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1

Genetic background affects susceptibility to tumoral stem cell reprogramming  

PubMed Central

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

Garcia-Ramirez, Idoia; Ruiz-Roca, Lucia; Martin-Lorenzo, Alberto; Blanco, Oscar; Garcia-Cenador, Maria Begona; Garcia-Criado, Francisco Javier; Vicente-Duenas, Carolina; Sanchez-Garcia, Isidro

2013-01-01

2

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

Microsoft Academic Search

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

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

2005-01-01

3

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

PubMed Central

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

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

2013-01-01

4

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

Genetic Susceptibility to Lymphoma  

PubMed Central

BACKGROUND Genetic susceptibility studies of lymphoma may serve to identify at risk populations and to elucidate important disease mechanisms. METHODS This review considered all studies published through October 2006 on the contribution of genetic polymorphisms in the risk of lymphoma. RESULTS Numerous studies implicate the role of genetic variants that promote B-cell survival and growth with increased risk of lymphoma. Several reports including a large pooled study by InterLymph, an international consortium of non-Hodgkin lymphoma (NHL) case-control studies, found positive associations between variant alleles in TNF -308G>A and IL10 -3575T>A genes and risk of diffuse large B-cell lymphoma. Four studies reported positive associations between a GSTT1 deletion and risk of Hodgkin and non-Hodgkin lymphoma. Genetic studies of folate-metabolizing genes implicate folate in NHL risk, but further studies that include folate and alcohol assessments are needed. Links between NHL and genes involved in energy regulation and hormone production and metabolism may provide insights into novel mechanisms implicating neuro- and endocrine-immune cross-talk with lymphomagenesis, but will need replication in larger populations. CONCLUSIONS Numerous studies suggest that common genetic variants with low penetrance influence lymphoma risk, though replication studies will be needed to eliminate false positive associations. PMID:17606447

Skibola, Christine F.; Curry, John D.; Nieters, Alexandra

2010-01-01

6

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.

7

Genetic Architecture of Intrinsic Antibiotic Susceptibility  

Microsoft Academic Search

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

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

2009-01-01

8

Genetic susceptibility to substance dependence  

Microsoft Academic Search

Despite what is often believed, the majority of those who experiment with substances with a dependence potential do not develop dependence. However, there is a subpopulation of users that easily becomes dependent on substances, and these individuals exhibit pre-existing comorbid traits, including novelty seeking and antisocial behavior. There appears to be a genetic basis for the susceptibility to dependence and

N Hiroi; S Agatsuma

2005-01-01

9

Genetic susceptibility to lung cancer.  

PubMed

Lung cancer is a highly environmental disease, but cancer researchers have long been interested in investigating genetic susceptibility to lung cancer. This paper is a historical review and provides updated perspectives on lung cancer susceptibility research. The recent introduction of easier genotyping methods and the availability of an almost complete human genome database facilitated the association study to thousands of cases and controls for millions of genetic markers. Discoveries in the field of behavior genetics, that is, the genetic aspects of smoking behavior and nicotine addiction, unexpectedly indicated that polymorphisms in the human central nervous system play an important role in eventually leading to lung cancer. These findings were achieved by using comprehensive approaches, such as a genome, transcriptome, or proteome approach, and the studies were often conducted without a hypothesis. Another-omics approach, the "adductome" or "exposome" approach to how life style information can be integrated into the framework of genetic association studies, has recently emerged. These new paradigms will influence the area of lung cancer risk evaluation in genome cohort studies. PMID:21622282

Sugimura, Haruhiko; Tao, Hong; Suzuki, Masaya; Mori, Hiroki; Tsuboi, Masaru; Matsuura, Shun; Goto, Masