocephalus by hindering the proper flow of cerebrospinal fluid. As a result, hydrocephalus can be associated with primary ciliary dyskinesia, a rare pediatric syndrome resulting from defects in ciliary and flagellar motility. Although the prevalence of hydrocephalus in primary ciliary dyskinesia patients is low, it is a common hallmark of the disease in mouse models, suggesting that distinct genetic mechanisms underlie the differences in the development and physiology of human and mouse brains. Mouse models of primary ciliary dyskinesia reveal strain-specific differences in the appearance and severity of hydrocephalus, indicating the presence of genetic modifiers segregating in inbred strains. These models may provide valuable insight into the genetic mechanisms that regulate susceptibility to hydrocephalus under the conditions of ependymal ciliary dysfunction. PMID:23686703

Lee, Lance

2013-05-17

205

Markers of genetic susceptibility in human environmental hygiene and toxicology: The role of selected CYP, NAT and GST genes  

Microsoft Academic Search

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and

Ricarda Thier; Thomas Brüning; Peter H. Roos; Hans-Peter Rihs; Klaus Golka; Yon Ko; Hermann M. Bolt

2003-01-01

206

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

PubMed Central

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

2011-01-01

207

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

PubMed Central

Background RNA interference (RNAi) is a powerful tool to study gene function in organisms that are not amenable to classical forward genetics. Hence, together with the ease of comprehensively identifying genes by new generation sequencing, RNAi is expanding the scope of animal species and questions that can be addressed in terms of gene function. In the case of genetic mutants, the genetic background of the strains used is known to influence the phenotype while this has not been described for RNAi experiments. Results Here we show in the red flour beetle Tribolium castaneum that RNAi against Tc-importin ?1 leads to different phenotypes depending on the injected strain. We rule out off target effects and show that sequence divergence does not account for this difference. By quantitatively comparing phenotypes elicited by RNAi knockdown of four different genes we show that there is no general difference in RNAi sensitivity between these strains. Finally, we show that in case of Tc-importin ?1 the difference depends on the maternal genotype. Conclusions These results show that in RNAi experiments strain specific differences have to be considered and that a proper documentation of the injected strain is required. This is especially important for the increasing number of emerging model organisms that are being functionally investigated using RNAi. In addition, our work shows that RNAi is suitable to systematically identify the differences in the gene regulatory networks present in populations of the same species, which will allow novel insights into the evolution of animal diversity.

2013-01-01

208

Expression of Drosophila Mushroom Body Mutations in Alternative Genetic Backgrounds: A Case Study of the Mushroom Body Miniature Gene (mbm)  

Microsoft Academic Search

Mutations in 12 genes regulating Drosophila melanogaster mushroom body (MB) development were each studied in two genetic backgrounds. In all cases, brain structure was qualitatively or quantitatively different after replacement of the ``original'' genetic background with that of the Canton Special wild-type strain. The mushroom body miniature gene (mbm) was investigated in detail. mbm supports the maintenance of MB Kenyon

J. Steven de Belle; Martin Heisenberg

1996-01-01

209

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

PubMed

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

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

2011-06-06

210

Toll-Like Receptor 4 Region Genetic Variants are Associated with Susceptibility to Melioidosis  

PubMed Central

Melioidosis is a tropical infection caused by the Gram-negative soil saprophyte Burkholderia pseudomallei. Despite broad exposure of northeast Thais, disease develops in only a small proportion of individuals. Although diabetes is a risk factor, the mechanisms of host susceptibility to melioidosis are still poorly understood. We postulated that Toll-like receptors (TLRs) regulate host susceptibility to disease, and that genetic variation in TLRs is associated with melioidosis. We analyzed the frequency of eight previously described TLR pathway polymorphisms in 490 cases compared to 950 non-hospitalized controls or 458 hospitalized controls. Based on these results, we then analyzed the frequency of additional TLR4 or TLR6-1-10 region polymorphisms in cases and controls. We found that the TLR41196C>T variant was associated with protection from melioidosis when compared to non-hospitalized controls. The TLR1742A>G and TLR1?7202A>G variants were associated with melioidosis when compared to hospitalized controls. In further analyses, we found that two additional TLR4 region polymorphisms were associated with disease. In diabetics, three other TLR6-1-10 region polymorphisms were associated with disease when compared to hospitalized controls. We conclude that TLR genetic variants may modulate host susceptibility to melioidosis. Confirmation of these findings and further investigation of the mechanisms is required.

West, T. Eoin; Chierakul, Wirongrong; Chantratita, Narisara; Limmathurotsakul, Direk; Wuthiekanun, Vanaporn; Emond, Mary J.; Hawn, Thomas R.; Peacock, Sharon J.; Skerrett, Shawn J.

2012-01-01

211

Genetic Susceptibility to Tuberculosis Associated with Cathepsin Z Haplotype in a Ugandan Household Contact Study  

PubMed Central

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), causes 9 million new cases worldwide and 2 million deaths annually. Genetic linkage and association analyses have suggested several chromosomal regions and candidate genes involved in TB susceptibility. This study examines the association of TB disease susceptibility with a selection of biologically relevant genes on regions on chromosomes 7 (IL6 and CARD11) and 20 (CTSZ and MC3R), and fine mapping of the chromosome 7p22-p21 region, identified through our genome scan. We analyzed 565 individuals from Kampala, Uganda who were previously included in our genome-wide linkage scan. Association analyses were conducted for 1417 single-nucleotide polymorphisms (SNPs) that passed quality control. None of the candidate gene or fine mapping SNPs were found significantly associated with TB susceptibility (P > 0.10). When we restricted the analysis to HIV-negative individuals, two SNPs on chromosome 7 were significantly associated with TB susceptibility (P < 0.05). Haplotype analyses identified a significant risk haplotype in Cathepsin X (CTSZ) (p=0.0281, OR = 1.5493, 95% CI [1.039, 2.320]).

Baker, Allison R.; Zalwango, Sarah; Malone, LaShaunda L.; Igo, Robert P.; Qiu, Feiyou; Nsereko, Mary; Adams, Mark D.; Supelak, Pamela; Mayanja-Kizza, Harriet; Boom, W. Henry; Stein, Catherine M.

2011-01-01

212

Genetic susceptibility to tuberculosis associated with cathepsin Z haplotype in a Ugandan household contact study.  

PubMed

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), causes 9 million new cases worldwide and 2 million deaths annually. Genetic linkage and association analyses have suggested several chromosomal regions and candidate genes involved in TB susceptibility. This study examines the association of TB disease susceptibility with a selection of biologically relevant genes on regions on chromosomes 7 (IL6 and CARD11) and 20 (CTSZ and MC3R) and fine mapping of the chromosome 7p22-p21 region identified through our genome scan. We analyzed 565 individuals from Kampala, Uganda, who were previously included in our genome-wide linkage scan. Association analyses were conducted for 1,417 single-nucleotide polymorphisms (SNP) that passed quality control. None of the candidate gene or fine mapping SNPs was significantly associated with TB susceptibility (p > 0.10). When we restricted the analysis to HIV-negative individuals, 2 SNPs on chromosome 7 were significantly associated with TB susceptibility (p < 0.05). Haplotype analyses identified a significant risk haplotype in cathepsin X (CTSZ; p = 0.0281, odds ratio = 1.5493, 95% confidence interval [1.039, 2.320]). PMID:21354459

Baker, Allison R; Zalwango, Sarah; Malone, LaShaunda L; Igo, Robert P; Qiu, Feiyou; Nsereko, Mary; Adams, Mark D; Supelak, Pamela; Mayanja-Kizza, Harriet; Boom, W Henry; Stein, Catherine M

2011-02-25

213

Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa  

PubMed Central

The sst1 locus has been identified in a mouse model to control resistance and susceptibility of Mycobacterium tuberculosis infection. Subsequent studies have now identified Ipr1 (intracellular pathogen resistance 1) to be the gene responsible. Ipr1 is encoded within the sst1 locus and is expressed in the tuberculosis lung lesions and macrophages of sst1-resistant, but not sst1-susceptible mice. We have therefore examined the closest human homologue of Ipr1, SP110, for its ability to control susceptibility to M. tuberculosis infection in humans. In a study of families from The Gambia we have identified three polymorphisms that are associated with disease. On examination of additional families from Guinea-Bissau and the Republic of Guinea, two of these associations were independently replicated. These variants are in strong linkage disequilibrium with each other and lie within a 31-kb block of low haplotypic diversity, suggesting that a polymorphism within this region has a role in genetic susceptibility to tuberculosis in humans.

Tosh, Kerrie; Campbell, Sarah J.; Fielding, Katherine; Sillah, Jackson; Bah, Boubacar; Gustafson, Per; Manneh, Kebba; Lisse, Ida; Sirugo, Giorgio; Bennett, Steve; Aaby, Peter; McAdam, Keith P. W. J.; Bah-Sow, Oumou; Lienhardt, Christian; Kramnik, Igor; Hill, Adrian V. S.

2006-01-01

214

The Flowering Repressor SVP Underlies a Novel Arabidopsis thaliana QTL Interacting with the Genetic Background  

PubMed Central

The timing of flowering initiation is a fundamental trait for the adaptation of annual plants to different environments. Large amounts of intraspecific quantitative variation have been described for it among natural accessions of many species, but the molecular and evolutionary mechanisms underlying this genetic variation are mainly being determined in the model plant Arabidopsis thaliana. To find novel A. thaliana flowering QTL, we developed introgression lines from the Japanese accession Fuk, which was selected based on the substantial transgression observed in an F2 population with the reference strain Ler. Analysis of an early flowering line carrying a single Fuk introgression identified Flowering Arabidopsis QTL1 (FAQ1). We fine-mapped FAQ1 in an 11 kb genomic region containing the MADS transcription factor gene SHORT VEGETATIVE PHASE (SVP). Complementation of the early flowering phenotype of FAQ1-Fuk with a SVP-Ler transgen demonstrated that FAQ1 is SVP. We further proved by directed mutagenesis and transgenesis that a single amino acid substitution in SVP causes the loss-of-function and early flowering of Fuk allele. Analysis of a worldwide collection of accessions detected FAQ1/SVP-Fuk allele only in Asia, with the highest frequency appearing in Japan, where we could also detect a potential ancestral genotype of FAQ1/SVP-Fuk. In addition, we evaluated allelic and epistatic interactions of SVP natural alleles by analysing more than one hundred transgenic lines carrying Ler or Fuk SVP alleles in five genetic backgrounds. Quantitative analyses of these lines showed that FAQ1/SVP effects vary from large to small depending on the genetic background. These results support that the flowering repressor SVP has been recently selected in A. thaliana as a target for early flowering, and evidence the relevance of genetic interactions for the intraspecific evolution of FAQ1/SVP and flowering time.

Mendez-Vigo, Belen; Martinez-Zapater, Jose M.; Alonso-Blanco, Carlos

2013-01-01

215

Evolutionary concepts in ecotoxicology: tracing the genetic background of differential cadmium sensitivities in invertebrate lineages.  

PubMed

In many toxicological and ecotoxicological studies and experimental setups, the investigator is mainly interested in traditional parameters such as toxicity data and effects of toxicants on molecular, cellular or physiological functions of individuals, species or statistical populations. It is clear, however, that such approaches focus on the phenotype level of animal species, whilst the genetic and evolutionary background of reactions to environmental toxicants may remain untold. In ecotoxicological risk assessment, moreover, species sensitivities towards pollutants are often regarded as random variables in a statistical approach. Beyond statistics, however, toxicant sensitivity of every species assumes a biological significance, especially if we consider that sensitivity traits have developed in lineages of species with common evolutionary roots. In this article, the genetic and evolutionary background of differential Cd sensitivities among invertebrate populations and species and their potential of adaptation to environmental Cd exposure will be highlighted. Important evolutionary and population genetic concepts such as genome structure and their importance for evolutionary adaptation, population structure of affected individuals, as well as micro and macroevolutionary mechanisms of Cd resistance in invertebrate lineages will be stressed by discussing examples of work from our own laboratory along with a review of relevant literature data and a brief discussion of open questions along with some perspectives for further research. Both, differences and similarities in Cd sensitivity traits of related invertebrate species can only be understood if we consider the underlying evolutionary processes and genetic (or epigenetic) mechanisms. Keeping in mind this perception can help us to better understand and interpret more precisely why the sensitivity of some species or species groups towards a certain toxicant (or metal) may be ranked in the lower or higher range of species sensitivity distributions. Hence, such a perspective will transcend a purely statistical view of the sensitivity distributions concept, and will enhance ecotoxicology in many respects. PMID:23576190

Dallinger, Reinhard; Höckner, Martina

2013-04-11

216

The flowering repressor SVP underlies a novel Arabidopsis thaliana QTL interacting with the genetic background.  

PubMed

The timing of flowering initiation is a fundamental trait for the adaptation of annual plants to different environments. Large amounts of intraspecific quantitative variation have been described for it among natural accessions of many species, but the molecular and evolutionary mechanisms underlying this genetic variation are mainly being determined in the model plant Arabidopsis thaliana. To find novel A. thaliana flowering QTL, we developed introgression lines from the Japanese accession Fuk, which was selected based on the substantial transgression observed in an F(2) population with the reference strain Ler. Analysis of an early flowering line carrying a single Fuk introgression identified Flowering Arabidopsis QTL1 (FAQ1). We fine-mapped FAQ1 in an 11 kb genomic region containing the MADS transcription factor gene SHORT VEGETATIVE PHASE (SVP). Complementation of the early flowering phenotype of FAQ1-Fuk with a SVP-Ler transgen demonstrated that FAQ1 is SVP. We further proved by directed mutagenesis and transgenesis that a single amino acid substitution in SVP causes the loss-of-function and early flowering of Fuk allele. Analysis of a worldwide collection of accessions detected FAQ1/SVP-Fuk allele only in Asia, with the highest frequency appearing in Japan, where we could also detect a potential ancestral genotype of FAQ1/SVP-Fuk. In addition, we evaluated allelic and epistatic interactions of SVP natural alleles by analysing more than one hundred transgenic lines carrying Ler or Fuk SVP alleles in five genetic backgrounds. Quantitative analyses of these lines showed that FAQ1/SVP effects vary from large to small depending on the genetic background. These results support that the flowering repressor SVP has been recently selected in A. thaliana as a target for early flowering, and evidence the relevance of genetic interactions for the intraspecific evolution of FAQ1/SVP and flowering time. PMID:23382706

Méndez-Vigo, Belén; Martínez-Zapater, José M; Alonso-Blanco, Carlos

2013-01-31

217

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

PubMed

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

Seagraves, Nikki J; McBride, Kim L

2012-08-08

218

Genetic Background Has a Major Impact on Differences in Sleep Resulting from Environmental Influences in Drosophila  

PubMed Central

Study Objectives: To determine the effect of different genetic backgrounds on demographic and environmental interventions that affect sleep and evaluate variance of these measures; and to evaluate sleep and variance of sleep behaviors in 6 divergent laboratory strains of common origin. Design: Assessment of the effects of age, sex, mating status, food sources, and social experience using video analysis of sleep behavior in 2 different strains of Drosophila, white1118ex (w1118ex) and white Canton-S (wCS10). Sleep was also determined for 6 laboratory strains of Canton-S and 3 inbred lines. The variance of total sleep was determined for all groups and conditions. Measurements and Results: The circadian periods and the effects of age upon sleep were the same between w1118ex and wCS10 strains. However, the w1118ex and wCS10 strains demonstrated genotype-dependent differences in the effects upon sleep of sex, mating status, social experience, and being on different foods. Variance of total sleep was found to differ in a genotype dependent manner for interventions between the w1118ex and wCS10 strains. Six different laboratory Canton-S strains were found to have significantly different circadian periods (P < 0.001) and sleep phenotypes (P < 0.001). Three inbred lines showed reduced variance for sleep measurements. Conclusions: One must control environmental conditions in a rigorously consistent manner to ensure that sleep data may be compared between experiments. Genetic background has a significant impact upon changes in sleep behavior and variance of behavior due to demographic factors and environmental interventions. This represents an opportunity to discover new genes that modify sleep/wake behavior. Citation: Zimmerman JE; Chan MT; Jackson N; Maislin G; Pack AI. Genetic background has a major impact on differences in sleep resulting from environmental influences in Drosophila. SLEEP 2012;35(4):545-557.

Zimmerman, John E.; Chan, May T.; Jackson, Nicholas; Maislin, Greg; Pack, Allan I.

2012-01-01

219

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

SciTech Connect

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

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

2004-06-15

220

Genetic control of susceptibility to diethylnitrosamine and dimethylbenzanthracene carcinogenesis in rats.  

PubMed Central

The susceptibility to cancer induction after a single dose of diethylnitrosamine in male rats and a single dose of dimethylbenzanthracene in female rats was examined in the grc- strain R16 and the grc+ strain ACP, both of which have the same major histocompatibility complex genes but differ in the grc region. No tumor-promoting regimens were used, and the animals were fed only laboratory chou. The R16 males developed liver cancer and the R16 females developed breast cancer, there also were malignancies in other organs in some animals. By contrast, the ACP males did not develop any malignancies, and the ACP females had a significantly lower prevalence of malignant tumors. Thus the susceptibility to cancer in these two strains of rats has a genetic basis associated with genes in the grc region, and is independent of the carcinogen used, the action of a promoter, and the sex of the animals. Images Figure 1 Figure 2 Figure 3

Melhem, M. F.; Kunz, H. W.; Gill, T. J.

1991-01-01

221

Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease  

PubMed Central

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10?10) and with hepatic inflammation (P=3.7×10?4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

Romeo, Stefano; Kozlitina, Julia; Xing, Chao; Pertsemlidis, Alexander; Cox, David; Pennacchio, Len A.; Boerwinkle, Eric; Cohen, Jonathan C.; Hobbs, Helen H.

2008-01-01

222

[Susceptibility genetic variants in Hungarian morbus Crohn and ulcerative colitis patients].  

PubMed

We examined several susceptibility genetic variants to inflammatory bowel disease (Crohn's disease, ulcerative colitis) in Hungarian population, such as the CARD15 R702W, G908R, 1007finsC genetic variants, the SLC22A4 C1672T and SLC22A5 G-207C variants and their determined TC haplotype, the CTLA4 gene A+49G genetic variant and the rs10889677 C/A, rs2201841 T/C, rs1884444 G/T variants of the IL23R gene. We examined 201 adult patients with Crohn's disease, 241 adult patients with ulcerative colitis and 19 pediatric patients with Crohn's disease. For control 235 adult and 49 pediatric subjects were used. The genotyping was carried out using PCR/RFLP methods and direct sequencing. From the CARD15 gene mutations in the adult Crohn's disease population the 1007finsC, while in the pediatric population the 1007finsC and the G908R were significantly associated with an increased risk for Crohn's disease. We found no significant differences comparing the results of the patients and the controls by the SLC22A4, SLC22A5 genetic variants and the TC haplotype. The A+49G variant of the CTLA4 gene was not an independent determinant to inflammatory bowel disease. We found that the IL23R gene variants, rs10889677 C/A and rs2201841 T/C appear to increase susceptibility to Crohn's disease. It depends on the different populations whether this genetic variant means an obligatory risk factor to inflammatory bowel disease. PMID:19103559

Magyari, Lili; Melegh, Béla

2009-01-11

223

Genetic variants within ultraconserved elements and susceptibility to right- and left-sided colorectal adenocarcinoma  

PubMed Central

We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC patients and 551 healthy controls. The study comprised of a training set (520 cases and 341 controls) and a replication set (267 cases and 210 controls). We observed associations in rs7849 and rs1399685 with CRC risk. For example, a dose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63–1.00; P for trend = 0.05) associated with the variant allele of rs7849 in the training set. The significant trend toward a decrease in CRC risk was confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52–0.99; P for trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) risk, significant association was observed for the variant-containing genotypes of rs1399685 (OR, 1.77; 95% CI, 1.02–3.06) and the risk was replicated in the replication population (OR, 2.04; 95% CI, 1.02–4.07). The variant genotypes of rs9784100 and rs7849 conferred decreased risk but the associations were not replicated. Three right-sided CRC (RCRC) susceptibility loci were identified in rs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint effects and potential higher order gene–gene interactions among significant variants further categorized patients into different risk groups. Our results strongly suggest that several genetic variants in the UCEs may contribute to CRC susceptibility, individually and jointly, and that different genetic etiology may be involved in RCRC and LCRC.

Lin, Moubin; Eng, Cathy; Hawk, Ernest T.; Huang, Maosheng; Greisinger, Anthony J.; Gu, Jian; Ellis, Lee M.; Wu, Xifeng; Lin, Jie

2012-01-01

224

Autoimmune Thyroiditis and Diabetes: Dissecting the Joint Genetic Susceptibility in a Large Cohort of Multiplex Families  

PubMed Central

Context: Epidemiological data support a shared genetic susceptibility to autoimmune thyroid disease (AITD) and type 1 diabetes (T1D). Both diseases frequently occur within the same family and in the same individual. Patients developing both T1D and AITD are considered to have an autoimmune polyglandular syndrome type 3 variant (APS3v). Objective: The goals of this study were to identify the joint susceptibility loci/genes for T1D and AITD. Settings: The study was conducted at an academic medical center. Participants and Main Outcome Measures: We used whole genome and candidate gene approaches in a data set of 88 families multiplex for T1D and AITD (448 individuals). Results: We identified three loci, on chromosomes 2p, 6p, and Xp, showing linkage when individuals with either T1D or AITD were classified as affected. The 6p locus contained the human leukocyte antigen class II genes, and the Xp locus contained the FOXP3 gene. Three loci, on 2q, 6p (human leukocyte antigen class II), and Xp, showed evidence for linkage when only APS3v individuals (T1D+AITD) were classified as affected. Analysis of positional candidate genes strongly supported CTLA-4 as the gene on 2q associated with APS3v and FOXP3 as the gene on Xp associated with T1D or AITD and APS3v. In addition, the PTPN22 and insulin variable number tandem repeat genes showed significant associations with T1D or AITD in our families. Conclusions: Our results demonstrate a strong shared genetic susceptibility to T1D and AITD, with most shared genes involved in immune regulation, suggesting that immune dysregulation plays an important role in the joint susceptibility to T1D and AITD.

Villano, Maria Justina B.; Huber, Amanda K.; Greenberg, David A.; Golden, Brian K.; Concepcion, Erlinda; Tomer, Yaron

2009-01-01

225

The role of disease perceptions and results sharing in psychological adaptation after genetic susceptibility testing: the REVEAL Study  

Microsoft Academic Search

This study evaluates the extent to which psychological adaptation (validated measures of depressive symptoms, anxiety, and test-specific distress) after genetic susceptibility testing is influenced by changes in beliefs about Alzheimer's disease (AD) and sharing of test results with others. Adult children of AD patients (N=269) from a randomized clinical trial involving genetic testing for apolipoprotein E (APOE) provided information before,

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

2010-01-01

226

Vegetables and antioxidant-related nutrients, genetic susceptibility, and non-Hodgkin lymphoma risk  

Microsoft Academic Search

Genetic susceptibility to DNA oxidation, carcinogen metabolism, and altered DNA repair may increase non-Hodgkin lymphoma (NHL)\\u000a risk, whereas vegetables- and antioxidant-related nutrients may decrease risk. We evaluated the interaction of a priori-defined\\u000a dietary factors with 28 polymorphisms in these metabolic pathways. Incident cases (n = 1,141) were identified during 1998–2000 from four cancer registries and frequency-matched to population-based controls\\u000a (n = 949). We estimated

Linda E. Kelemen; Sophia S. Wang; Unhee Lim; Wendy Cozen; Maryjean Schenk; Patricia Hartge; Yan Li; Nathaniel Rothman; Scott Davis; Stephen J. Chanock; Mary H. Ward; James R. Cerhan

2008-01-01

227

Genetic Background of Patients from a University Medical Center in Manhattan: Implications for Personalized Medicine  

PubMed Central

Background The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex. Methods and Findings To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N?=?326), African Americans (N?=?324) and Hispanics (N?=?327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within- and between-group heterogeneity. Conclusion As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.

Tayo, Bamidele O.; Teil, Marie; Tong, Liping; Qin, Huaizhen; Khitrov, Gregory; Zhang, Weijia; Song, Quinbin; Gottesman, Omri; Zhu, Xiaofeng; Pereira, Alexandre C.; Cooper, Richard S.; Bottinger, Erwin P.

2011-01-01

228

Genetic Background Strongly Influences the Bone Phenotype of P2X7 Receptor Knockout Mice  

PubMed Central

The purinergic P2X7 receptor is expressed by bone cells and has been shown to be important in both bone formation and bone resorption. In this study we investigated the importance of the genetic background of the mouse strains on which the P2X7 knock-out models were based by comparing bone status of a new BALB/cJ P2X7?/? strain with a previous one based on the C57BL/6 strain. Female four-month-old mice from both strains were DXA scanned on a PIXImus densitometer; femurs were collected for bone strength measurements and serum for bone marker analysis. Bone-related parameters that were altered only slightly in the B6 P2X7?/? became significantly altered in the BALB/cJ P2X7?/? when compared to their wild type littermates. The BALB/cJ P2X7?/? showed reduced levels of serum C-telopeptide fragment (s-CTX), higher bone mineral density, and increased bone strength compared to the wild type littermates. In conclusion, we have shown that the genetic background of P2X7?/? mice strongly influences the bone phenotype of the P2X7?/? mice and that P2X7 has a more significant regulatory role in bone remodeling than found in previous studies.

Syberg, Susanne; Petersen, Solveig; Beck Jensen, Jens-Erik; Gartland, Alison; Teilmann, Jenni; Chessell, Iain; Steinberg, Thomas H.; Schwarz, Peter; J?rgensen, Niklas Rye

2012-01-01

229

qDTY1.1, a major QTL for rice grain yield under reproductive-stage drought stress with a consistent effect in multiple elite genetic backgrounds  

PubMed Central

Background Drought is one of the most important abiotic stresses causing drastic reductions in yield in rainfed rice environments. The suitability of grain yield (GY) under drought as a selection criterion has been reported in the past few years. Most of the quantitative trait loci (QTLs) for GY under drought in rice reported so far has been in the background of low-yielding susceptible varieties. Such QTLs have not shown a similar effect in multiple high- yielding drought-susceptible varieties, thus limiting their use in marker-assisted selection. Genetic control of GY under reproductive-stage drought stress (RS) in elite genetic backgrounds was studied in three F3:4 mapping populations derived from crosses of N22, a drought-tolerant aus cultivar, with Swarna, IR64, and MTU1010, three high-yielding popular mega-varieties, with the aim to identify QTLs for GY under RS that show a consistent effect in multiple elite genetic backgrounds. Three populations were phenotyped under RS in the dry seasons (DS) of 2009 and 2010 at IRRI. For genotyping, whole-genome scans for N22/MTU1010 and bulked segregant analysis for N22/Swarna and N22/IR64 were employed using SSR markers. Results A major QTL for GY under RS, qDTY1.1, was identified on rice chromosome 1 flanked by RM11943 and RM431 in all three populations. In combined analysis over two years, qDTY1.1 showed an additive effect of 29.3%, 24.3%, and 16.1% of mean yield in N22/Swarna, N22/IR64, and N22/MTU1010, respectively, under RS. qDTY1.1 also showed a positive effect on GY in non-stress (NS) situations in N22/Swarna, N22/IR64 over both years, and N22/MTU1010 in DS2009. Conclusions This is the first reported QTL in rice with a major and consistent effect in multiple elite genetic backgrounds under both RS and NS situations. Consistency of the QTL effect across different genetic backgrounds makes it a suitable candidate for use in marker-assisted breeding.

2011-01-01

230

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

PubMed

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

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

2002-03-01

231

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

PubMed Central

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.

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

2002-01-01

232

Contribution of NTRK2 to the genetic susceptibility to anorexia nervosa, Harm avoidance and minimum body mass index  

Microsoft Academic Search

Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders (ED) with complex genetic and environmental components. Genetic studies and animal models support the participation of brain-derived neurotrophic factor (BDNF) in the vulnerability to AN and BN. We investigated the genetic contribution of the BDNF-specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) to the susceptibility to ED. We have

M Ribases; M Gratacos; A Badia; L Jimenez; R Solano; J Vallejo; F Fernandez-Aranda; X Estivill

2005-01-01

233

Development of a peptidoglycan-polysaccharide murine model of Crohn's disease: effect of genetic background.  

PubMed

The peptidoglycan-polysaccharide (PGPS) model using inbred rats closely mimics Crohn's disease. Our aim was to identify mouse strains that develop ileocolitis in response to bowel wall injection with PGPS. Mouse strains studied included NOD2 knockout animals, RICK/RIP2 knockout animals, and genetically inbred strains that are susceptible to inflammation. Mice underwent laparotomy with intramural injection of PGPS or human serum albumin in the terminal ileum, ileal Peyer's patches, and cecum. Gross abdominal score, cecal histologic score, and levels of pro-fibrotic factor mRNAs were determined 20 to 32 days after laparotomy. PGPS-injected wild-type and knockout mice with mutations in the NOD2 pathway had higher abdominal scores than human serum albumin-injected mice. The RICK knockout animals tended to have higher mean abdominal scores than the NOD2 knockout animals, but the differences were not significant. CBA/J mice were shown to have the most robust response to PGPS, demonstrating consistently higher abdominal scores than other strains. Animals killed on day 26 had an average gross abdominal score of 6.1 ± 1.5, compared with those on day 20 (3.0 ± 0.0) or day 32 (2.8 ± 0.9). PGPS-injected CBA/J mice studied 26 days after laparotomy developed the most robust inflammation and most closely mimicked the PGPS rat model and human Crohn's disease. PMID:23619717

Reingold, Laura; Rahal, Kinan; Schmiedlin-Ren, Phyllissa; Rittershaus, Ahren C; Bender, Diane; Owens, Scott R; Adler, Jeremy; Zimmermann, Ellen M

2013-05-01

234

Identification of a new susceptibility variant for multiple sclerosis in OAS1 by population genetics analysis.  

PubMed

Contrasting results have been reported concerning the association of a splice-site polymorphism (rs10774671) in OAS1 with multiple sclerosis (MS). We analysed two OAS1 regions encompassing alternatively spliced exons. While the region carrying the splice-site variant is neutrally evolving, a signature of long-standing balancing selection was observed across an alternative exon 7. Analysis of variants in this exon identified an insertion/deletion polymorphism (rs11352835, A/-) that originates predicted products with distinct C termini. This variant is located along the major branch of the haplotype genealogy, suggesting that it may represent the selection target. A case/control study for MS indicated that rs11352835 is associated with disease susceptibility (for an allelic model with the deleted allele predisposing to MS, OR 1.27, 95% CI 1.072-1.513, p = 0.010). No association was found between rs10774671 and MS. As the two SNPs are in linkage disequilibrium in Europeans, the previously reported association between rs10774671 and MS susceptibility might be driven by rs11352835, possibly explaining the contrasting results previously observed for the splice-site polymorphism. Thus, we describe a novel susceptibility variant for MS in OAS1 and show that population genetic analyses can be instrumental to the identification of selection targets and, consequently, of functional polymorphisms with an effect on phenotypic traits. PMID:21735172

Cagliani, Rachele; Fumagalli, Matteo; Guerini, Franca R; Riva, Stefania; Galimberti, Daniela; Comi, Giacomo P; Agliardi, Cristina; Scarpini, Elio; Pozzoli, Uberto; Forni, Diego; Caputo, Domenico; Asselta, Rosanna; Biasin, Mara; Paraboschi, Elvezia M; Bresolin, Nereo; Clerici, Mario; Sironi, Manuela

2011-07-07

235

Genetic control of susceptibility to infection with Candida albicans in mice.  

PubMed

Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value?=?2.43×10(-11)) and a novel effect on distal chromosome 11 (P value?=?7.63×10(-9)). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFN?. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n?=?158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD?=?4.59), and a chromosome 8 locus (Carg3; LOD?=?3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner. PMID:21533108

Radovanovic, Irena; Mullick, Alaka; Gros, Philippe

2011-04-20

236

Seeking genetic susceptibility variants for colorectal cancer: the EPICOLON consortium experience.  

PubMed

The EPICOLON consortium was initiated in 1999 by the Gastrointestinal Oncology Group of the Spanish Gastroenterology Association. It recruited consecutive, unselected, population-based colorectal cancer (CRC) cases and control subjects matched by age and gender without personal or familial history of cancer all over Spain with the main goal of gaining knowledge in Lynch syndrome and familial CRC. This epidemiological, prospective and multicentre study collected extensive clinical data and biological samples from ?2000 CRC cases and 2000 controls in Phases 1 and 2 involving 25 and 14 participating hospitals, respectively. Genetic susceptibility projects in EPICOLON have included candidate-gene approaches evaluating single-nucleotide polymorphisms/genes from the historical category (linked to CRC risk by previous studies), from human syntenic CRC susceptibility regions identified in mouse, from the CRC carcinogenesis-related pathways Wnt and BMP, from regions 9q22 and 3q22 with positive linkage in CRC families, and from the mucin gene family. This consortium has also participated actively in the identification 5 of the 16 common, low-penetrance CRC genetic variants identified so far by genome-wide association studies. Finishing their own pangenomic study and performing whole-exome sequencing in selected CRC samples are among EPICOLON future research prospects. PMID:22294762

Castellví-Bel, Sergi; Ruiz-Ponte, Clara; Fernández-Rozadilla, Ceres; Abulí, Anna; Muñoz, Jenifer; Bessa, Xavier; Brea-Fernández, Alejandro; Ferro, Marta; Giráldez, María Dolores; Xicola, Rosa M; Llor, Xavier; Jover, Rodrigo; Piqué, Josep M; Andreu, Montserrat; Castells, Antoni; Carracedo, Angel

2012-03-01

237

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

PubMed

Classical scrapie disease is a transmissible spongiform encephalopathy of sheep that is enzootic in the United States. Susceptibility of sheep to classical scrapie is linked to single nucleotide polymorphisms in the prion protein gene (PRNP), forming the basis for genetic testing strategies used by national efforts to eradicate scrapie. Such efforts are occasionally hampered by inconclusive results stemming from the detection of "complex" genotypes. Naturally occurring cases of ovine chimerism are thought to account for some of these instances. In the current report, 4 naturally occurring ovine chimeras are documented through cytogenetic and molecular analyses. All 4 of these sheep had chimeric cells circulating in their blood. Blood and alternate tissue samples of ear punch and hair bulbs from one of these chimeras was submitted in batch with similar samples from control sheep for routine scrapie genetic relative susceptibility testing. A complex PRNP genotype was detected in the blood of the chimeric female but not in the alternate tissue samples or in the control sheep samples. The results demonstrate that naturally occurring blood chimerism can confound current testing efforts. The potential impacts of undetected chimeras on current scrapie eradication efforts are discussed. PMID:19407081

Schneider, David A; Tibary, Ahmed; Raudsepp, Terje; Das, Pranab J; O'Rourke, Katherine I

2009-05-01

238

Are SCN1A gene mutations responsible for genetic susceptibility to subacute sclerosing panencephalitis?  

PubMed

Dravet syndrome, characterized predominantly by myoclonus, has a striking clinical resemblance to subacute sclerosing panencephalitis (SSPE). Patients with Dravet syndrome develop significant mental decline with advancing age of affected child like in SSPE. It is well established that SCN1A gene mutations are associated with Dravet syndrome. Even periodic EEG complexes have been described in Dravet syndrome. In addition to Dravet syndrome, several other types of acute and subacute encephalopathic syndromes having clinical and electroencephalographic resemblance to SSPE are associated with SCN1A gene mutations. SSPE is a devastating progressive inflammatory disorder of the central nervous system. It is caused by persistent infection of the brain by an aberrant measles virus. Only a few of a vast number of measles infected pediatric population develop SSPE. There are several reports describing presence of SSPE is close relatives and it has been described previously in sibling and twin pairs. A genetic susceptibility for development of SSPE is likely. In fact, a variety of genetic abnormalities have already been described in patients with SSPE. It can also be argued that because of striking clinical resemblance between Dravet and various epileptic and encephalopathic syndromes associated with SCN1A gene mutations and SSPE, SCN1A gene abnormalities may also be responsible for susceptibility to SSPE in measles infected children. PMID:22098725

Garg, Ravindra Kumar

2011-11-17

239

Genetic variation of the CYP17 and susceptibility to endometrial cancer: a meta-analysis.  

PubMed

Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of EC. Cytochrome P450c17? (CYP17), a gene that codes for a key enzyme (cytochrome P450c17?) in a rate-limiting step of estrogen biosynthesis has attracted considerable attention as a candidate gene for EC. The relationship between CYP17 and EC has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 3,258 cases and 4,614 controls for -34T>C (rs743572) polymorphism of the CYP17 gene to evaluate the effect of CYP17 on genetic susceptibility for EC. An overall random effects odds ratio of 0.71 (95% confidence interval 0.58-0.88, P=0.001) was found under recessive genetic model. Stratified analysis based on ethnicity, sample size and Hardy-Weinberg equilibrium status was conducted to explore potential heterogeneity. This meta-analysis demonstrated that the C allele of -34T>C in CYP17 is a protective factor associated with decreased EC susceptibility, but these associations vary in different ethnic populations. PMID:23649771

Xu, Jun; Lin, Xiao; Zhu, Haoping; Zhang, Zhiling; Yang, Baohua

2013-05-07

240

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

PubMed Central

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.

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

2011-01-01

241

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

PubMed Central

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.

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

2009-01-01

242

Impact of Genetic Background on Allele Selection in a Highly Mutable Candida albicans Gene, PNG2  

PubMed Central

In many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation and evasion of the immune response. In some contingency genes mutability is achieved through DNA repeats within the coding region. The fungal human pathogen Candida albicans has 2600 repeat-containing ORFs. For those investigated (ALS genes, HYR1, HYR2, CEK1, RLM1) many protein variants with differing amino acid repeat regions exist, as expected for contingency genes. However, specific alleles dominate in different clades, which is unexpected if allele variation is used for short-term adaptation. Generation of new alleles of repeat-containing C. albicans ORFs has never been observed directly. Here we present evidence for restrictions on the emergence of new alleles in a highly mutable C. albicans repeat-containing ORF, PNG2, encoding a putative secreted or cell surface glycoamidase. In laboratory cultures new PNG2 alleles arose at a rate of 2.8×10?5 (confidence interval 3.3×10?6?9. 9×10?5) per cell per division, comparable to rates measured for contingency genes. Among 80 clinical isolates 17 alleles of different length and 23 allele combinations were distinguishable; sequence differences between repeat regions of identical size suggest the existence of 36 protein variants. Specific allele combinations predominated in different genetic backgrounds, as defined by DNA fingerprinting and multilocus sequence typing. Given the PNG2 mutation rate, this is unexpected, unless in different genetic backgrounds selection favors different alleles. Specific alleles or allele combinations were not preferentially associated with C. albicans isolates from particular body sites or geographical regions. Our results suggest that the mutability of PNG2 is not used for short-term adaptation or evasion of the immune system. Nevertheless the large number of alleles observed indicates that mutability of PNG2 may assist C. albicans strains from different genetic backgrounds optimize their interaction with the host in the long term.

Zhang, Ningxin; Cannon, Richard D.; Holland, Barbara R.; Patchett, Mark L.; Schmid, Jan

2010-01-01

243

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures  

PubMed Central

Background Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. Methodology/Principal Findings A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. Conclusions/Significance The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.

Perroud, Nader; Ponsole-Lenfant, Magali; Cillario, Jennifer; Roll, Patrice; Roeckel-Trevisiol, Nathalie; Crespel, Ariel; Balzar, Jorg; Schlachter, Kurt; Gruber-Sedlmayr, Ursula; Pataraia, Ekaterina; Baumgartner, Christoph; Zimprich, Alexander; Zimprich, Fritz; Malafosse, Alain; Szepetowski, Pierre

2010-01-01

244

Genetic Background Modulates the Phenotype of a Mouse Model of DYT1 Dystonia  

PubMed Central

DYT1 dystonia is a debilitating neurological disease characterized by involuntary twisting movements. The disease is caused by an in-frame deletion (GAG, “?E”) mutation in the TOR1A gene that encodes the torsinA protein. Intriguingly, only 30% of mutation carriers exhibit motor symptoms despite the fact that functional brain imaging studies show abnormal brain metabolism in all carriers. Because genetic modifiers may be a determinant of this reduced penetrance, we examined the genetic contribution of three different inbred strains of mice on the DYT1 mutation in animals that are homozygous (Tor1a?E/?E) or heterozygous (Tor1a?E/+; disease state) for the disease-causing ?E mutation. We find that the DBA/2J, C57BL/6J, and CD1-ICR contribution of genes significantly alter lifespan in Tor1a?E/?E mice, which die during the first few days of life on the 129S6/SvEvTac (129) background. The C57BL/6J (B6) strain significantly decreases life expectancy of Tor1a?E/?E animals but, like 129S6/SvEvTac Tor1a?E/+ mice, congenic C57BL/6J Tor1a?E/+ mice do not exhibit any motor abnormalities. In contrast, the DBA/2J (D2) strain significantly increases life expectancy. This effect was not present in congenic DBA/2J Tor1a?E/?E mice, indicating that the extended lifespan of F2 129/D2 mice was due to a combination of homozygous and heterozygous allelic effects. Our observations suggest that genetic modifiers may alter the penetrance of the ?E mutation, and that mapping these modifiers may provide fresh insight into the torsinA molecular pathway.

Tanabe, Lauren M.; Martin, Caitlin; Dauer, William T.

2012-01-01

245

Mapping of genes controlling aluminum tolerance in rice: comparison of different genetic backgrounds.  

PubMed

Aluminum toxicity is the main factor limiting the productivity of crop plants in acid soils, particularly in the tropics and subtropics. In this study, a doubled-haploid population derived from the rice ( Oryza sativa L.) breeding lines CT9993 and IR62266 was used to map genes controlling Al tolerance. A genetic linkage map consisting of 280 DNA markers (RFLP, AFLP and SSR) was constructed to determine the position and nature of quantitative trait loci (QTLs) affecting Al tolerance. Three characters - control root length (CRL), Al-stressed root length (SRL) and root length ratio (RR) - were evaluated for the DH lines and the parents at the seedling stage in nutrient solution. A total of 20 QTLs controlling root growth under Al stress and control conditions were detected and distributed over 10 of the 12 rice chromosomes, reflecting multigenic control of these traits. The two QTLs of largest effect, qALRR-1-1 and qALRR-8 for root length ratio (a measurement of Al tolerance) were localized on chromosomes 1 and 8, respectively. Three other QTLs in addition to qALRR-8 were apparently unique in the CT9993 x IR62266 mapping population, which may explain the high level of Al tolerance in CT9993. Comparative mapping identified a conserved genomic region on chromosome 1 associated with Al tolerance across three rice genetic backgrounds. This region provides an important starting point for isolating genes responsible for different mechanisms of aluminum tolerance and understanding the genetic nature of this trait in rice and other cereals. PMID:12207224

Nguyen, V T; Nguyen, B D; Sarkarung, S; Martinez, C; Paterson, A H; Nguyen, H T

2002-06-07

246

Comparison of genetic variation of breast cancer susceptibility genes in Chinese and German populations.  

PubMed

Genome-wide association studies (GWAS) identified several genetic risk factors for breast cancer, however, most of them were validated among women of European ancestry. This study examined single-nucleotide polymorphisms (SNPs) contributing to breast cancer in Chinese (984 cases and 2206 controls) and German (311 cases and 960 controls) populations. Eighteen SNPs significantly associated with breast cancer, previously identified in GWAS were genotyped. Twelve SNPs passed quality control and were subjected to statistical analysis. Seven SNPs were confirmed to be significantly associated with breast cancer in the Chinese population, reflecting three independent loci (ESR1, FGFR2, TOX3) and five of these were also confirmed in the German population. The strongest association was identified for rs2046210 in the Chinese (odds ratio (OR)=1.42, 95% confidence interval (CI)=1.28-1.59, P=1.9 × 10(-10)) and rs3803662 in the German population (OR=1.43, 95% CI=1.17-1.74, P=4.01 × 10(-4)), located upstream of the ESR1 and TOX3 gene, respectively. For the first time, rs3757318 at 6q25.1, located next to the gene encoding estrogen receptor ? (ESR1) was found to be strongly associated with breast cancer (OR=1.33, 95% CI=1.18-1.49, P=1.94 × 10(-6)) in the Chinese population. The frequency of this variant was markedly lower in the German population and the association was not significant. Despite the genetic differences, essentially the same risk loci were identified in the Chinese and the German populations. Our study suggested the existence of common genetic factors as well as disease susceptibility differences for breast cancer in both populations and highlighted the importance of performing comparison analyses for disease susceptibility within ethnic populations. PMID:23486537

Barzan, David; Veldwijk, Marlon R; Herskind, Carsten; Li, Yang; Zhang, Bo; Sperk, Elena; Du, Wei-Dong; Zhang, Xue-Jun; Wenz, Frederik

2013-03-13

247

Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study.  

PubMed

Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia, where Japan and Korea have the highest incidence in the world. Gastric cancer is classified into intestinal and diffuse types. While the former is almost absolutely caused by Helicobacter pylori infection as the initial insult, the latter seems to include cases in which the role of infection is limited, if any, and a contribution of genetic factors is anticipated. Previously, we performed a genome-wide association study (GWAS) on diffuse-type GC by using single nucleotide polymorphisms (SNP) catalogued for Japanese population (JSNP), and identified a prostate stem cell antigen (PSCA) gene encoding a glycosylphosphatidylinositol-anchored cell surface antigen as a GC susceptibility gene. From the second candidate locus identified using the GWAS, 1q22, we found the Mucin 1 (MUC1) gene encoding a cell membrane-bound mucin protein as another gene related to diffuse-type GC. A two-allele analysis based on risk genotypes of the two genes revealed approximately 95% of Japanese population have at least one of the two risk genotypes, and approximately 56% of the population have both risk genotypes. The two-SNP genotype might offer ample room to further stratify a high GC risk subpopulation in Japan and Asia by adding another genetic and/or non-genetic factor. Recently, a GWAS on the Chinese population disclosed an additional three GC susceptibility loci: 3q13.31, 5p13.1 and 10q23. PMID:23057512

Saeki, Norihisa; Ono, Hiroe; Sakamoto, Hiromi; Yoshida, Teruhiko

2012-11-24

248

Genetic Variation in the ?2-Adrenocepter Gene Is Associated with Susceptibility to Bacterial Meningitis in Adults  

PubMed Central

Recently, the biased ?2-adrenoceptor/?-arrestin pathway was shown to play a pivotal role in crossing of the blood brain barrier by Neisseria meningitidis. We hypothesized that genetic variation in the ?2-adrenoceptor gene (ADRB2) may influence susceptibility to bacterial meningitis. In a prospective genetic association study we genotyped 542 patients with CSF culture proven community acquired bacterial meningitis and 376 matched controls for 2 functional single nucleotide polymorphisms in the ?2-adrenoceptor gene (ADRB2). Furthermore, we analyzed if the use of non-selective beta-blockers, which bind to the ?2-adrenoceptor, influenced the risk of bacterial meningitis. We identified a functional polymorphism in ADRB2 (rs1042714) to be associated with an increased risk for bacterial meningitis (Odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04–1.76; p?=?0.026). The association remained significant after correction for age and was more prominent in patients with pneumococcal meningitis (OR 1.52, 95% CI 1.12–2.07; p?=?0.007). For meningococcal meningitis the difference in genotype frequencies between patients and controls was similar to that in pneumococcal meningitis, but this was not statistically significant (OR 1.43, 95% CI 0.60–3.38; p?=?0.72). Patients with bacterial meningitis had a lower frequency of non-selective beta-blockers use compared to the age matched population (0.9% vs. 1.8%), although this did not reach statistical significance (OR 1.96 [95% CI 0.88–4.39]; p?=?0.09). In conclusion, we identified an association between a genetic variant in the ?2-adrenoceptor and increased susceptibility to bacterial meningitis. The potential benefit of pharmacological treatment targeting the ?2-adrenoceptor to prevent bacterial meningitis in the general population or patients with bacteraemia should be further studied in both experimental studies and observational cohorts.

Adriani, Kirsten S.; Brouwer, Matthijs C.; Baas, Frank; Zwinderman, Aeilko H.; van der Ende, Arie; van de Beek, Diederik

2012-01-01

249

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

PubMed

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

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

2013-06-24

250

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

PubMed Central

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

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

2008-01-01

251

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

PubMed

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

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

2008-03-19

252

H?rthle Cells Predict Hypothyroidism in Interferon-? Transgenic Mice of Different Genetic Backgrounds  

PubMed Central

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.

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

2012-01-01

253

Common genetic background in anorexia nervosa and obsessive compulsive disorder: preliminary results from an association study.  

PubMed

Several lines of evidence, including psychopathological, neurobiological, pharmacological and epidemiological data, supported the association between Anorexia Nervosa (AN) and Obsessive-Compulsive Disorder (OCD). The aim of the present study is to test the hypothesis of partial common genetic background of both disease, AN and OCD. A total of 116 patients with AN, 74 patients with OCD and 91 controls participated in this study. 213 single-nucleotide polymorphisms (SNPs) in 28 candidate genes were analyzed. Five SNPs achieved 0.004 (the nominal p-value expected by chance), 3 with empirical significant p-values (rs10070190 (CDH9) p = 1 × 10(-3), rs4825476 (GRIA3) p = 4 × 10(-4), and rs1074815 (TPH2) p = 8 × 10(-4)) and 2 additional polymorphisms showing nominal significance (rs2834070 (OLIG2) p = 2 × 10(-3) and rs11783752 (SCL18A1) p = 3 × 10(-3)), were found to be related to both AN and OCD. In addition, rs3825885 (NTRK3, p = 9 × 10(-4)) was identified as an AN risk variant, and rs11179027 (TPH2, p = 2 × 10(-3)) as an OCD marker. The ROC analysis confirmed these results and showed interaction among the significant SNPs. The preliminary results we report here reveal a partial common genetic background in AN and OCD, in agreement with previous clinical findings of common symptomathology between these two diseases and open the field of possible treatments for AN. The interaction observed between the associated polymorphisms, could indicate that there is a biological interaction between the serotonin (TPH2 and SLC18A1) and glutamate (GRIA3) pathways and the factors related to neurogenesis (CDH9, OLIG2 and NTRK3) for the explanation of etiopathophysiology in both diseases. However, the results must be replicated in studies with larger cohorts in order to confirm these associations. PMID:23337130

Mas, Sergi; Plana, Maria Teresa; Castro-Fornieles, Josefina; Gassó, Patricia; Lafuente, Amalia; Moreno, Elena; Martinez, Esteban; Milà, Montserrat; Lazaro, Luisa

2013-01-19

254

Chromosome 5H of Hordeum species involved in reduction in grain hardness in wheat genetic background.  

PubMed

Grain hardness is an important factor affecting end-use quality in wheat. Mutations of the puroindoline genes, which are located on chromosome 5DS, control a majority of grain texture variations. Hordoindoline genes, which are the puroindoline gene homologs in barley, are located on chromosome 5HS and are also responsible for grain texture variation. In this study, we used three types of wheat-barley species (Hordeum vulgare, H. vulgare ssp. spontaneum, and H. chilense) chromosome addition lines and studied the effect of chromosome 5H of these species on wheat grain characteristics. The 5H chromosome addition lines showed significantly lower grain hardness and higher grain weight than the corresponding wheat parents. The effect of enhancing grain softness was largest in the wheat-H. chilense line regardless of having an increase in grain weight similar to those in the wheat-H. vulgare and wheat-H. spontaneum lines. Our results indicated that chromosome 5H of the Hordeum species plays a role in enhancing grain softness and increasing grain weight in the wheat genetic background, and the extent of effect on grain hardness depends on the type of Hordeum species. Protein analysis of hordoindolines indicated that profiles of 2D-electrophoresis of hordoindolines were different among Hordeum species and hordoindolines in the addition lines appeared to be most abundant in wheat-H. chilense line. The differences in enhancing grain softness among the Hordeum species might be attributed to the quantity of hordoindolines expressed in the 5H chromosome addition lines. These results suggested that the barley hordoindolines located on chromosome 5HS play a role in reducing grain hardness in the wheat genetic background. PMID:21739140

Yanaka, Mikiko; Takata, Kanenori; Terasawa, Yohei; Ikeda, Tatsuya M

2011-07-08

255

An Unbiased Systems Genetics Approach to Mapping Genetic Loci Modulating Susceptibility to Severe Streptococcal Sepsis  

PubMed Central

Striking individual differences in severity of group A streptococcal (GAS) sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL) on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%–30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases.

Abdeltawab, Nourtan F.; Aziz, Ramy K.; Kansal, Rita; Rowe, Sarah L.; Su, Yin; Gardner, Lidia; Brannen, Charity; Nooh, Mohammed M.; Attia, Ramy R.; Abdelsamed, Hossam A.; Taylor, William L.; Lu, Lu; Williams, Robert W.; Kotb, Malak

2008-01-01

256

Genetic background and gender effects on gross phenotypes in congenic lines of ALS2/alsin-deficient mice.  

PubMed

Loss-of-function mutations in human ALS2 account for several juvenile recessive motor neuron diseases (MNDs). To understand the molecular basis underlying motor dysfunction in ALS2-linked MNDs, several lines of Als2(-/-) mice with a mixed genetic background were thus far generated, and their phenotypes were thoroughly characterized. However, several phenotypic discrepancies among different Als2-deficient lines became evident. To investigate whether genetic backgrounds are associated with such discrepancies, we here generated congenic lines of Als2(-/-) mice on two different genetic backgrounds; C57BL/6 (B6) and FVB/N (FVB), and investigated their gross phenotypes. Both B6 and FVB congenic lines were viable and fertile with no evidences for obvious abnormalities. There were no differences in growth curves between wild-type and Als2(-/-) mice on each genetic background. Remarkably, Als2(-/-) mice on a FVB, but not a B6, background exhibited a shorter life span than wild-type litters. Further, B6 female, but not male, Als2(-/-) mice showed a significantly lower spontaneous rearing activity than wild-type litters. These genetic background- and/or gender-specific findings suggest the presence of modifiers for life span and motor activities in Als2(-/-) mice. These congenic mice should provide a useful means to understand the molecular and genetic basis for variable expression of pathological phenotypes in MNDs. PMID:20558214

Hadano, Shinji; Yoshii, Yasuhiro; Otomo, Asako; Kunita, Ryota; Suzuki-Utsunomiya, Kyoko; Pan, Lei; Kakuta, Shigeru; Iwasaki, Yasuo; Iwakura, Yoichiro; Ikeda, Joh-E

2010-06-14

257

Genetic counselling and testing for susceptibility to breast, ovarian and colon cancer: where are we today?  

PubMed Central

Recent advances in our understanding of the genetic characteristics of cancer will change approaches to genetic screening and counselling. Cancer results from multiple, cumulative mutations in genes that regulate cell replication and differentiation. In familial cancer a germ-line mutation is passed on in an autosomal dominant pattern, but cancer will develop in people who inherit the defect only if other mutations also occur in susceptible somatic cells. The tumour-suppressor gene known as BRCA1 is thought to affect half of those families who have an inherited breast cancer syndrome and most families with a breast and ovarian cancer syndrome. Another gene, BRCA2, is thought to affect most of the remaining families with a breast-cancer-only syndrome. Hereditary nonpolyposis colon cancer (HNPCC) is caused by mutations in surveillance genes that protect DNA from the spontaneous errors that occur during cell division. Because there are no outcome data on which to base practice guidelines for genetic screening or management of asymptomatic carriers in families at risk, testing should be restricted to research settings.

Cole, D E; Gallinger, S; McCready, D R; Rosen, B; Engel, J; Malkin, D

1996-01-01

258

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

PubMed Central

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

2012-01-01

259

Carbimazole-induced myositis in the treatment of Graves' disease: a complication in genetically susceptible individuals?  

PubMed

A 24-year-old Chinese woman with Graves' disease presented with myositis two months after treatment with carbimazole. The patient's myositis resolved with hydration and cessation of carbimazole. No other causes of myositis were found, and a change in the medication to propylthiouracil was uneventful. Review of the literature suggests a possible genetic susceptibility, as the majority of reported cases are Asian in origin, similar to patients who present with thyroid periodic paralysis. Changing the antithyroid drugs (ATDs) administered, decreasing the dose of pre-existing ATDs in the treatment regimen or addition of levothyroxine has been shown to result in clinical improvement of this complication. These observations suggest various mechanisms of carbimazole-induced myositis in the treatment of Graves' disease, including the direct effect of ATDs on myocytes, immune-related responses secondary to ATDs and rapid decrements in thyroid hormone with ensuing myositis. PMID:23900475

Lim, Adoree Yi Ying; Kek, Peng Chin; Soh, Abel Wah Ek

2013-07-01

260

Genetic Polymorphism of Cancer Susceptibility Genes and HPV Infection in Cervical Carcinogenesis.  

PubMed

It is widely accepted that specific human papillomavirus (HPV) types are the central etiologic agent of cervical carcinogenesis. However, a number of infected women do not develop invasive lesions, suggesting that other environmental and host factors may play decisive roles in the persistence of HPV infection and further malignant conversion of cervical epithelium. Although many previous reports have focused on HPV and environmental factors, the role of host susceptibility to cervical carcinogenesis is largely unknown. Here, we review the findings of genetic association studies in cervical carcinogenesis with special reference to polymorphisms of glutathione-S-transferase (GST) isoforms, p53 codon 72, murine double-minute 2 homolog (MDM2) gene promoter 309, and FAS gene promoter -670 together with HPV types including our recent research results. PMID:21660264

Nunobiki, Osamu; Ueda, Masatsugu; Toji, Eisaku; Yamamoto, Michiko; Akashi, Kyoko; Sato, Naomi; Izuma, Shinji; Torii, Kiyo; Tanaka, Ichiro; Okamoto, Yoshiaki; Noda, Sadamu

2011-05-31

261

Genetic Polymorphism of Cancer Susceptibility Genes and HPV Infection in Cervical Carcinogenesis  

PubMed Central

It is widely accepted that specific human papillomavirus (HPV) types are the central etiologic agent of cervical carcinogenesis. However, a number of infected women do not develop invasive lesions, suggesting that other environmental and host factors may play decisive roles in the persistence of HPV infection and further malignant conversion of cervical epithelium. Although many previous reports have focused on HPV and environmental factors, the role of host susceptibility to cervical carcinogenesis is largely unknown. Here, we review the findings of genetic association studies in cervical carcinogenesis with special reference to polymorphisms of glutathione-S-transferase (GST) isoforms, p53 codon 72, murine double-minute 2 homolog (MDM2) gene promoter 309, and FAS gene promoter -670 together with HPV types including our recent research results.

Nunobiki, Osamu; Ueda, Masatsugu; Toji, Eisaku; Yamamoto, Michiko; Akashi, Kyoko; Sato, Naomi; Izuma, Shinji; Torii, Kiyo; Tanaka, Ichiro; Okamoto, Yoshiaki; Noda, Sadamu

2011-01-01

262

Evaluation of breast cancer susceptibility using improved genetic algorithms to generate genotype SNP barcodes.  

PubMed

Genetic association is a challenging task for the identification and characterization of genes that increase the susceptibility to common complex multifactorial diseases. To fully execute genetic studies of complex diseases, modern geneticists face the challenge of detecting interactions between loci. A genetic algorithm (GA) is developed to detect the association of genotype frequencies of cancer cases and noncancer cases based on statistical analysis. An improved genetic algorithm (IGA) is proposed to improve the reliability of the GA method for high-dimensional SNP-SNP interactions. The strategy offers the top five results to the random population process, in which they guide the GA toward a significant search course. The IGA increases the likelihood of quickly detecting the maximum ratio difference between cancer cases and noncancer cases. The study systematically evaluates the joint effect of 23 SNP combinations of six steroid hormone metabolisms, and signaling-related genes involved in breast carcinogenesis pathways were systematically evaluated, with IGA successfully detecting significant ratio differences between breast cancer cases and noncancer cases. The possible breast cancer risks were subsequently analyzed by odds-ratio (OR) and risk-ratio analysis. The estimated OR of the best SNP barcode is significantly higher than 1 (between 1.15 and 7.01) for specific combinations of two to 13 SNPs. Analysis results support that the IGA provides higher ratio difference values than the GA between breast cancer cases and noncancer cases over 3-SNP to 13-SNP interactions. A more specific SNP-SNP interaction profile for the risk of breast cancer is also provided. PMID:23929860

Yang, Cheng-Hong; Lin, Yu-Da; Chuang, Li-Yeh; Chang, Hsueh-Wei

263

Genetic Polymorphism of Matrix Metalloproteinase Family and Chronic Obstructive Pulmonary Disease Susceptibility: a Meta-analysis  

PubMed Central

Matrix metalloproteinase (MMP) family is considered to be associated with chronic obstructive pulmonary disease (COPD) pathogenesis, however, no consistent results have been provided by previous studies. In this report, we performed Meta analysis to investigate the association between four kinds of MMP single nucleotide polymorphisms (SNP, MMP1 -1607 1G/2G, MMP3 -1171 5A/6A, MMP9 -1562 C/T, MMP12 -82 A/G) and COPD risk from 21 studies including 4184 cases and 5716 controls. Both overall and subgroup association between SNP and COPD susceptibility were tested. There was no evident association between MMP polymorphisms and COPD susceptibility in general population. On the other hand, subgroup analysis suggested that MMP9 -1562 C/T polymorphism was related to COPD, as we found that C allele carriers were at lower risk in some subgroups stratified by lung function, age and genotype identification method, compared with TT homozygotes. Our results indicated the genotype TT might be one genetic risk factor of severe COPD.

Zhou, Hongbin; Wu, Yinfang; Jin, Yan; Zhou, Jiesen; Zhang, Chao; Che, Luanqing; Jing, Jiyong; Chen, Zhihua; Li, Wen; Shen, Huahao

2013-01-01

264

IL-1RN VNTR polymorphism and genetic susceptibility to cervical cancer in Portugal.  

PubMed

Human Papillomavirus infection is considered as the main etiological factor of cervical cancer (ICC), although, the role of host genetic factors in ICC susceptibility has been increasing. Immunological response is crucial for the prevention of viral associated diseases. Interleukin 1 receptor antagonist (IL-1RN) is considered to be an important regulator of host immunity and several studies have shown a potential role of a 86 bp VNTR polymorphism within intron 2 of the IL-1RN gene in host immune response variability. We investigated the role of this polymorphism in cervical cancer development in Portugal with a case-control study developed with peripheral blood samples from 196 healthy women and 340 women with cervical lesions from the Northern Region of Portugal. We observed that IL-1RN Allele 2 homozygosis was significantly higher in cases than in controls. In fact, IL-1RN A2*A2 homozygous revealed to be associated with an increased risk of HSIL + ICC (OR = 1.90; 95 % IC 1.13-3.21; p = 0.015). Furthermore, we also observed that median age of onset of HSIL + ICC was significantly different (46.0 vs 52.0) in IL-1RN A2*A2 homozygous comparing to non-A2*A2 (p = 0.028). Our results indicated that IL-1RN A2 allele is associated with an increased susceptibility to cervical cancer development, probably by increasing predisposition to shorter immune responses. PMID:23053980

Sousa, Hugo; Santos, Alexandra M; Catarino, Raquel; Pinto, Daniela; Moutinho, José; Canedo, Paulo; Machado, José Carlos; Medeiros, Rui

2012-10-10

265

Genetic identification of multiple loci that control breast cancer susceptibility in the rat.  

PubMed Central

We have used a rat model of induced mammary carcinomas in an effort to identify breast cancer susceptibility genes. Using genetic crosses between the carcinoma-resistant Copenhagen (COP) and carcinoma-sensitive Wistar-Furth rats, we have confirmed the identification of the Mcs1 locus that modulates tumor number. We have now also identified two additional loci, Mcs2 and Mcs3. These three loci map to chromosomes 2, 7, and 1, respectively, and interact additively to suppress mammary carcinoma development in the COP strain. They are responsible for a major portion of the tumor-resistant phenotype of the COP rat. No loss of heterozygosity was observed surrounding the three loci. A fourth COP locus, Mcs4, has also been identified on chromosome 8 and acts in contrast to increase the number of carcinomas. These results show that mammary carcinoma susceptibility in the COP rat is a polygenic trait. Interestingly, a polymorphism in the human genomic region homologous to the rat Mcs4 region is associated with an increased breast cancer risk in African-American women. The isolation of the Mcs genes may help elucidate novel mechanisms of carcinogenesis, provide information important for human breast cancer risk estimation, and also provide unique drug discovery targets for breast cancer prevention.

Shepel, L A; Lan, H; Haag, J D; Brasic, G M; Gheen, M E; Simon, J S; Hoff, P; Newton, M A; Gould, M N

1998-01-01

266

Analysis of a p53 mutation associated with cancer susceptibility for biochemistry and genetic laboratory courses.  

PubMed

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 amplified, and the PCR products are digested with the BstUI enzyme to detect the 72 codon polymorphism. Polyacrylamide gel electrophoresis is used to resolve the PCR products, and the results are statistically analyzed in the context of human population genetics. Blood samples in FTA cards were also collected from 50 women to detect the mutation in a wide range of ages and assess its relationship to familial cancer susceptibility. This module enables students to use materials and methods that are routinely used by scientific researchers to analyze polymorphisms. Therefore, it can be used for laboratory exercises in traditional biochemistry curricula as well as in the growing field of genomic science and education. PMID:21567743

Soto-Cruz, Isabel; Legorreta-Herrera, Martha

2009-07-01

267

Genetic variants of the XRCC1 gene and susceptibility to esophageal cancer: a meta-analysis  

PubMed Central

To summarize published data on the role of common genetic variants of the X-ray repair cross-complementing group 1 (XRCC1) gene in susceptibility to esophageal cancer (EC), we performed a meta-analysis including 11 eligible publications with 3,306 patients and 6,852 controls for Arg399Gln and 832 patients and 1,418 controls for Arg194Trp. Overall, the variant Gln399 allele was not associated with EC risk, compared with the Arg399 allele in the populations included in the analysis. However, stratified analysis revealed that Gln399 allele was associated with an increased EC risk among Chinese populations in a recessive model (OR, 1.33; 95% CI 1.01–1.76; fixed effects) and by homozygote contrast (OR, 1.35; 95% CI 1.01–1.81), particularly for the tumor histology of squamous cell carcinoma (OR, 1.34; 95% CI 1.03–1.73 for the recessive model) and (OR, 1.34; 95% CI 1.02–1.76 for the homozygote contrast). There was no apparent effect of the Trp194 allele, compared to the Arg194 allele, on the EC risk in all analyses. These results suggest that the XRCC1 Arg399Gln polymorphism may be a potential biomarker of EC susceptibility in Chinese populations, particularly for squamous cell carcinoma. Further larger studies with multi-ethnic populations are required to further assess the association between XRCC1 polymorphisms and EC risk.

Yin, Ming; Tan, Dongfeng; Wei, Qingyi

2009-01-01

268

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

PubMed Central

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

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

2011-01-01

269

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

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.

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

2013-01-01

270

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis.  

PubMed

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

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

2013-10-09

271

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

PubMed

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

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

2013-01-04

272

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

PubMed

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. PMID:21291902

Mortensen, Holly M; Euling, Susan Y

2011-02-01

273

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

PubMed Central

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

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

2008-01-01

274

Genetic susceptibility to heroin addiction; a candidate-gene association study  

PubMed Central

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction, by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in non-coding regions of the genes encoding the mu (OPRM1; rs510769, rs3778151), kappa (OPRK1; rs6473797), and delta opioid receptors, (OPRD1; rs2236861, rs2236857 and rs3766951), the neuropeptide galanin (GAL; rs694066), the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multi-locus genotype patterns showed nominally significant associations (e.g. OPRM1; P = 0.0006 and CSNK1E; P = 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P = 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction that is worthy of future study.

Levran, O.; Londono, D.; O'Hara, K.; Nielsen, D. A.; Peles, E.; Rotrosen, J.; Casadonte, P.; Linzy, S.; Randesi, M.; Ott, J.; Adelson, M.; Kreek, M. J.

2010-01-01

275

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

PubMed

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:Cx43(f/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. This article is part of a Special Issue entitled Electrical Synapses. PMID:22771707

Iacobas, S; Iacobas, D A; Spray, D C; Scemes, E

2012-07-05

276

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

PubMed

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

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

2003-04-01

277

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

PubMed

The past decade has seen rapid advances in the identification of associations between candidate genes and a range of common multifactorial disorders. This paper evaluates public attitudes towards the complexity of genetic risk prediction in psychiatry involving susceptibility genes, uncertain penetrance and gene-environment interactions on which successful molecular-based mental health interventions will depend. A qualitative approach was taken to enable the exploration of the views of the public. Four structured focus groups were conducted with a total of 36 participants. The majority of participants indicated interest in having a genetic test for susceptibility to major depression, if it was available. Having a family history of mental illness was cited as a major reason. After discussion of perceived positive and negative implications of predictive genetic testing, nine of 24 participants initially interested in having such a test changed their mind. Fear of genetic discrimination and privacy issues predominantly influenced change of attitude. All participants still interested in having a predictive genetic test for risk for depression reported they would only do so through trusted medical professionals. Participants were unanimously against direct-to-consumer genetic testing marketed through the Internet, although some would consider it if there was suitable protection against discrimination. The study highlights the importance of general practitioner and public education about psychiatric genetics, and the availability of appropriate treatment and support services prior to implementation of future predictive genetic testing services. PMID:19690586

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

2010-01-01

278

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

PubMed Central

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

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

2003-01-01

279

Host Genetics in Granuloma Formation: HumanLike Lung Pathology in Mice with Reciprocal Genetic Susceptibility to M. tuberculosis and M. avium  

Microsoft Academic Search

Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I\\/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas

Elena Kondratieva; Nadya Logunova; Konstantin Majorov; Mikhail Averbakh; Alexander Apt; Olivier Neyrolles

2010-01-01

280

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

Microsoft Academic Search

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

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

2010-01-01

281

Selective Susceptibility to Inhibitors of GABA Synthesis and Antagonists of GABA A Receptor in Rats with Genetic Absence Epilepsy  

Microsoft Academic Search

Thalamocortical spike-and-wave discharges characterize the nonconvulsive absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS

Marguerite Vergnes; Any Boehrer; Sophie Reibel; Simone Simler; Christian Marescaux

2000-01-01

282

Bioenergetic and genetic parameters in relation to susceptibility of blue mussels, Mytilus edulis (L.) to summer mortality  

Microsoft Academic Search

Our study examined whether the differences in susceptibility to summer mass mortality of two stocks of mussels from the Magdalen Islands (Québec, Canada) are related to bioenergetic and\\/or genetic factors. The relative importance of maintenance and maximal metabolic rates, scope for growth (SFG) and the O:N ratio were followed over time to assess whether the increased incidence of mortality in

Réjean Tremblay; Bruno Myrand; Jean-Marie Sevigny; Pierre Blier; Helga Guderley

1998-01-01

283

Evaluation of Genetic Susceptibility Loci for Chronic Hepatitis B in Chinese: Two Independent Case-Control Studies  

PubMed Central

Background A recent genome-wide scan has identified two genetic variants in the HLA-DP region strongly associated with hepatitis B infection in Japanese. This study evaluates the effects of these risk variants in Chinese, where the HBV infection is the most popular in the world. Methods and Findings We have assessed the relationship between these two single nucleotide polymorphisms (rs3077 and rs9277535) and chronic hepatitis B infection in two independent case-control studies. The first population in Chinese Han included 736 patients and 782 spontaneously recovered controls. The second set was established in Chinese Zhuang minority of 177 patients and 208 controls. Both A alleles of rs3077 and rs9277535 significantly deceased the risk to CHB in Chinese Han (OR?=?0.540, 95%CI: 0.464–0.628, P?=?4.068×10?16 and OR?=?0.696, 95%CI: 0.601–0.806, P?=?1.062×10?6, respectively). Conceivably, rs9277535 was found to be associated with decreased risk of the disease in Chinese Zhuang, with an OR of 0.606 (95%CI, 0.441–0.833, P?=?0.002). Conclusion Chronic hepatitis B susceptibility loci in HLA-DP region (rs3077 and rs9277535) identified by genome-wide scan in Japanese population were validated in Chinese population. These findings might provide clues to develop screening and surveillance strategies.

Zhang, Wei; Zhu, Da-Hai; Wang, Ying; Li, Yan-Ping; Tian, Yao; Li, Rong-Cheng; Li, Zhuo; Zhu, Xinlin; Li, Jun-Hong; Cai, Jun; Liu, Li; Miao, Xiao-Ping; Liu, Ying; Li, Hui

2011-01-01

284

Telomere length homeostasis and telomere position effect on a linear human artificial chromosome are dictated by the genetic background  

PubMed Central

Telomere position effect (TPE) is the influence of telomeres on subtelomeric epigenetic marks and gene expression. Previous studies suggested that TPE depends on genetic background. As these analyses were performed on different chromosomes, cell types and species, it remains unclear whether TPE represents a chromosome—rather than genetic background-specific regulation. We describe the development of a Linear Human Artificial Chromosome (L-HAC) as a new tool for telomere studies. The L-HAC was generated through the Cre-loxP-mediated addition of telomere ends to an existing circular HAC (C-HAC). As it can be transferred to genetically distinct cell lines and animal models the L-HAC enables the study of TPE in an unprecedented manner. The HAC was relocated to four telomerase-positive cell lines via microcell-mediated chromosome transfer and subsequently to mice via blastocyst injection of L-HAC+-ES-cells. We could show consistent genetic background-dependent adaptation of telomere length and telomere-associated de novo subtelomeric DNA methylation in mouse ES-R1 cells as well as in mice. Expression of the subtelomeric neomycin gene was inversely correlated with telomere length and subtelomeric methylation. We thus provide a new tool for functional telomere studies and provide strong evidence that telomere length, subtelomeric chromatin marks and expression of subtelomeric genes are genetic background dependent.

Weuts, An; Voet, Thierry; Verbeeck, Jelle; Lambrechts, Nathalie; Wirix, Evelyne; Schoonjans, Luc; Danloy, Sophie; Marynen, Peter; Froyen, Guy

2012-01-01

285

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

Microsoft Academic Search

Background  Asthma and allergy represent complex phenotypes, which disproportionately burden ethnic minorities in the United States. Strong\\u000a evidence for genomic factors predisposing subjects to asthma\\/allergy is available. However, methods to utilize this information\\u000a to identify high risk groups are variable and replication of genetic associations in African Americans is warranted.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We evaluated 41 single nucleotide polymorphisms (SNP) and a deletion corresponding

Bonnie R Joubert; David M Reif; Stephen W Edwards; Kevin A Leiner; Edward E Hudgens; Peter Egeghy; Jane E Gallagher; Elaine Cohen Hubal

2011-01-01

286

An Enterobacter plasmid as a new genetic background for the transposon Tn1331  

PubMed Central

Background Genus Enterobacter includes important opportunistic nosocomial pathogens that could infect complex wounds. The presence of antibiotic resistance genes in these microorganisms represents a challenging clinical problem in the treatment of these wounds. In the authors’ screening of antibiotic-resistant bacteria from complex wounds, an Enterobacter species was isolated that harbors antibiotic-resistant plasmids conferring resistance to Escherichia coli. The aim of this study was to identify the resistance genes carried by one of these plasmids. Methods The plasmids from the Enterobacter isolate were propagated in E. coli and one of the plasmids, designated as pR23, was sequenced by the Sanger method using fluorescent dyeterminator chemistry on a genetic analyzer. The assembled sequence was annotated by search of the GenBank database. Results Plasmid pR23 is composed of the transposon Tn1331 and a backbone plasmid that is identical to the plasmid pPIGDM1 from Enterobacter agglomerans. The multidrug-resistance transposon Tn1331, which confers resistance to aminoglycoside and beta lactam antibiotics, has been previously isolated only from Klebsiella. The Enterobacter plasmid pPIGDM1, which carries a ColE1-like origin of replication and has no apparent selective marker, appears to provide a backbone for propagation of Tn1331 in Enterobacter. The recognition sequence of Tn1331 transposase for insertion into pPIGDM1 is the pentanucleotide TATTA, which occurs only once throughout the length of this plasmid. Conclusion Transposition of Tn1331 into the Enterobacter plasmid pPIGDM1 enables this transposon to propagate in this Enterobacter. Since Tn1331 was previously isolated only from Klebsiella, this report suggests horizontal transfer of this transposon between the two bacterial genera.

Alavi, Mohammad R; Antonic, Vlado; Ravizee, Adrien; Weina, Peter J; Izadjoo, Mina; Stojadinovic, Alexander

2011-01-01

287

Mutant genetic background affects the functional rearrangement and kinetic properties of JMJD2b histone demethylase.  

PubMed

We have studied JMJD2b histone demethylase, which antagonizes H3K9me3 in the pericentromeric heterochromatin. In cells with a deficiency in the histone methyltransferase SUV39h, the level of full-length JMJD2b (JMJD2b-GFP-1086) at chromocenters was reduced, corresponding to a global decrease in JMJD2b and H3K9me3. In wild-type fibroblasts, the chromatin of ribosomal genes, which is dense with H3K9 methylation, lacked JMJD2b-GFP-1086, while mutant and truncated forms of JMJD2b densely occupied the nucleolar compartment. This implies that the PHD Zn-fingers and Tudor domains, which were removed in truncated JMJD2b, are responsible for the aberrant JMJD2b function. Intriguingly, the JMJD2b-GFP-1086 level was significantly higher in tumor cell nucleoli. The kinetic properties of JMJD2b-GFP-1086 in the nucleoli and nucleoplasm of normal and tumor cells were similar; ?50% recovery of prebleached intensity was reached after <1 s. However, the mobile fraction of JMJD2b-GFP-1086 was increased in SUV39h-deficient cells. Similarly, the mobile fractions of mutant JMJD2b(1-424)H189A-GFP and truncated JMJD2b(1-424)GFP were greater than that measured for the full-length protein. We suggest that nucleoli are the site of an aberrant function of JMJD2b, the kinetic properties of which can be influenced by a mutant genetic background. PMID:21073875

Bártová, Eva; Stixová, Lenka; Galiová, Gabriela; Harni?arová Horáková, Andrea; Legartová, So?a; Kozubek, Stanislav

2010-11-10

288

Association of recurrent furunculosis with Panton-Valentine leukocidin and the genetic background of Staphylococcus aureus.  

PubMed

Staphylococcus aureus is a major cause of skin and soft tissue infections, such as furuncles, carbuncles, and abscesses, but it also frequently colonizes the human skin and mucosa without causing clinical symptoms. Panton-Valentine leukocidin (PVL) is a pore-forming toxin that has been associated with soft tissue infections and necrotizing pneumonia. We have compared the genotypes, virulence gene repertoires, and phage patterns of 74 furunculosis isolates with those of 108 control strains from healthy nasal carriers. The large majority of furunculosis strains were methicillin sensitive. Clonal cluster (CC) 121 (CC121) and CC22 accounted for 70% of the furunculosis strains but for only 8% of the nasal isolates. The PVL-encoding genes luk-PV were detected in 85% of furunculosis strains, while their prevalence among colonizing S. aureus strains was below 1%. luk-PV genes were distributed over several lineages (CCs 5, 8, 22, 30, and 121 and sequence type 59). Even within the same lineages, luk-PV-positive phages characterized furunculosis strains, while their luk-PV-negative variants were frequent among nasal strains. The very tight epidemiological linkage between luk-PV and furunculosis, which could be separated from the genetic background of the S. aureus strain as well as from the gene makeup of the luk-PV-transducing phage, lends support to the notion of an important role for PVL in human furunculosis. These results make a case for the determination of luk-PV in recurrent soft tissue infections with methicillin-sensitive as well as methicillin-resistant S. aureus. PMID:20200289

Masiuk, Helena; Kopron, Katarzyna; Grumann, Dorothee; Goerke, Christiane; Kolata, Julia; Jursa-Kulesza, Joanna; Giedrys-Kalemba, Stefania; Bröker, Barbara M; Holtfreter, Silva

2010-03-03

289

Association of Recurrent Furunculosis with Panton-Valentine Leukocidin and the Genetic Background of Staphylococcus aureus? †  

PubMed Central

Staphylococcus aureus is a major cause of skin and soft tissue infections, such as furuncles, carbuncles, and abscesses, but it also frequently colonizes the human skin and mucosa without causing clinical symptoms. Panton-Valentine leukocidin (PVL) is a pore-forming toxin that has been associated with soft tissue infections and necrotizing pneumonia. We have compared the genotypes, virulence gene repertoires, and phage patterns of 74 furunculosis isolates with those of 108 control strains from healthy nasal carriers. The large majority of furunculosis strains were methicillin sensitive. Clonal cluster (CC) 121 (CC121) and CC22 accounted for 70% of the furunculosis strains but for only 8% of the nasal isolates. The PVL-encoding genes luk-PV were detected in 85% of furunculosis strains, while their prevalence among colonizing S. aureus strains was below 1%. luk-PV genes were distributed over several lineages (CCs 5, 8, 22, 30, and 121 and sequence type 59). Even within the same lineages, luk-PV-positive phages characterized furunculosis strains, while their luk-PV-negative variants were frequent among nasal strains. The very tight epidemiological linkage between luk-PV and furunculosis, which could be separated from the genetic background of the S. aureus strain as well as from the gene makeup of the luk-PV-transducing phage, lends support to the notion of an important role for PVL in human furunculosis. These results make a case for the determination of luk-PV in recurrent soft tissue infections with methicillin-sensitive as well as methicillin-resistant S. aureus.

Masiuk, Helena; Kopron, Katarzyna; Grumann, Dorothee; Goerke, Christiane; Kolata, Julia; Jursa-Kulesza, Joanna; Giedrys-Kalemba, Stefania; Broker, Barbara M.; Holtfreter, Silva

2010-01-01

290

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

PubMed

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html). PMID:18349832

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

2008-03-18

291

Genetic Variability of the ?-Tubulin Genes in Benzimidazole-Susceptible and -Resistant Strains of Haemonchus Contortus  

PubMed Central

Benzimidazole anthelmintics are the most common chemotherapeutic agents used to remove intestinal helminths from farm animals. The development of drug resistance within helminth populations is wide-spread and can render these drugs essentially useless. The mechanism of benzimidazole resistance appears to be common to many species ranging from fungi to nematodes and involves alterations in the genes encoding ?-tubulin. During the selection process resulting in resistance, there must be quantitative changes in the population gene pool. Knowledge of these changes would indicate the mechanisms underlying the spread of resistance in the population, which in turn could be used to design more effective drug administration strategies. To this end we have identified allelic variation at two ?-tubulin genes in Haemonchus contortus using restriction map analysis of individual adults. Extremely high levels of variation were identified at both loci within a susceptible strain. In two independently derived benzimidazole resistant strains, allele frequencies at both loci were significantly different from the susceptible strain but not from each other. The same alleles at both loci, in both resistant strains, were favored by selection with benzimidazoles, suggesting that both loci are involved in determining benzimidazole resistance. These data confirm that changes in allele frequency, rather than novel genetic rearrangements induced by exposure to the drug, explain the changes associated with benzimidazole resistance. These results also show that any DNA based test for the development of benzimidazole resistance must take into account the frequency of alleles present in the population and not simply test for the presence or absence of specific allelic types.

Beech, R. N.; Prichard, R. K.; Scott, M. E.

1994-01-01

292

Genetic susceptibility of the donor kidney contributes to the development of renal damage after syngeneic transplantation.  

PubMed

Solitary kidneys, especially in rats, appear vulnerable to develop functional and structural damage. However, differences in susceptibility exist between strains. It is not clear whether this is intrinsic to the kidney or due to environmental factors. Therefore, the aim of the present study was to investigate possible differences in genetic susceptibility for renal damage. By transplanting different rat donor kidneys into a normotensive, histocompatible recipient, the kidneys were exposed to the same blood pressure profiles, metabolic and hormonal environment. Kidneys from young adult hypertensive fawn-hooded (FHH) rats, a strain showing early onset renal damage, normotensive, renal damage-resistant August x Copenhagen-Irish (ACI), and (ACI x FHH) F1 donors were transplanted into male F1 recipients. The native kidneys of the recipients were removed 1 week after transplantation. The results were mutually compared and to their unilaterally nephrectomized littermates. Systolic blood pressure (SBP) and albuminuria (UaV) were determined at the time of transplantation and at 8 and 16 weeks. The histomorphologic analysis included the incidence of focal glomerulosclerosis (FGS), and determination of chronic transplant dysfunction according to the BANFF criteria. A negative impact of the transplantation technique in this syngeneic situation could not be detected as F1 transplants did not differ functionally and morphologically from their UNx controls. Transplanting an ACI kidney did not result in significant changes of SBP, UaV, and incidence of FGS compared to F1 transplants and ACI-UNx. In contrast, FHH kidneys did show a progressive increase of UaV and glomerulosclerosis and a significantly higher BANFF score, whereas the SBP did not differ from F1 transplants. The moderate hypertension seen in FHH did not travel with the kidney. Compared to the FHH-UNx rats, transplantation of a FHH kidney did significantly attenuate the increase of UaV and FGS. The susceptibility of the donor kidney appears to be an important factor in the development of chronic renal damage. This may play a role in the long-term functional changes seen after clinical renal transplantation. PMID:10371370

Kouwenhoven, E A; van Dokkum, R P; Marquet, R L; Heemann, U W; de Bruin, R W; IJzermans, J N; Provoost, A P

1999-06-01

293

Influence of genetic susceptibility on the urinary excretion of 8-hydroxydeoxyguanosine of firefighters  

PubMed Central

OBJECTIVES—Oxidative DNA damage has been implicated in carcinogenesis. The DNA damage can be assessed from the urinary excretion of the DNA-repair product 8-hydroxydeoxyguanosine (8-OH-dG). The factors were investigated that influenced the excretion of urinary 8-OH-dG in 78 firefighters.?METHODS—53 Out of 78 firefighters were exposed to fire within 5 days of the study and 25 were not. 8-OH-dG was measured by ELISA and the distribution of the genotypes of CYP1A1, CYP2E1, GSTM1, and GSTT1 was measured by polymerase chain reaction.?RESULTS—The homozygous wild type frequencies of CYP1A1 MspI, CYP1A1 ile-val, CYP2E1, GSTM1, and GSTT1 were 31.5%, 56.2%, 60.3%, 50.7%, and 53.4%, respectively. The geometric mean of urinary 8-OH-dG was 14.1 ng/mg creatinine in more active firefighters and 12.3 ng/mg creatinine in non-exposed and less active subjects. Significantly increased concentrations of urinary 8-OH-dG were found to be associated with cigarette smoking, and 14% of the variation of 8-OH-dG was explained by cigarettes smoked per day. The CYP1A1 MspI, CYP1A1 ile-val, GSTM1, and GSTT1 genetic polymorphisms were not found to be significantly associated with the urinary excretion of 8-OH-dG. However, the subjects carrying the CYP2E1 mutant type excreted higher concentrations of 8-OH-dG and there was a marginally significant interaction of GSTT1 with firefighting activity. Multiple regression analysis confirmed that smoking was the strongest predictor of excretion of 8-OH-dG. Age, body mass index, and firefighting activity were not significant predictive factors for urinary 8-OH-dG.?CONCLUSION—Smoking and CYP2E1 gene polymorphism may be important factors in carcinogenesis and the GSTT1 positive genotype may be a genetic susceptibility factor in firefighters who are exposed regularly to various chemical carcinogens.???Keywords: firefighters; 8-hydroxydeoxyguanosine; susceptibility

Hong, Y.; Park, H.; Ha, E.

2000-01-01

294

The Physiological Effects of Deleting the Mouse Slc30a8 Gene Encoding Zinc Transporter-8 Are Influenced by Gender and Genetic Background  

PubMed Central

Objective The SLC30A8 gene encodes the islet-specific transporter ZnT-8, which is hypothesized to provide zinc for insulin-crystal formation. A polymorphic variant in SLC30A8 is associated with altered susceptibility to type 2 diabetes. Several groups have examined the effect of global Slc30a8 gene deletion but the results have been highly variable, perhaps due to the mixed 129SvEv/C57BL/6J genetic background of the mice studied. We therefore sought to remove the conflicting effect of 129SvEv-specific modifier genes. Methods The impact of Slc30a8 deletion was examined in the context of the pure C57BL/6J genetic background. Results Male C57BL/6J Slc30a8 knockout (KO) mice had normal fasting insulin levels and no change in glucose-stimulated insulin secretion (GSIS) from isolated islets in marked contrast to the ?50% and ?35% decrease, respectively, in both parameters observed in male mixed genetic background Slc30a8 KO mice. This observation suggests that 129SvEv-specific modifier genes modulate the impact of Slc30a8 deletion. In contrast, female C57BL/6J Slc30a8 KO mice had reduced (?20%) fasting insulin levels, though this was not associated with a change in fasting blood glucose (FBG), or GSIS from isolated islets. This observation indicates that gender also modulates the impact of Slc30a8 deletion, though the physiological explanation as to why impaired insulin secretion is not accompanied by elevated FBG is unclear. Neither male nor female C57BL/6J Slc30a8 KO mice showed impaired glucose tolerance. Conclusions Our data suggest that, despite a marked reduction in islet zinc content, the absence of ZnT-8 does not have a substantial impact on mouse physiology.

Pound, Lynley D.; Sarkar, Suparna A.; Ustione, Alessandro; Dadi, Prasanna K.; Shadoan, Melanie K.; Lee, Catherine E.; Walters, Jay A.; Shiota, Masakazu; McGuinness, Owen P.; Jacobson, David A.; Piston, David W.; Hutton, John C.; Powell, David R.; O'Brien, Richard M.

2012-01-01

295

Participation in Breast Cancer Genetic Counseling: The Influence of Educational Level, Ethnic Background, and Risk Perception  

Microsoft Academic Search

Genetic counseling has been suggested as a means of providing information and support to women with a family history of breast cancer. Yet women who undergo cancer genetic counseling in the United States generally consist of only a subset of those at risk, namely well-educated, upper-middle class, European American and Jewish women. We report outcomes from a study that provided

Julie Culver; Wylie Burke; Yutaka Yasui; Sharon Durfy

2001-01-01

296

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

PubMed Central

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.

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

1998-01-01

297

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

PubMed

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

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

2011-06-24

298

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

PubMed Central

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.

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

299

Trait Components Provide Tools to Dissect the Genetic Susceptibility of Migraine  

PubMed Central

The commonly used “end diagnosis” phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components—individual clinical symptoms of migraine—to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.

Anttila, V.; Kallela, M.; Oswell, G.; Kaunisto, M. A.; Nyholt, D. R.; Hamalainen, E.; Havanka, H.; Ilmavirta, M.; Terwilliger, J.; Sobel, E.; Peltonen, L.; Kaprio, J.; Farkkila, M.; Wessman, M.; Palotie, A.

2006-01-01

300

[Genetic consequences of an increased radiation background at mouse-like rodents].  

PubMed

The frequency of genetic disturbances in germ-line and in somatic cells was studied in animals caught in radionuclide-cotaminated areas within the 30-km Chernobyl NPP zone as well as in model experiments in laboratory mice exposed to chronic external gamma-radiation or to the internal action of incorporated radionuclides (131I, 137Cs, 238Pu). The results of genetic and of cytologic analysis of germ-line and somatic cells in the caught or exposed house mice and in laboratory mice after incorporation of radionuclides are presented. An estimation of relative genetic efficiency of the most harmful radionuclides was made. PMID:16869159

Pomerantseva, M D; Rama?ia, L K; Rubanovich, A V; Shevchenko, V A

301

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

PubMed

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

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

2010-11-04

302

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

PubMed Central

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.

Villanueva, Pia; Newbury, Dianne F; Jara, Lilian; De Barbieri, Zulema; Mirza, Ghazala; Palomino, Hernan M; Fernandez, Maria Angelica; Cazier, Jean-Baptiste; Monaco, Anthony P; Palomino, Hernan

2011-01-01

303

Association between N142D genetic polymorphism of GSTO2 and susceptibility to colorectal cancer.  

PubMed

Expression pattern analysis has been revealed that glutathione S-transferase omega 2 (GSTO2, a member of class omega) is ubiquitously expressed. Over expression of GSTO2 induced apoptosis. The gene encoding GSTO2 was localized to human chromosome 10q24.3, a region that may harbor gene(s) involved in the developing of colorectal cancer. To investigate the association between GSTO2 N142D genetic polymorphism and susceptibility to colorectal cancer the present study was done. We studied 63 (26 females, 37 males) colorectal cancer patients and 126 (52 females, 74 males) healthy individuals. The control subjects were frequency matched for age and gender with the colorectal cancer group. The genotypes were performed using RFLP-PCR method. The ND and DD genotypes were not associated with risk of colorectal cancer, in comparison with the NN genotype. Family history for cancer in the first degree of relatives significantly differed between cases and controls (P = 0.012). The profiles of GSTO2 genotypes and family history in control and cancerous groups were compared to each other. Subjects with NN genotype and positive family history significantly were at high risk to develop colorectal cancer in comparison with subjects with DD or ND genotypes and negative family history (P = 0.003). Present findings indicating that GSTO2 NN genotype increase the risk of colorectal cancer in persons with positive family history for cancer in the first degree relatives. PMID:21113667

Masoudi, Mohammad; Saadat, Iraj; Omidvari, Shahpour; Saadat, Mostafa

2010-11-27

304

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

PubMed

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

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

2009-03-06

305

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

PubMed Central

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.

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

2010-01-01

306

The conditional nature of genetic interactions: the consequences of wild-type backgrounds on mutational interactions in a genome-wide modifier screen.  

PubMed

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 sd(E3) allele in two wild-type genetic backgrounds using molecularly defined deletions. We demonstrate that ~74% of all modifiers of the sd(E3) 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

Chari, Sudarshan; Dworkin, Ian

2013-08-01

307

Original Article Genetic variants of the XRCC1 gene and susceptibility to esophageal cancer: a meta-analysis  

Microsoft Academic Search

To summarize published data on the role of common genetic variants of the X-ray repair cross- complementing group 1 (XRCC1) gene in susceptibility to esophageal cancer (EC), we performed a meta-analysis including 11 eligible publications with 3,306 patients and 6,852 controls for Arg399Gln and 832 patients and 1,418 controls for Arg194Trp. Overall, the variant Gln399 allele was not associated with

Ming Yin; Dongfeng Tan; Qingyi Wei

2009-01-01

308

Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease  

Microsoft Academic Search

Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to com- mon disease1-4, but are plagued by the impression that they are not consistently reproducible5,6. In principle, the inconsis- tency may be due to false positive studies, false negative stud- ies or true variability in association among different populations4-8. The critical question is whether false

Kirk E. Lohmueller; Celeste L. Pearce; Malcolm Pike; Eric S. Lander; Joel N. Hirschhorn

2003-01-01

309

A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22  

PubMed Central

Background: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22–31, 3q21–24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22–31, and EPHB1 and MRAS in 3q21–q24. Methods: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22–31 and 3q21–q24. Results: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. Conclusions: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.

Abuli, A; Fernandez-Rozadilla, C; Giraldez, M D; Munoz, J; Gonzalo, V; Bessa, X; Bujanda, L; Rene, J M; Lanas, A; Garcia, A M; Salo, J; Arguello, L; Vilella, A; Carreno, R; Jover, R; Xicola, R M; Llor, X; Carvajal-Carmona, L; Tomlinson, I P M; Kerr, D J; Houlston, R S; Pique, J M; Carracedo, A; Castells, A; Andreu, M; Ruiz-Ponte, C; Castellvi-Bel, S

2011-01-01

310

Genetic association and gene expression analysis of TGFB1 contributes towards the susceptibility to otosclerosis.  

PubMed

Otosclerosis (OTSC) is a common form of acquired hearing loss due to disturbed bone remodeling in the otic capsule of the middle ear. It has been known the transforming growth factor-beta1 (TGFB1) produced by osteoblast is the most abundant growth factor in human bone. Previous studies have shown the contribution of single nucleotide polymorphisms (SNPs) in TGFB1 towards the risk of developing otosclerosis in some ethnic populations. The present study was aimed to investigate the genetic association and expression profiles of the TGFB1 in otosclerosis patients. Two SNPs (c.-800G?>?A, c.-509C?>?T) in the promoter region and three SNPs (c.29T?>?C, c.74G?>?C and c.788C?>?T) in the coding region were genotyped in 170 cases and 170 controls. The genetic association analysis revealed the significant association between c.-509C?>?T (P?=?0.0067, OR?=?1.562, 95% CI?=?1.140-2.139) and otosclerosis. The increased minor allele 'T' frequency in cases (0.42) compared to controls (0.31) indicates its possible role in etiology of the disease. The minor allele frequencies for the SNPs c.-800G?>?A, c.29T?>?C, c.74G?>?C were similar among the cases (0.04, 0.47, 0.08) and controls (0.05, 0.42, 0.07). We found c.788C?>?T was monomorphic in this population. Interestingly, a 4 locus haplotype (G-T-T-G) from these SNPs was found to be significantly associated with OTSC (P?=?0.0077). We identified a de novo heterozygous mutation c.-832G?>?A in the promoter region of TGFB1 in one patient. In secondary analysis, we investigated the possibility of abnormal TGFB1 expression and irregular bone growth in otosclerosis by expression analysis of TGFB1 mRNA in disease tissue compared to control. We found relatively increased expression of TGFB1 mRNA in the stapes tissues of cases compared to controls (P?=?0.0057). In conclusion, this study identified a risk variant c.-509C?>?T and a risk haplotype G-T-T-G in the TGFB1 gene which contribute towards the susceptibility to otosclerosis. PMID:23703862

Priyadarshi, Saurabh; Ray, Chinmay Sundar; Panda, Khirod Chandra; Desai, Ashim; Nayak, Soumya Ranjan; Biswal, Narayan Chandra; Ramchander, Puppala Venkat

2013-05-23

311

Arsenic metabolism, genetic susceptibility, and risk of premalignant skin lesions in Bangladesh.  

PubMed

We conducted a case-control study to investigate interindividual variability in susceptibility to health effects of inorganic arsenic due to arsenic metabolism efficiency, genetic factors, and their interaction. A total of 594 cases of arsenic-induced skin lesions and 1,041 controls was selected from baseline participants in a large prospective cohort study in Bangladesh. Adjusted odds ratios (OR) for skin lesions were estimated in relation to the polymorphisms in the glutathione S-transferase omega1 and methylenetetrahydrofolate reductase genes, the percentage of monomethylarsonous acid (%MMA) and dimethylarsinic acid (%DMA) in urine, and the ratios of MMA to inorganic arsenic and DMA to MMA. Water arsenic concentration was positively associated with %MMA and inversely associated with %DMA. The dose-response relationship of risk of skin lesion with %MMA was more apparent than those with other methylation indices; the ORs for skin lesions in relation to increasing %MMA quartiles were 1.00 (reference), 1.33 [95% confidence interval (95% CI), 0.92-1.93], 1.68 (95% CI, 1.17-2.42), and 1.57 (95% CI, 1.10-2.26; P for trend = 0.01). The ORs for skin lesions in relation to the methylenetetrahydrofolate reductase 677TT/1298AA and 677CT/1298AA diplotypes (compared with 677CC/1298CC diplotype) were 1.66 (95% CI, 1.00-2.77) and 1.77 (95% CI, 0.61-5.14), respectively. The OR for skin lesions in relation to the glutathione S-transferase omega1 diplotype containing all at-risk alleles was 3.91 (95% CI, 1.03-14.79). Analysis of joint effects of genotypes/diplotypes with water arsenic concentration and urinary %MMA suggests additivity of these factors. The findings suggest that arsenic metabolism, particularly the conversion of MMA to DMA, may be saturable and that differences in urinary arsenic metabolites, genetic factors related to arsenic metabolism, and their joint distributions modulate arsenic toxicity. PMID:17548696

Ahsan, Habibul; Chen, Yu; Kibriya, Muhammad G; Slavkovich, Vesna; Parvez, Faruque; Jasmine, Farzana; Gamble, Mary V; Graziano, Joseph H

2007-06-01

312

Genetic variants in inflammation pathway genes and asthma in glioma susceptibility  

PubMed Central

Single nucleotide polymorphisms (SNPs) in inflammation-related genes have previously been shown to alter risks of developing various cancers. However, the effects of such SNPs on glioma risk remain unclear. We used a multistrategic approach to elucidate the relationship between glioma risk, asthma/allergies, and 23 literature-based functional SNPs in 11 inflammation genes. Genotyping was conducted on 373 histologically confirmed adult glioma patients and 365 cancer-free controls from the Harris County Brain Tumor Study. Deviations from the Hardy–Weinberg equilibrium were assessed using the ?2-test, and Akaike's information criterion was used to determine the best genetic model for each SNP. Odds ratios (ORs) were calculated both for each SNP individually and for grouped analyses, examining the effects of the numbers of adverse alleles on glioma risk in participants with and without asthma. In the single-locus analysis of the 23 examined SNPs, 1 pro-inflammatory and 2 anti-inflammatory gene SNPs were significantly associated with glioma risk (COX2/PTGS2, rs20417 [OR = 1.41]; IL10, rs1800896 [OR = 1.57]; and IL13, rs20541 [OR = 0.39], respectively). When we examined the joint effects of the risk-conferring alleles of these 3 SNPs, we found a significant trend indicating that the risk increases as the number of adverse alleles increase (P = .005). Stratifying by asthma status, we found that this dose–response-like trend of increasing risk is only present among those without asthma/allergies (P < .0001). Our study indicates that polymorphisms in inflammation genes are associated with glioma susceptibility, especially when a history of asthma/allergies is absent.

Amirian, E.; Liu, Yanhong; Scheurer, Michael E.; El-Zein, Randa; Gilbert, Mark R.; Bondy, Melissa L.

2010-01-01

313

Phosphodiesterase 11A (PDE11A) Genetic Variants May Increase Susceptibility to Prostatic Cancer  

PubMed Central

Context: Among the genomic loci harboring potential candidate genes for prostatic cancer (PCa) is the 2q31-33 chromosomal region that harbors the gene encoding phosphodiesterase 11A (PDE11A). In addition, the combined cancer genome expression metaanalysis datasets included PDE11A among the top 1% down-regulated genes in PCa. Objective: In the present study, we screened 50 unrelated PCa patients of Brazilian descent for PDE11A coding defects. Design: The study consisted of PDE11A sequencing, in vitro functional assays, and immunostaining analysis. Results: We identified eight different sequence alterations in 15 patients (30%): one stop-codon and seven missense mutations. Three of the variants (R202C, Y658C, and E840K) were novel, and the remaining five (Y727C, R804H, R867G, M878V, and R307X) have been associated with predisposition to adrenal or testicular tumors. The overall prevalence of PDE11A-inactivating sequence variants among PCa patients was significantly higher than in 287 healthy controls (0.16 vs. 0.051, respectively, P < 0.001, odds ratio 3.81, 95% confidence interval 1.86–7.81) and the R202C, Y658C, and E840K substitutions were not found in controls. All missense mutations led to decreased PDE11A activity in human embryonic kidney 293 and PC3M cells and immunostaining of PCa samples with sequence changes showed decreased PDE11A protein expression. Conclusion: Our data suggest that, like in the adrenal cortex and the testicular germ cells, PDE11A-inactivating genetic alterations may play a role in susceptibility to PCa.

Faucz, Fabio Rueda; Horvath, Anelia; Rothenbuhler, Anya; Almeida, Madson Q.; Libe, Rossella; Raffin-Sanson, Marie-Laure; Bertherat, Jerome; Carraro, Dirce Maria; Soares, Fernando Augusto; de Campos Molina, Gustavo; Campos, Antonio H.; Alexandre, Rodrigo B.; Bendhack, Marcelo Luiz; Nesterova, Maria; Stratakis, Constantine A.

2011-01-01

314

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

PubMed Central

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.

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

315

Recent Advances in the Characterization of Genetic Factors Involved in Human Susceptibility to Infection by Schistosomiasis  

PubMed Central

Human resistance to infection by schistosomes is associated to a strong Th2 immune. However a persistent Th2 response can cause severe kidney and liver disease in human. In this review, we mainly focused on the control of infection levels caused by schistosomes. Several experimental models allowed us to better understand the immunological mechanisms of the host against schistosome infection. High IgE and eosinophil levels are associated with resistance to infection by schistosomes and this effect is counterbalanced by IgG4. IgE and eosinophils are highly dependent on IL-4, IL-13, and Il-5, which are three main Th2 cytokines. We also examined the genetic factors involved in human susceptibility to infection by schistosomiasis. Infection levels are mainly regulated by a major locus SM1, in 5q31-q33 region, which contains the genes encoding for the IL-4, IL-13, and Il-5 cytokines. An association between an IL13 polymorphism, rs1800925, and infection levels has been shown. This polymorphism synergistically acts with another polymorphism (rs324013) in the STAT6 gene, encoding for the signal transducer of the IL13 pathway. This pathway has also been involved in atopic disorders. As helminthiasis, atopy is the result of aberrant Th2 cytokine response to allergens, with an increased production of IL-4, IL-13, Il-9 and Il-5, with high amounts of allergen-specific and total IgE and eosinophilia. However, the Th2 immune response is protective in helminthiasis but aggravating in atopic disorders. Several studies reported interplay between helminthic infections and allergic reactions. The different results are discussed here.

Isnard, Amandine; Chevillard, Christophe

2008-01-01

316

The Historical/Philosophical Background of Education in Human Genetics in the United States  

ERIC Educational Resources Information Center

The purpose of this paper is to isolate the historical and philosophical treatment of genetics in school and college curricula. To do this, a qualitative analysis was made of 128 biology textbooks or textbook series published between the years 1907 and 1977. The results of this study are reported. (Author/MA)

Hurd, Paul DeHart

1978-01-01

317

Role of Repeated Lung Injury and Genetic Background in Bleomycin-induced Fibrosis  

Microsoft Academic Search

Current hypotheses of the pathogenesis of many forms of pul- monary fibrosis suggest that (i ) a stimulus results in repeated or prolonged episodes of lung injury, and (ii) genetic factors modulate the outcome of the injury. The commonly employed single-exposure bleomycin model results in only temporary fi- brosis. Therefore, we evaluated whether repeated bleomycin exposures, in the setting of

Man Pyo Chung; Martha M. Monick; Nabeel Y. Hamzeh; Noah S. Butler; Linda S. Powers; Gary W. Hunninghake

2003-01-01

318

Moroccan mitochondrial genetic background suggests prehistoric human migrations across the Gibraltar Strait  

Microsoft Academic Search

Migrations into Africa from the Levant have greatly determined the mitochondrial genetic landscape of North Africa. After analyzing samples from North Morocco to Spain, we show that three fourths of the Moroccan individuals belong to Western Eurasian haplogroups and the frequencies of these are much more similar to those of the Iberian Peninsula than to those of the Middle East.

Taha Rhouda; Diana Martínez-Redondo; Aurora Gómez-Durán; Noureddine Elmtili; Mouhamed Idaomar; Carmen Díez-Sánchez; Julio Montoya; Manuel José López-Pérez; Eduardo Ruiz-Pesini

2009-01-01

319

Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in Staphylococcus aureus  

Microsoft Academic Search

Daptomycin is a lipopeptide antibiotic with potent activity against gram-positive bacteria. Complete-genome comparisons of laboratory-derived Staphylococcus aureus with decreased susceptibility to daptomycin and their susceptible parent were used to identify genes that contribute to reduced susceptibility to daptomycin. Selective pressure of growth in sublethal concentrations of daptomycin resulted in the accumulation of mutations over time correlating with incremental decreases in

Lisa Friedman; Jeff D. Alder; Jared A. Silverman

2006-01-01

320

Genetic variation in nucleotide excision repair pathway genes influence prostate and bladder cancer susceptibility in North Indian population  

PubMed Central

BACKGROUND: Inherited polymorphisms of XPD and XPC genes may contribute to subtle variations in NER DNA repair capacity and genetic susceptibility to development of urological cancer such as prostate and bladder cancer. MATERIALS AND METHODS: We genotyped four Single Nucleotide Polymorphs (SNPs) of the DNA repair gene XPD and XPC in 195 prostate cancer (PCa) and 212 bladder cancer (BC) patients and 250 healthy controls from the same area. XPD Exon 10 (G>A) by amplification refractory mutation system and Exon 23 (A>C), XPC Intron 9 (Ins/Del) and Exon 15 (A>C) were genotyped by PCR-RFLP. RESULTS: Variant genotype of XPC demonstrated association with PCa as well as in BC (P, 0.013; P, 0.003). Combined genotype (GA+AA) revealed association with PCa and in BC (P, 0.012, P, 0.002). Variant allele also demonstrated risk in both the cancer. Diplotype of XPD and XPC was associated with a significant increase in PCa and BC risk. Variant (+/+) genotype of XPC intron 9 shown increased risk with PCa and in BC (P, 0.012; P, 0.032). CC genotype of XPC exon 15 revealed increase risk (P, 0.047) with PCa not in BC. In clinopathological grade variant allele of XPC intron 9 and 15 demonstrated risk with high grade of tumor and bone metastasis of PCa. In BC variant allele of XPD exon 10 and 15 also shown association with tumor grade. XPC intron 9 influences the risk of BC in former tobacco users in BC. CONCLUSIONS: Our result support that SNPs in XPD and XPC gene may reduce NER repair capacity and play a major role for PCa and BC in North India.

Mittal, Rama D.; Mandal, Raju K.

2012-01-01

321

COMMON HUMAN GENETIC VARIANTS AND HIV-1 SUSCEPTIBILITY: A GENOME-WIDE SURVEY IN A HOMOGENEOUS AFRICAN POPULATION  

PubMed Central

To date, CCR5 variants remain the only human genetic factors to be confirmed to impact HIV-1 acquisition. However, protective CCR5 variants are largely absent in African populations, in which sporadic resistance to HIV-1 infection is still unexplained. Here we perform a genome-wide association study (GWAS) in a population of 1,532 individuals from Malawi, a country with high prevalence of HIV-1 infection, to investigate whether common genetic variants associate with HIV-1 susceptibility in Africans. Using single nucleotide polymorphisms (SNPs) present on the genome-wide chip, we also investigated previously reported associations with HIV-1 susceptibility or acquisition. Recruitment was coordinated by the Center for HIV/AIDS Vaccine Immunology at two sexually transmitted infection clinics. HIV status was determined by HIV rapid tests and nucleic acid testing. After quality control, the population consisted of 848 high-risk seronegative and 531 HIV-1 seropositive individuals. Logistic regression testing in an additive genetic model was performed for SNPs that passed quality control. No single SNP yielded a significant P-value after correction for multiple testing. The study was sufficiently powered to detect markers with genotype relative risk ? 2.0 and minor allele frequencies ?12%. This is the first GWAS of host determinants of HIV-1 susceptibility, performed in an African population. The absence of any significant association can have many possible explanations: rarer genetic variants or common variants with weaker effect could be responsible for the resistance phenotype; alternatively, resistance to HIV-1 infection might be due to non-genetic parameters or to complex interactions between genes, immunity and environment.

PETROVSKI, Slave; FELLAY, Jacques; SHIANNA, Kevin V.; CARPENETTI, Nicole; KUMWENDA, Johnstone; KAMANGA, Gift; KAMWENDO, Deborah D.; LETVIN, Norman L.; McMICHAEL, Andrew J.; HAYNES, Barton F.; COHEN, Myron S.; GOLDSTEIN, David B.

2011-01-01

322

Chromosome number doubling of 2x potato lines with diverse genetic background through tissue culture  

Microsoft Academic Search

Summary  Twelve 2x potato clones of diverse genetic origin were tested for doubling of their chromosome number by placing stem and\\u000a petiole segments in the regeneration medium (Hermsen et al., 1981). Eleven of the 12 clones yielded doubled plants (2n=4x=48).\\u000a The percentages of regenerated tetraploid plants varied from 0 to 77% among the genotypes tested. The high rates of successful\\u000a doubling

A. Sonnino; M. Iwanaga; A. henostroza

1988-01-01

323

Basal and induced micronucleus frequencies in human lymphocytes with different GST and NAT2 genetic backgrounds  

Microsoft Academic Search

Basal and induced frequencies of genetic damage can be modulated by different host factors, including genes involved in phase II metabolism. Since polymorphic variants in the glutathione S-transferase (GST) and N-acetyl transferase (NAT) genes have been associated with cancer risk, we explored the possible links between GSTM1, GSTP1, GSTT1 and NAT2 variants and the frequency of micronuclei (MN) in human

Alba Hernández; Noel Xamena; Sara Gutiérrez; Antonia Velázquez; Amadeu Creus; Jordi Surrallés; Pere Galofré; Ricardo Marcos

2006-01-01

324

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

Microsoft Academic Search

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

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

2001-01-01

325

Locomotor Activity in D2 Dopamine Receptor-Deficient Mice Is Determined by Gene Dosage, Genetic Background, and Developmental Adaptations  

Microsoft Academic Search

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (Flint et al., 1995). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129\\/Sv 3 C57BL\\/6) D2 dopamine receptor (D2R)- deficient mice by gene targeting and investigated the contribu- tion of genetic background to open-field activity and rotarod performance. Horizontal activity

Michele A. Kelly; Marcelo Rubinstein; Tamara J. Phillips; Christina N. Lessov; Sue Burkhart-Kasch; Ge Zhang; James R. Bunzow; Yuan Fang; Gregory A. Gerhardt; David K. Grandy; Malcolm J. Low

1998-01-01

326

Genetic Susceptible Locus in NOTCH2 Interacts with Arsenic in Drinking Water on Risk of Type 2 Diabetes  

PubMed Central

Background Chronic exposure to arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM) but the underlying molecular mechanism remains unclear. Objectives This study evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes associated with diabetes and arsenic exposure in drinking water on the risk of developing T2DM. Methods In 2009–2011, we conducted a follow up study of 957 Bangladeshi adults who participated in a case-control study of arsenic-induced skin lesions in 2001–2003. Logistic regression models were used to evaluate the association between 38 SNPs in 18 genes and risk of T2DM measured at follow up. T2DM was defined as having a blood hemoglobin A1C level greater than or equal to 6.5% at follow-up. Arsenic exposure was characterized by drinking water samples collected from participants' tubewells. False discovery rates were applied in the analysis to control for multiple comparisons. Results Median arsenic levels in 2001–2003 were higher among diabetic participants compared with non-diabetic ones (71.6 µg/L vs. 12.5 µg/L, p-value <0.001). Three SNPs in ADAMTS9 were nominally associated with increased risk of T2DM (rs17070905, Odds Ratio (OR) ?=?2.30, 95% confidence interval (CI) 1.17–4.50; rs17070967, OR?=?2.02, 95%CI 1.00–4.06; rs6766801, OR?=?2.33, 95%CI 1.18–4.60), but these associations did not reach the statistical significance after adjusting for multiple comparisons. A significant interaction between arsenic and NOTCH2 (rs699780) was observed which significantly increased the risk of T2DM (p for interaction?=?0.003; q-value?=?0.021). Further restricted analysis among participants exposed to water arsenic of less than 148 µg/L showed consistent results for interaction between the NOTCH2 variant and arsenic exposure on T2DM (p for interaction ?=?0.048; q-value?=?0.004). Conclusions These findings suggest that genetic variation in NOTCH2 increased susceptibility to T2DM among people exposed to inorganic arsenic. Additionally, genetic variants in ADAMTS9 may increase the risk of T2DM.

Pan, Wen-Chi; Kile, Molly L.; Seow, Wei Jie; Lin, Xihong; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Mostofa, Golam; Lu, Quan; Christiani, David C.

2013-01-01

327

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

Microsoft Academic Search

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

Peter Demant; Marie Lipoldová

2006-01-01

328

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

PubMed Central

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

2011-01-01

329

Refinement of the background genetic map of Xq26-q27 and gene localisation for Boerjeson-Forssman-Lehmann syndrome  

SciTech Connect

A detailed map of genetic markers was constructed around the gene for the X-linked mental retardation syndrome of Borjeson-Forssman-Lehmann (BFLS). A multipoint linkage map of framework markers across Xq26-27, based on CEPH families, was integrated with the physical map, based on a YAC contig, to confirm marker order. The remaining genetic markers, which could not be ordered by linkage, were added to create the comprehensive genetic background map, in the order determined by physical mapping, to determine genetic distances between adjacent markers. This background genetic map is applicable to the refinement of the regional localization for any disease gene mapping to this region. The BFLS gene was localized using this background map in an extended version of the family described by Turner et al. The regional localization for BFLS extends between recombination events at DXS425 and DXS105, an interval of 24.6 cM on the background genetic map. The phenotypic findings commonly seen in the feet of affected males and obligate carrier females may represent a useful clinical indicator of carrier status in potential female carriers in the family. Recombination between DXS425 and DXS105 in a female with such characteristic feet suggests that the distal limit of the regional localization for the BFLS gene might reasonably be reduced to DXS294 for the purpose of selecting candidate genes, reducing the interval for the BFLS gene to 15.5 cM. Positional candidate genes from the interval between DXS425 and DXS105 include the SOX3 gene, mapped between DXS51(52A) and DXS98(4D-8). SOX3 may have a role in regulating the development of the nervous system. The HMG-box region of this single exon gene was examined by PCR for a deletion and then sequenced. No deviation from normal was observed, excluding mutations in the conserved HMG-box region as the cause of BFLS in this family. 27 refs., 1 fig., 2 tabs.

Gedeon, A.K.; Kozman, H.M.; Mulley, J.C. [Univ. of Adelaide (Australia)] [and others

1996-07-12

330

Genetic susceptibility to obesity and diet intakes: association and interaction analyses in the Malmö Diet and Cancer Study.  

PubMed

Gene-environment interactions need to be studied to better understand the obesity. We aimed at determining whether genetic susceptibility to obesity associates with diet intake levels and whether diet intakes modify the genetic susceptibility. In 29,480 subjects of the population-based Malmö Diet and Cancer Study (MDCS), we first assessed association between 16 genome-wide association studies identified obesity-related single-nucleotide polymorphisms (SNPs) with body mass index (BMI) and associated traits. We then conducted association analyses between a genetic risk score (GRS) comprising of 13 replicated SNPs and the individual SNPs, and relative dietary intakes of fat, carbohydrates, protein, fiber and total energy intake, as well as interaction analyses on BMI and associated traits among 26,107 nondiabetic MDCS participants. GRS associated strongly with increased BMI (P = 3.6 × 10(-34)), fat mass (P = 6.3 × 10(-28)) and fat-free mass (P = 1.3 × 10(-24)). Higher GRS associated with lower total energy intake (P = 0.001) and higher intake of fiber (P = 2.3 × 10(-4)). No significant interactions were observed between GRS and the studied dietary intakes on BMI or related traits. Of the individual SNPs, after correcting for multiple comparisons, NEGR1 rs2815752 associated with diet intakes and BDNF rs4923461 showed interaction with protein intake on BMI. In conclusion, our study does not provide evidence for a major role for macronutrient-, fiber- or total energy intake levels in modifying genetic susceptibility to obesity measured as GRS. However, our data suggest that the number of risk alleles as well as some of the individual obesity loci may have a role in regulation of food and energy intake and that some individual loci may interact with diet. PMID:23861046

Rukh, Gull; Sonestedt, Emily; Melander, Olle; Hedblad, Bo; Wirfält, Elisabet; Ericson, Ulrika; Orho-Melander, Marju

2013-07-17

331

Moroccan mitochondrial genetic background suggests prehistoric human migrations across the Gibraltar Strait.  

PubMed

Migrations into Africa from the Levant have greatly determined the mitochondrial genetic landscape of North Africa. After analyzing samples from North Morocco to Spain, we show that three fourths of the Moroccan individuals belong to Western Eurasian haplogroups and the frequencies of these are much more similar to those of the Iberian Peninsula than to those of the Middle East. This is particularly true for the mitochondrial haplogroups H1, H3 and V, which experienced a late-glacial expansion from this region, that repopulated much of Central and Northern Europe. Iberian Peninsula was also a source for prehistoric migrations to North Africa. PMID:19631765

Rhouda, Taha; Martínez-Redondo, Diana; Gómez-Durán, Aurora; Elmtili, Noureddine; Idaomar, Mouhamed; Díez-Sánchez, Carmen; Montoya, Julio; López-Pérez, Manuel José; Ruiz-Pesini, Eduardo

2009-07-23

332

Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large Scale Evaluation of Genetic Variants  

PubMed Central

Background This study was aimed to identify novel susceptibility variants for second primary tumor (SPT) or recurrence in curatively treated early stage head and neck squamous cell carcinoma (HNSCC) patients. Methods We constructed a custom chip containing a comprehensive panel of 9645 chromosomal and mitochondrial single nucleotide polymorphisms (SNPs) representing 998 cancer-related genes selected by a systematic prioritization schema. Using this chip, we genotyped 150 early-stage HNSCC patients with and 300 matched patients without SPT/recurrence from a prospectively conducted randomized trial and assessed the association of these SNPs with risk of SPT/recurrence. Results Individually, six chromosomal SNPs and seven mitochondrial SNPs (mtSNPs) were significantly associated with risk of SPT/recurrence after adjustment for multiple comparisons. A strong gene-dosage effect was observed these SNPs were combined, as evidenced by a progressively increasing SPT/recurrence risk as the number of unfavorable genotypes increased (P for trend < 1.00×10?20). Several polygenic analyses suggest an important role of interconnected functional network and gene-gene interaction in modulating SPT/recurrence. Furthermore, incorporation of these genetic markers into a multivariate model improved significantly the discriminatory ability over the models containing only clinical and epidemiologic variables. Conclusions This is the first large scale systematic evaluation of germline genetic variants for their roles in HNSCC SPT/recurrence. The study identified several promising susceptibility loci and demonstrated the cumulative effect of multiple risk loci in HNSCC SPT/recurrence. Furthermore, this study underscores the importance of incorporating germline genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes.

Wu, Xifeng; Spitz, Margaret R.; Lee, J. Jack; Lippman, Scott M.; Ye, Yuanqing; Yang, Hushan; Khuri, Fadlo R.; Kim, Edward; Gu, Jian; Lotan, Reuben; Hong, Waun K.

2010-01-01

333

Genetic susceptibility to S. aureus mastitis in sheep: differential expression of mammary epithelial cells in response to live bacteria or supernatant.  

PubMed

Staphylococcus aureus is a prevalent pathogen for mastitis in dairy ruminants and is responsible for both clinical and subclinical mastitis. Mammary epithelial cells (MEC) represent not only a physical barrier against bacterial invasion but are also active players of the innate immune response permitting infection clearance. To decipher their functions in general and in animals showing different levels of genetic predisposition to Staphylococcus in particular, MEC from ewes undergoing a divergent selection on milk somatic cell count were stimulated by S. aureus. MEC response was also studied according to the stimulation condition with live bacteria or culture supernatant. The early MEC response was studied during a 5 h time course by microarray to identify differentially expressed genes with regard to the host genetic background and as a function of the conditions of stimulation. In both conditions of stimulation, metabolic processes were altered, the apoptosis-associated pathways were considerably modified, and inflammatory and immune responses were enhanced with the upregulation of il1a, il1b, and tnfa and several chemokines known to enhance neutrophil (cxcl8) or mononuclear leukocyte (ccl20) recruitment. Genes associated with oxidative stress were increased after live bacteria stimulation, whereas immune response-related genes were higher after supernatant stimulation in the early phase. Only 20 genes were differentially expressed between Staphylococcus spp-mastitis resistant and susceptible animals without any clearly defined role on the control of infection. To conclude, this suggests that MEC may not represent the cell type at the origin of the difference of mastitis susceptibility, at least as demonstrated in our genetic model. Supernatant or heat-killed S. aureus produce biological effects that are essentially different from those induced by live bacteria. PMID:22337903

Bonnefont, Cécile M D; Rainard, Pascal; Cunha, Patricia; Gilbert, Florence B; Toufeer, Mehdi; Aurel, Marie-Rose; Rupp, Rachel; Foucras, Gilles

2012-02-14

334

Genetic and Functional Profiling of Crohn's Disease: Autophagy Mechanism and Susceptibility to Infectious Diseases  

PubMed Central

Crohn's disease is a complex disease in which genome, microbiome, and environment interact to produce the immunological background of the disease. Disease in childhood is more extensive and characterized by a rapid progression, leading to severe repercussions in the course of the disorder. Several genetic variations have been associated with an increased risk of developing the disease and most of these are also implicated in other autoimmune disorders. The gut has many tiers of defense against incursion by luminal microbes, including the epithelial barrier and the innate and adaptive immune responses. Moreover, recent evidence shows that bacterial and viral infections, as well as inflammasome genes and genes involved in the autophagy process, are implicated in Crohn's disease pathogenesis. The aim of this review is to establish how much the diagnostic system can improve, thus increasing the success of Crohn's disease diagnosis. The major expectation for the near future is to be able to anticipate the possible consequences of the disease already in childhood, thus preventing associated complications, and to choose the best treatment for each patient.

Bianco, Anna Monica; Girardelli, Martina; Tommasini, Alberto; Martelossi, Stefano

2013-01-01

335

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

PubMed Central

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.

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

2010-01-01

336

Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data  

Microsoft Academic Search

Objective  To examine associations between recently identified common type 2 diabetes (T2D) susceptibility genetic variants and pancreatic\\u000a cancer risk.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Using data on individuals of European ancestry from the Cancer Genetic Markers of Susceptibility PanScan-I study (1,763 pancreatic\\u000a cancer cases and 1,802 controls), we tested associations for 37 T2D susceptibility variants with pancreatic cancer risk. Associations\\u000a with pancreatic cancer were also tested

Brandon L. Pierce; Melissa A. Austin; Habibul Ahsan

2011-01-01

337

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

PubMed Central

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

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

2013-01-01

338

Genetic susceptibility to multiple primary neoplasms in the upper aero-digestive tract: genotype score and phenotype correlation.  

PubMed

Early detection and treatment of head and neck cancer has led to increased patient survival. However such patients are at a high risk for multiple primary neoplasm(s) (MPN). In order to study the genetic susceptibility to MPN, 22 candidate SNPs were genotyped based on which a distinctive Genotype Score was created using Additive, Dominant and Recessive models. Using lymphoblastoid cell lines (LCLs) generated from these individuals, the Genotype Score was correlated with carcinogen sensitivity in vitro. LCLs from MPN patients exhibited significantly higher Genotype Score and showed resistance to genotoxic agents compared to matched controls. This report demonstrates quantitative assessment of cumulative effect of gene polymorphisms and its correlation with carcinogen sensitivity for predicting susceptibility to MPN. PMID:23348701

Hussain, Tabish; Kotnis, Ashwin; Sarin, Rajiv; Mulherkar, Rita

2013-01-21

339

Genetic variation for susceptibility to storm-induced stem breakage in Solidago altissima: The role of stem height and morphology  

NASA Astrophysics Data System (ADS)

While storms can have obvious ecological impacts on plants, plants' potential to respond evolutionarily to selection for increased resistance to storm damage has received little study. We took advantage of a thunderstorm with strong wind and hail to examine genetic variation for resistance to stem breakage in the herbaceous perennial Solidago altissima. The storm broke the apex of nearly 10% of 1883 marked ramets in a common-garden plot containing 26 genets of S. altissima. Plant genets varied 20-fold in resistance to breakage. Stem height was strongly correlated with resistance to breakage, with taller stems being significantly more susceptible. A stem's growth form (erect versus nodding) had no detectable effect on its resistance to breakage. Therefore, we rejected the hypothesis that a function of the nodding, or "candy-cane," morphology is protection of the apex from storm damage. The significant genetic variation in S. altissima for stem breakage suggests that this plant has the capacity to respond to selection imposed by storms - particularly through changes in mean stem height. Tradeoffs between breakage resistance and competition for light and pollinators may act to maintain a large amount of genetic variation in stem height.

Wise, Michael J.; Abrahamson, Warren G.

2010-07-01

340

MUTYH Gln324His gene polymorphism and genetic susceptibility for lung cancer in a Japanese population  

PubMed Central

Background Genetic polymorphisms of DNA repair enzymes in the base excision repair (BER) pathway, may lead to genetic instability and lung cancer carcinogenesis. We investigated the interactions among the gene polymorphisms in DNA repair genes and lung cancer. Methods We analyzed associations among OGG1 Ser326Cys and MUTYH Gln324His gene polymorphisms in relation to lung cancer risk using PCR-RFLP. The study involved 108 lung cancer patients and 121 non-cancer controls divided into non-smokers, smokers according to pack-years smoked in Japanese. Results The results showed that the MUTYH His/His genotype compared with Gln/Gln genotype showed an increased risk for lung cancer (adjusted odds ratio [OR] 3.03, confidence interval [95%CI], 1.31–7.00, p = 0.010), whereas there was no significant increase for the Gln/His genotype (adjusted OR 1.35, 95%CI 0.70–2.61, p = 0.376). The MUTYH His/His genotype was at a borderline increased risk for both adenocarcinoma and squamous cell carcinoma (adjusted OR 2.50, 95%CI 0.95–6.62, p = 0.065 for adenocarcinoma; adjusted OR 3.20, 95%CI 0.89–11.49, p = 0.075 for squamous cell carcinoma, respectively). However, the OGG1 Ser/Cys or Cys/Cys genotypes compared with the Ser/Ser genotype did not have significantly increased risk for lung cancer, containing either adenocarcinoma or squamous cell carcinoma. The joint effect of tobacco exposure and the MUTYH His/His genotype compared with the Gln/Gln genotype showed a significant association with lung cancer risk in smokers, and there was not significantly increased in non-smokers (adjusted OR 3.82, 95%CI 1.22–12.00, p = 0.022 for smokers; adjusted OR 2.60, 95%CI 0.60–11.25, p = 0.200 for non-smokers, respectively). The effect of tobacco exposure and the OGG1 Ser326Cys showed also no significant risk for lung cancer. Conclusion Our findings suggest that the MUTYH Gln324His polymorphism appear to play an important role in modifying the risk for lung cancer in the Japanese population.

Miyaishi, Aiko; Osawa, Kayo; Osawa, Yasunori; Inoue, Natsuko; Yoshida, Kana; Kasahara, Mayumi; Tsutou, Akimitsu; Tabuchi, Yoshiki; Sakamoto, Kazuo; Tsubota, Noriaki; Takahashi, Juro

2009-01-01

341

Contribution of Serotype and Genetic Background to Virulence of Serotype 3 and Serogroup 11 Pneumococcal Isolates?†  

PubMed Central

The capsular serotype has long been associated with the virulence of Streptococcus pneumoniae. Here we present an in-depth study of phenotypic and genetic differences between serotype 3 and serogroup 11 S. pneumoniae clinical isolates from both the general and indigenous populations of Australia. Both serotypes/groups included clonally unrelated strains with differences in well-known polymorphic virulence genes, such as nanA and pspA, as demonstrated by multilocus sequence typing and Western blot analysis. Nonetheless, the serotype 3 strains were consistently and significantly more virulent in mice than the serogroup 11 strains. Despite extensive genomic analysis, noncapsular genes common to one serotype/group but not the other were not identified. Nevertheless, following the conversion of a serotype 11A isolate to serotype 3 and subsequent analysis in an intranasal infection model, it was evident that both capsular and noncapsular factors determine the virulence phenotype in mice. However, it appears that these noncapsular factors vary from strain to strain.

McAllister, Lauren J.; Ogunniyi, Abiodun D.; Stroeher, Uwe H.; Leach, Amanda J.; Paton, James C.

2011-01-01

342

Transcriptome Atlases of Mouse Brain Reveals Differential Expression Across Brain Regions and Genetic Backgrounds  

PubMed Central

Mouse models play a crucial role in the study of human behavioral traits and diseases. Variation of gene expression in brain may play a critical role in behavioral phenotypes, and thus it is of great importance to understand regulation of transcription in mouse brain. In this study, we analyzed the role of two important factors influencing steady-state transcriptional variation in mouse brain. First we considered the effect of assessing whole brain vs. discrete regions of the brain. Second, we investigated the genetic basis of strain effects on gene expression. We examined the transcriptome of three brain regions using Affymetrix expression arrays: whole brain, forebrain, and hindbrain in adult mice from two common inbred strains (C57BL/6J vs. NOD/ShiLtJ) with eight replicates for each brain region and strain combination. We observed significant differences between the transcriptomes of forebrain and hindbrain. In contrast, the transcriptomes of whole brain and forebrain were very similar. Using 4.3 million single-nucleotide polymorphisms identified through whole-genome sequencing of C57BL/6J and NOD/ShiLtJ strains, we investigated the relationship between strain effect in gene expression and DNA sequence similarity. We found that cis-regulatory effects play an important role in gene expression differences between strains and that the cis-regulatory elements are more often located in 5? and/or 3? transcript boundaries, with no apparent preference on either 5? or 3? ends.

Sun, Wei; Lee, Seunggeun; Zhabotynsky, Vasyl; Zou, Fei; Wright, Fred A.; Crowley, James J.; Yun, Zaining; Buus, Ryan J.; Miller, Darla R.; Wang, Jeremy; McMillan, Leonard; Pardo-Manuel de Villena, Fernando; Sullivan, Patrick F.

2012-01-01

343

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

PubMed Central

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

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

2012-01-01

344

Establishment and characterization of MRT cell lines from genetically engineered mouse models and the influence of genetic background on their development.  

PubMed

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

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

2012-12-27

345

Genetically resistant (Ityr) and susceptible (Itys) congenic mouse strains show similar cytokine responses following infection with Salmonella dublin.  

PubMed

IFN-gamma, TNF-alpha, IL-1, and granulocyte-macrophage CSF (GM-CSF) play an important role in host resistance to infection with nontyphoid Salmonella. In mice, resistance to Salmonella is determined by alleles of the susceptibility gene, Nramp, which maps to the Ity/Lsh/Bcg locus and is expressed in macrophages. In vitro studies suggested that macrophages from Salmonella-susceptible mice (Itys phenotype) are impaired functionally in their ability to produce, or stimulate the production of, cytokines such as TNF-alpha and IFN-gamma. BALB/c and BALB/c.DBA2 Idh-lb-Ityr-Pep-3b mice are congenic strains that differ at the Ity/Lsh/Bcg locus and in their susceptibility to Salmonella infection. These strains were used to question whether differences in the host cytokine response determine the outcome of Salmonella infection in genetically susceptible and resistant mice. As reported in this work, the in vivo response to Salmonella dublin infection in both Itys and Ityr mice was characterized by increased expression of IFN-gamma, TNF-alpha, GM-CSF, IL-1 alpha, IL-2, IL-6, IL-10, and IL-12 p40. In contrast, expression of IL-4, IL-5, and TGF-beta 1 was not altered, or decreased, during the course of infection. Moreover, the kinetics and magnitude of the cytokine response following S. dublin infection were similar in susceptible Itys and resistant Ityr mice, even though the former group died while the latter survived the infection. Thus, in vivo cytokine responses that are associated with survival of Ityr mice following S. dublin infection do not confer protection in mice of the Itys phenotype. PMID:8609409

Eckmann, L; Fierer, J; Kagnoff, M F

1996-04-15

346

Disorders of sex development: update on the genetic background, terminology and risk for the development of germ cell tumors  

Microsoft Academic Search

Background  Considerable progress has been made on genetic mechanisms involved in disorders of sex development and on tumor formation\\u000a in dysgenetic gonads. Clinical and psychological outcome of patients are, as far as evaluated, unsatisfactory at present.\\u000a Guidelines are emerging in order to optimize long-term outcome in the future.\\u000a \\u000a \\u000a \\u000a Data sources  The information obtained in this review is based on recent original publications

Martine Cools; Leendert H. J. Looijenga; Katja P. Wolffenbuttel; Sten L. S. Drop

2009-01-01

347

Genetic Polymorphisms in CYP2E1: Association with Schizophrenia Susceptibility and Risperidone Response in the Chinese Han Population  

PubMed Central

Background CYP2E1 is a member of the cytochrome P450 superfamily, which is involved in the metabolism and activation of both endobiotics and xenobiotics. The genetic polymorphisms of CYP2E1 gene (Chromosome 10q26.3, Accession Number NC_000010.10) are reported to be related to the development of several mental diseases and to be involved in the clinical efficacy of some psychiatric medications. We investigated the possible association of CYP2E1 polymorphisms with susceptibility to schizophrenia in the Chinese Han Population as well as the relationship with response to risperidone in schizophrenia patients. Methods In a case-control study, we identified 11 polymorphisms in the 5' flanking region of CYP2E1 in 228 schizophrenia patients and 384 healthy controls of Chinese Han origin. From among the cases, we chose 130 patients who had undergone 8 weeks of risperidone monotherapy to examine the relationship between their response to risperidone and CYP2E1 polymorphisms. Clinical efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS). Results Statistically significant differences in allele or genotype frequencies were found between cases and controls at rs8192766 (genotype p?=?0.0048, permutation p?=?0.0483) and rs2070673 (allele: p?=?0.0018, permutation p?=?0.0199, OR?=?1.4528 95%CI?=?1.1487–1.8374; genotype: p?=?0.0020, permutation p?=?0.0225). In addition, a GTCAC haplotype containing 5 SNPs (rs3813867, rs2031920, rs2031921, rs3813870 and rs2031922) was observed to be significantly associated with schizophrenia (p?=?7.47E-12, permutation p<0.0001). However, no association was found between CYP2E1 polymorphisms/haplotypes and risperidone response. Conclusions Our results suggest that CYP2E1 may be a potential risk gene for schizophrenia in the Chinese Han population. However, polymorphisms of the CYP2E1 gene may not contribute significantly to individual differences in the therapeutic efficacy of risperidone. Further studies in larger groups are warranted to confirm our results.

Wei, Zhiyun; Shen, Lu; Xiong, Yuyu; Wu, Xi; Niu, Jiamin; Han, Xia; Tian, Zhengan; Yang, Lun; Feng, Guoyin; He, Lin; Qin, Shengying

2012-01-01

348

Genetic mapping of a cloned sequence responsible for susceptibility to ecotropic murine leukemia viruses.  

PubMed Central

A mouse cDNA that confers susceptibility to ecotropic murine leukemia viruses following transfection into human EJ cells has been cloned and sequenced. We show that this sequence is likely to be Rec-1, the chromosome 5 locus originally defined by studies with somatic cell hybrids as responsible for virus susceptibility, and provide a specific chromosomal map position for this locus by analysis of an interspecies backcross. This locus maps in the distal region of chromosome 5 and is thus not within the cluster of retrovirus-related genes near the centromere. Images

Kozak, C A; Albritton, L M; Cunningham, J

1990-01-01

349

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures  

Microsoft Academic Search

BackgroundHuman mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make

Sarah Jamali; Annick Salzmann; Nader Perroud; Magali Ponsole-Lenfant; Jennifer Cillario; Patrice Roll; Nathalie Roeckel-Trevisiol; Ariel Crespel; Jorg Balzar; Kurt Schlachter; Ursula Gruber-Sedlmayr; Ekaterina Pataraia; Christoph Baumgartner; Alexander Zimprich; Fritz Zimprich; Alain Malafosse; Pierre Szepetowski; Francesc Palau

2010-01-01

350

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

Microsoft Academic Search

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

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

2011-01-01

351

Molecular backgrounds of age-related osteoporosis from mouse genetics approaches.  

PubMed

Backgrounds underlying age-related bone loss can be classified into two categories: systemic abnormality and osteoblast dysfunction. The former includes insufficiency of vitamin D or estrogen, causing a negative balance of calcium metabolism. We propose the contribution of an aging-suppressing gene, klotho, as a novel systemic factor, as a mouse deficient in the klotho gene exhibits multiple aging phenotypes including osteopenia with a low bone turnover. As a factor intrinsic to osteoblasts, we investigated the role of PPARgamma, a key regulator of adipocyte differentiation, based on the facts that osteoblasts and adipocytes share a common progenitor. Heterozygous PPARgamma-deficient mice exhibited high bone mass by stimulating osteoblastogenesis from bone marrow progenitors, and this effect became prominent with aging, indicating involvement of PPARgamma-dependent bone formation in the pathophysiology of age-related bone loss. The local environment of osteoblasts is mainly controlled by cytokines/growth factors, among which insulin-like growth factor-I (IGF-I) is the most possible candidate whose production and activity are decreased with aging. Bone phenotypes of deficient mice of insulin receptor substrates (IRS-1 and IRS-2), essential molecules for intracellular signaling of IGF-I, revealed that IRS-1 is essential to maintain bone turnover by up-regulating anabolic and catabolic functions of osteoblasts, while IRS-2 is needed to keep the predominance of the anabolic function over the catabolic function. A next task ahead of us will be to elucidate the network system of these factors underlying age-related osteoporosis. PMID:17123175

Kawaguchi, Hiroshi

2006-06-01

352

The C57BL/6 genetic background confers cardioprotection in iron-overloaded mice  

PubMed Central

Background Chronic transfusion therapy causes a progressive iron overload that damages many organs including the heart. Recent evidence suggests that L-type calcium channels play an important role in iron uptake by cardiomyocytes under conditions of iron overload. Given that beta-adrenergic stimulation significantly enhances L-type calcium current, we hypothesised that beta-adrenergic blocking drugs could reduce the deleterious effects of iron overload on the heart. Methods Iron overload was generated by intraperitoneal injections of iron dextran (1g/kg) administered once a week for 8 weeks in male C57bl/6 mice, while propranolol was administered in drinking water at the dose of 40 mg/kg/day. Cardiac function and ventricular remodelling were evaluated by echocardiography and histological methods. Results As compared to placebo, iron injection caused cardiac iron deposition. Surprisingly, despite iron overload, myocardial function and ventricular geometry in the iron-treated mice resulted unchanged as compared to those in the placebo-treated mice. Administration of propranolol increased cardiac performance in iron-overloaded mice. Specifically, as compared to the values in the iron-overloaded group, in iron-overloaded animals treated with propranolol left ventricular fractional shortening increased (from 31.6% to 44.2%, P =0.01) whereas left ventricular end-diastolic diameter decreased (from 4.1±0.1 mm to 3.5±0.1 mm, P =0.03). Propranolol did not alter cardiac systolic function or left ventricular sizes in the placebo group. Conclusions These results demonstrate that C57bl/6 mice are resistant to iron overload-induced myocardial injury and that treatment with propranolol is able to increase cardiac performance in iron-overloaded mice. However, since C57bl/6 mice were resistant to iron-induced injury, it remains to be evaluated further whether propranolol could prevent iron-overload cardiomyopathy.

Musumeci, Marco; Maccari, Sonia; Sestili, Paola; Massimi, Alessia; Corritore, Elisa; Marano, Giuseppe; Catalano, Liviana

2013-01-01

353

Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus  

PubMed Central

TGF? activation and signaling have been extensively studied in experimental models of allergen-induced asthma as potential therapeutic targets during chronic or acute phases of the disease. Outcomes of experimental manipulation of TGF? activity have been variable, in part due to use of different model systems. Using an ovalbumin (OVA)-induced mouse model of asthma, we here show that innate variation within TGF?1 genetic modifier loci, Tgfbm2 and Tgfbm3, alters disease susceptibility. Specifically, Tgfbm2129 and Tgfbm3C57 synergize to reverse accentuated airway hyperresponsiveness (AHR) caused by low TGF?1 levels in Tgfb1+/? mice of the NIH/OlaHsd strain. Moreover, epistatic interaction between Tgfbm2129 and Tgfbm3C57 uncouples the inflammatory response to ovalbumin from those of airway remodeling and airway hyperresponsiveness, illustrating independent genetic control of these responses. We conclude that differential inheritance of genetic variants of Tgfbm genes alters biological responses to reduced TGF?1 signaling in an experimental asthma model. TGF? antagonists for treatment of lung diseases might therefore give diverse outcomes, dependent on genetic variation.

Freimuth, Julia; Clermont, Frederic F.; Huang, Xiaozhu; DeSapio, Angela; Tokuyasu, Taku A.; Sheppard, Dean; Akhurst, Rosemary J.

2012-01-01

354

Quantitative Proteomic and Genetic Analyses of the Schizophrenia Susceptibility Factor Dysbindin Identify Novel Roles of the BLOC-1 Complex  

PubMed Central

The Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1) is a protein complex containing the schizophrenia susceptibility factor dysbindin, which is encoded by the gene DTNBP1. However, mechanisms engaged by dysbindin defining schizophrenia susceptibility pathways have not been quantitatively elucidated. Here, we discovered prevalent and novel cellular roles of the BLOC-1 complex in neuronal cells by performing large-scale Stable Isotopic Labeling of Cells in Culture quantitative proteomics (SILAC) combined with genetic analyses in dysbindin-null mice (Mus musculus) and the genome of schizophrenia patients. We identified 24 proteins that associate with the BLOC-1 complex many of which were altered in content/distribution in cells or tissues deficient in BLOC-1. New findings include BLOC-1 interactions with the COG complex, a Golgi apparatus tether, and antioxidant enzymes peroxiredoxins 1-2. Importantly, loci encoding eight of the 24 proteins are affected by genomic copy number variation in schizophrenia patients. Thus, our quantitative proteomic studies expand the functional repertoire of the BLOC-1 complex and provide insight into putative molecular pathways of schizophrenia susceptibility.

Gokhale, Avanti; Larimore, Jennifer; Werner, Erica; So, Lomon; De Luca, Andres Moreno; Lese-Martin, Christa; Lupashin, Vladimir V.; Smith, Yoland; Faundez, Victor

2012-01-01

355

Inherited genetic susceptibility to breast cancer: the beginning of the end or the end of the beginning?  

PubMed

Genome-wide association studies have identified 72 loci associated with breast cancer susceptibility. Seventeen of these are known to predispose to other cancers. High-penetrance susceptibility loci for breast cancer usually result from coding alterations, principally in genes involved in DNA repair, whereas almost all of the associations identified through genome-wide association studies are found in noncoding regions of the genome and are likely to involve regulation of genes in multiple pathways. However, the genes underlying most associations are not yet known. In this review, we summarize the findings from genome-wide association studies in breast cancer and describe the genes and mechanisms that are likely to be involved in the tumorigenesis process. We also discuss approaches to fine-scale mapping of susceptibility regions used to identify the likely causal variant(s) underlying the associations, a major challenge in genetic epidemiology. Finally, we discuss the potential impact of such findings on personalized medicine and future avenues for screening, prediction, and prevention programs. PMID:23973388

Ghoussaini, Maya; Pharoah, Paul D P; Easton, Douglas F

2013-08-23

356

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

ERIC Educational Resources Information Center

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

Soto-Cruz, Isabel; Legorreta-Herrera, Martha

2009-01-01

357

Genetic and Physiological Association of Diabetes Susceptibility with Raised Na^+\\/H^+ Exchange Activity  

Microsoft Academic Search

Insulin-dependent diabetes mellitus is a multigenic autoimmune disease, for which one of the best animal models is the nonobese diabetic (NOD) mouse strain. In both humans and NOD mice, major histocompatibility complex genes are implicated as risk factors in the disease process. Other susceptibility genes are also involved, and a number have been mapped in the mouse to specific chromosomal

Grant Morahan; Peter McClive; Dexing Huang; Peter Little; Alan Baxter

1994-01-01

358

Genetic Characterization of Vga ABC Proteins Conferring Reduced Susceptibility to Pleuromutilins in Staphylococcus aureus?  

PubMed Central

Retapamulin MICs of ?2 ?g/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.

Gentry, Daniel R.; McCloskey, Lynn; Gwynn, Michael N.; Rittenhouse, Stephen F.; Scangarella, Nicole; Shawar, Ribhi; Holmes, David J.

2008-01-01

359

Divergent ghrelin expression patterns in sheep genetically resistant or susceptible to gastrointestinal nematodes  

Microsoft Academic Search

Gastrointestinal nematodes are a major problem for pastoral ruminant production systems. This problem could be reduced by the application of breeding strategies that select for nematode resistant sheep, but no suitable molecular markers are available. Research selection flocks containing lines that are resistant (R) or susceptible (S) to gastrointestinal nematodes provide an excellent resource for discovering selectable markers, and for

Aaron Ingham; Moira Menzies; Peter Hunt; Antonio Reverter; Ross Windon; Nicholas Andronicos

2011-01-01

360

Genetic analysis of disease susceptibility in the Arabidopsis-Hyaloperonospora parasitica interaction  

Microsoft Academic Search

On a global scale the impact and costs of plant diseases on agriculture is enormous, highlighting the importance of the research on this topic. Plant disease is the result of a compatible interaction between plants and adapted pathogens. The knowledge on the molecular mechanisms underlying compatibility or disease susceptibility is limited. The aim of this study was to identify Arabidopsis

M. M. A. van Damme

2007-01-01

361

The role of catecholamines in seizure susceptibility: new results using genetically engineered mice  

Microsoft Academic Search

The catecholamines norepinephrine and dopamine are abundant in the CNS, and modulate neuronal excitability via G-protein-coupled receptor signaling. This review covers the history of research concerning the role of catecholamines in modulating seizure susceptibility in animal models of epilepsy. Traditionally, most work on this topic has been anatomical, pharmacological, or physiological in nature. However, the recent advances in transgenic and

David Weinshenker; Patricia Szot

2002-01-01

362

Genetic characterization of Vga ABC proteins conferring reduced susceptibility to pleuromutilins in Staphylococcus aureus.  

PubMed

Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates. PMID:18838584

Gentry, Daniel R; McCloskey, Lynn; Gwynn, Michael N; Rittenhouse, Stephen F; Scangarella, Nicole; Shawar, Ribhi; Holmes, David J

2008-10-06

363

Population Genetics of GYPB and Association Study between GYPB*S/s Polymorphism and Susceptibility to P. falciparum Infection in the Brazilian Amazon  

PubMed Central

Background Merozoites of Plasmodium falciparum invade through several pathways using different RBC receptors. Field isolates appear to use a greater variability of these receptors than laboratory isolates. Brazilian field isolates were shown to mostly utilize glycophorin A-independent invasion pathways via glycophorin B (GPB) and/or other receptors. The Brazilian population exhibits extensive polymorphism in blood group antigens, however, no studies have been done to relate the prevalence of the antigens that function as receptors for P. falciparum and the ability of the parasite to invade. Our study aimed to establish whether variation in the GYPB*S/s alleles influences susceptibility to infection with P. falciparum in the admixed population of Brazil. Methods Two groups of Brazilian Amazonians from Porto Velho were studied: P. falciparum infected individuals (cases); and uninfected individuals who were born and/or have lived in the same endemic region for over ten years, were exposed to infection but have not had malaria over the study period (controls). The GPB Ss phenotype and GYPB*S/s alleles were determined by standard methods. Sixty two Ancestry Informative Markers were genotyped on each individual to estimate admixture and control its potential effect on the association between frequency of GYPB*S and malaria infection. Results GYPB*S is associated with host susceptibility to infection with P. falciparum; GYPB*S/GYPB*S and GYPB*S/GYPB*s were significantly more prevalent in the in the P. falciparum infected individuals than in the controls (69.87% vs. 49.75%; P<0.02). Moreover, population genetics tests applied on the GYPB exon sequencing data suggest that natural selection shaped the observed pattern of nucleotide diversity. Conclusion Epidemiological and evolutionary approaches suggest an important role for the GPB receptor in RBC invasion by P. falciparum in Brazilian Amazons. Moreover, an increased susceptibility to infection by this parasite is associated with the GPB S+ variant in this population.

Amaral, Daphne R. T.; Costa, Daiane C.; Furlani, Natalia G.; Zuccherato, Luciana W.; Machado, Moara; Reid, Marion E.; Zalis, Mariano G.; Rossit, Andrea R.; Santos, Sidney E. B.; Machado, Ricardo L.; Lustigman, Sara

2011-01-01

364

Legal and ethical issues in genetic testing and counseling for susceptibility to breast, ovarian and colon cancer.  

PubMed

The prediction of susceptibility to heritable breast, ovarian and colon cancer raises important legal and ethical concerns. Health care professionals have a duty to disclose sufficient information to enable patients to make informed decisions. They must also safeguard the confidentiality of patient data. These duties may come into conflict if a positive finding in one patient implies that family members are also at risk. A legal distinction is made between a breach of confidentiality and the legitimate sharing of information in a patient's interest or to prevent harm to a third party. Physicians also have a fiduciary duty to warn. Other issues concern the legal liability assumed by genetic counsellors, whose disclosures may influence decisions about childbearing, for example, and the risk of socioeconomic discrimination faced by people with a known genetic susceptibility. Traditional ethical orientations and principals may be applied to these and other questions, but feminist ethics will likely have particular importance in the development of an ethical stance toward testing and counseling for heritable breast and ovarian cancer. PMID:8634959

Dickens, B M; Pei, N; Taylor, K M

1996-03-15

365

Influence of Sex and Genetic Background on Anxiety-Related and Stress-Induced Behaviour of Prodynorphin-Deficient Mice  

PubMed Central

The role of dynorphin/kappa opioid receptors in epilepsy and addiction are well accepted, but their function in emotional control is not yet fully understood. Data obtained from different strains of prodynorphin (Pdyn)- and kappa opioid receptor (KOP)-deficient mice do not provide a consistent picture of the functions of Dyn/KOP in anxiety, suggesting the influence of testing conditions and/or genetic background. Therefore, we investigated the behaviour and neurochemistry of male and female Pdyn KO mice on the balb/c and C57Bl/6N background. Consistent with our results obtained from male mice on the C57bl/6N background, we observed a less anxious phenotype in the elevated plus maze, open-field and light-dark test in male mice on the balb/c background. Female mice on the balb/c background also displayed less anxiety like behaviour; however these data reflect high trait anxiety and inter-individual differences. In contrast, female mice on the C57Bl/6N background displayed low trait anxiety and a paradigm-dependent reduction of anxiety. No differences were observed in the forced swim test, while balb/c Pdyn KO mice displayed prolonged immobility in the tail suspension test. In line with our previous results, we observed reduced CRH mRNA in the central amygdala in all groups of mice. In contrast, the recently observed CRH mRNA reduction in the hypothalamic paraventricular nucleus appears restricted to male, but not female mice. Our data support previous data suggesting a pronounced impact of endogenous prodynorphin-derived peptides on anxiety. Moreover, our data support the idea that the less anxious phenotype manifests only at elevated stress levels.

Kastenberger, Iris; Lutsch, Christian; Herzog, Herbert; Schwarzer, Christoph

2012-01-01

366

Influence of sex and genetic background on anxiety-related and stress-induced behaviour of prodynorphin-deficient mice.  

PubMed

The role of dynorphin/kappa opioid receptors in epilepsy and addiction are well accepted, but their function in emotional control is not yet fully understood. Data obtained from different strains of prodynorphin (Pdyn)- and kappa opioid receptor (KOP)-deficient mice do not provide a consistent picture of the functions of Dyn/KOP in anxiety, suggesting the influence of testing conditions and/or genetic background. Therefore, we investigated the behaviour and neurochemistry of male and female Pdyn KO mice on the balb/c and C57Bl/6N background. Consistent with our results obtained from male mice on the C57bl/6N background, we observed a less anxious phenotype in the elevated plus maze, open-field and light-dark test in male mice on the balb/c background. Female mice on the balb/c background also displayed less anxiety like behaviour; however these data reflect high trait anxiety and inter-individual differences. In contrast, female mice on the C57Bl/6N background displayed low trait anxiety and a paradigm-dependent reduction of anxiety. No differences were observed in the forced swim test, while balb/c Pdyn KO mice displayed prolonged immobility in the tail suspension test. In line with our previous results, we observed reduced CRH mRNA in the central amygdala in all groups of mice. In contrast, the recently observed CRH mRNA reduction in the hypothalamic paraventricular nucleus appears restricted to male, but not female mice. Our data support previous data suggesting a pronounced impact of endogenous prodynorphin-derived peptides on anxiety. Moreover, our data support the idea that the less anxious phenotype manifests only at elevated stress levels. PMID:22479578

Kastenberger, Iris; Lutsch, Christian; Herzog, Herbert; Schwarzer, Christoph

2012-03-29

367

Meta-analysis of susceptibility of woody plants to loss of genetic diversity through habitat fragmentation.  

PubMed

Shrubs and trees are assumed less likely to lose genetic variation in response to habitat fragmentation because they have certain life-history characteristics such as long lifespans and extensive pollen flow. To test this assumption, we conducted a meta-analysis with data on 97 woody plant species derived from 98 studies of habitat fragmentation. We measured the weighted response of four different measures of population-level genetic diversity to habitat fragmentation with Hedge's d and Spearman rank correlation. We tested whether the genetic response to habitat fragmentation was mediated by life-history traits (longevity, pollination mode, and seed dispersal vector) and study characteristics (genetic marker and plant material used). For both tests of effect size habitat fragmentation was associated with a substantial decrease in expected heterozygosity, number of alleles, and percentage of polymorphic loci, whereas the population inbreeding coefficient was not associated with these measures. The largest proportion of variation among effect sizes was explained by pollination mechanism and by the age of the tissue (progeny or adult) that was genotyped. Our primary finding was that wind-pollinated trees and shrubs appeared to be as likely to lose genetic variation as insect-pollinated species, indicating that severe habitat fragmentation may lead to pollen limitation and limited gene flow. In comparison with results of previous meta-analyses on mainly herbaceous species, we found trees and shrubs were as likely to have negative genetic responses to habitat fragmentation as herbaceous species. We also found that the genetic variation in offspring was generally less than that of adult trees, which is evidence of a genetic extinction debt and probably reflects the genetic diversity of the historical, less-fragmented landscape. PMID:22044646

Vranckx, Guy; Jacquemyn, Hans; Muys, Bart; Honnay, Olivier

2011-11-01

368

HLA and Celiac Disease Susceptibility: New Genetic Factors Bring Open Questions about the HLA Influence and Gene-Dosage Effects  

PubMed Central

Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03?01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03?01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03?01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03?01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03?01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals.

Medrano, Luz Maria; Dema, Barbara; Lopez-Larios, Arturo; Maluenda, Carlos; Bodas, Andres; Lopez-Palacios, Natalia; Figueredo, M. Angeles; Fernandez-Arquero, Miguel; Nunez, Concepcion

2012-01-01

369

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

PubMed

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

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

2001-02-10

370

Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis  

PubMed Central

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N?=?4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N?=?10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P?=?5×10?32–3×10?10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2?=?0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P?=?2.5×10?4). A seven–SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r?=?0.30, P?=?3×10?128). This model paralleled the known East–West gradient in disease risk. Moreover, the prediction of a South–North axis was confirmed by registry data showing that the prevalence of IgAN–attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

Kiryluk, Krzysztof; Li, Yifu; Sanna-Cherchi, Simone; Rohanizadegan, Mersedeh; Suzuki, Hitoshi; Eitner, Frank; Snyder, Holly J.; Choi, Murim; Hou, Ping; Scolari, Francesco; Izzi, Claudia; Gigante, Maddalena; Gesualdo, Loreto; Savoldi, Silvana; Amoroso, Antonio; Cusi, Daniele; Zamboli, Pasquale; Julian, Bruce A.; Novak, Jan; Wyatt, Robert J.; Mucha, Krzysztof; Perola, Markus; Kristiansson, Kati; Viktorin, Alexander; Magnusson, Patrik K.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari; Boland, Anne; Metzger, Marie; Thibaudin, Lise; Wanner, Christoph; Jager, Kitty J.; Goto, Shin; Maixnerova, Dita; Karnib, Hussein H.; Nagy, Judit; Panzer, Ulf; Xie, Jingyuan; Chen, Nan; Tesar, Vladimir; Narita, Ichiei; Berthoux, Francois; Floege, Jurgen; Stengel, Benedicte; Zhang, Hong; Lifton, Richard P.; Gharavi, Ali G.

2012-01-01

371

Genetic basis of HIV-1 resistance and susceptibility: an approach to understand correlation between human genes and HIV-1 infection.  

PubMed

HIV infection is the serious medical and public health issue of present generation. By 2005, it has already infected a cumulative total of more than sixty million people worldwide and the number of HIV positive cases are rising day by day. India is currently estimated to have about 5.1 million infected persons with HIV-1 or AIDS (second only to South Africa) and this number could increase to 24 million in the next ten years. This pandemic situation of the AIDS stimulated a plethora of longitudinal cohort studies which are designed to document medical heterogeneity as well as to mitigate the factors that regulate the HIV-1 infection, disease progression and the immune defenses. In recent years these genetic studies have led to the discovery of various MHC and non MHC encoded genes, which directly or indirectly influence the susceptibility and resistance to HIV infection and AIDS. These genes and their mutated forms and their products which play a major role in determining the susceptibility or resistance to HIV-1 infection and AIDS. These genes have been categorized into MHC or non MHC encoded genes. The MHC encoded genes which determine HIV resistance or susceptibility are HLA-B57, HLA-B58, HLA-B27, HLA-Bw4 and HLA-A11 in Southeast Asians. On the other hand, non MHC encoded genes are CCR5, CCR2, RANTES, CXCL12, CXCR6, CCL3L1, Interleukin-10 (IL-10), and interferon gamma. The site specific mutations in these genes determine the susceptibility or resistance to HIV-1 infection and AIDS. In future the study of host genes in relation to HIV-1 infection may provide the researchers to develop newer chemotherapeutic approaches to prevent or cure HIV-1 infection effectively. PMID:16999022

Kumar, Vijay; Prakash, O; Manpreet, S; Sumedh, G; Medhi, B

2006-09-01

372

IL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production  

PubMed Central

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report “allelic heterogeneity” at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.

Cooper, Jason; Downes, Kate; Anderson, David E.; Severson, Christopher; Clark, Pamela M.; Healy, Brian; Walker, Neil; Aubin, Cristin; Oksenberg, Jorge R.; Hauser, Stephen L.; Compston, Alistair; Sawcer, Stephen; De Jager, Philip L.; Wicker, Linda S.

2009-01-01

373

The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations.  

PubMed

Germline mutations in the DNA mismatch repair (MMR) gene MLH1 are associated with a large percentage of hereditary non-polyposis colorectal cancers. There are approximately 250 known human mutations in MLH1. Of these, one-third are missense variants that are often difficult to characterize with regards to pathogenicity. We analysed 28 alleles of baker's yeast MLH1 that correspond to non-truncating human mutant alleles listed in online HNPCC databases, 13 of which had not been previously studied in functional assays. Using the highly sensitive lys2::InsE-A(14) reversion rate assay, we determined the MMR proficiency conferred by each allele in the S288c strain of Saccharomyces cerevisiae. Seven alleles conferred a null phenotype for MMR and eight others showed significant MMR defects, suggesting that all 15 are likely to be pathogenic in humans. In addition, we observed a strong correlation between these results, limited results from previous functional assays and clinical data. To test whether the potential pathogenicity of certain alleles depends on the genetic background of the host, we examined the mutation rates conferred by the mlh1 alleles in a second yeast strain, SK1, which is approximately 0.7% divergent from S288c. Many alleles displayed a difference in MMR efficiency between strain backgrounds with decreasing differences as the severity of the MMR defect increased. These findings suggest that genetic background can play an important role in determining the pathogenicity of MMR alleles and may explain cases of atypical colorectal cancer inheritance. PMID:17210669

Wanat, Jennifer J; Singh, Nikhil; Alani, Eric

2007-01-08

374

Genetic background modulates behavioral impairments in R6/2 mice and suggests a role for dominant genetic modifiers in Huntington’s disease pathogenesis.  

PubMed

Variability and modification of the symptoms of Huntington’s disease (HD) are commonly observed in both patient populations and animal models of the disease. Utilizing a stable line of the R6/2 HD mouse model, the present study investigated the role of genetic background in the onset and severity of HD symptoms in a transgenic mouse. R6/2 congenic C57BL/6J and C57BL/6J×DBA/2J F1 (B6D2F1) mice were evaluated for survival and a number of behavioral phenotypes. This study reports that the presence of the DBA/2J allele results in amelioration or exacerbation of several HD-like phenotypes characteristic of the R6/2 mouse model and indicates the presence of dominant genetic modifiers of HD symptoms. This study is the first step in identifying genes that confer natural genetic variation and modify the HD symptoms. This identification may lead to novel targets for treatment and help elucidate the molecular mechanisms of HD pathogenesis. PMID:22290451

Cowin, Randi-Michelle; Bui, Nghiem; Graham, Deanna; Green, Jennie R; Yuva-Paylor, Lisa A; Weiss, Andreas; Paylor, Richard

2012-06-01

375

Role of Genetic Factors in Susceptibility to Experimental Hypertension due to Chronic Excess Salt Ingestion  

Microsoft Academic Search

THERE is considerable evidence indicating a familial trend in human essential hypertension1. A familial disease could be due exclusively to common environmental factors, exclusively to common genetic factors, or to an interaction of the two.

Lewis K. Dahl; Martha Heine; Lorraine Tassinari

1962-01-01

376

The effect of birth-weight with genetic susceptibility on depressive symptoms in childhood and adolescence  

Microsoft Academic Search

Low birth-weight has been associated with depression and related outcomes in adults, and with problem behaviours in children.\\u000a This study aimed to examine the association between low birth-weight for gestation and depressive symptoms in children and\\u000a adolescents and to examine whether the relationship is moderated by genetic risk for depression. An epidemiological, genetically\\u000a sensitive design was used including 2,046 twins

Frances Rice; Gordon T. Harold; Anita Thapar

2006-01-01

377

Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2  

Microsoft Academic Search

OBJECTIVE: Susceptibility to autoimmune hepatitis (AIH) type 1 has been associated with DRB1?03, DRB1?04, and DRB3 alleles in European and North-American whites, with DRB1?04 in Japan, and with DRB1?04 and DRB1?13 in Latin America. Very few studies have been performed on AIH type 2. The aim of the present study was to evaluate the association of AIH types 1 and

Paulo L. Bittencourt; Anna C. Goldberg; Eduardo L. R. Cançado; Gilda Porta; Flair J. Carrilho; Alberto Q. Farias; Selma A. Palacios; Josely M. Chiarella; Clarice P. Abrantes-Lemos; Vera L. Baggio; Antonio A. Laudanna; Jorge Kalil

1999-01-01

378

Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2  

Microsoft Academic Search

OBJECTIVES:Susceptibility to autoimmune hepatitis (AIH) type 1 has been associated with DRB1*03, DRB1*04, and DRB3 alleles in European and North-American whites, with DRB1*04 in Japan, and with DRB1*04 and DRB1*13 in Latin America. Very few studies have been performed on AIH type 2. The aim of the present study was to evaluate the association of AIH types 1 and 2

Paulo L. Bittencourt; Anna C. Goldberg; Eduardo L. R. Cancado; Gilda Porta; Flair J. Carrilho; Alberto Q. Farias; Selma A. Palacios; Josely M. Chiarella; Clarice P. Abrantes-Lemos; Vera L. Baggio; Antonio A. Laudanna; Jorge Kalil

1999-01-01

379

Genetic Characterization of Vga ABC Proteins Conferring Reduced Susceptibility to Pleuromutilins in Staphylococcus aureus  

Microsoft Academic Search

Retapamulin MICs of >2 g\\/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates. Members of the pleuromutilin class of antibiotics selectively inhibit bacterial protein synthesis through interaction with pro- karyotic ribosomes (11) and are

Daniel R. Gentry; Lynn McCloskey; Michael N. Gwynn; Stephen F. Rittenhouse; Nicole Scangarella; Ribhi Shawar; David J. Holmes

2008-01-01

380

Genetic and immunological parameters governing in vivo susceptibility\\/resistance to retrovirally induced murine malignant histiocytosis  

Microsoft Academic Search

Malignant histiocytosis sarcoma virus (MHSV) arose as a recombinant of c-Harvey-ras murine sarcoma virus (Ha-MuSV) and Friend mink cell focus-forming virus (F-MCFV). It is a defective acute transforming retrovirus that, along with Friend murine leukemia helper virus (F-MuLV), induces malignant histiocytosis (MH) in susceptible adult mice. We have assessed the in vivo susceptibil- ity to MHSV in inbred homozygous, F1

Angela Panoskaltsis-Mortari; R. Maarten Egeler; Thomas M. Yaeger; Sumiko Yoneji; Laura Schmitz; Frank Lilly; Mark E. Nesbit; Bruce R. Blazar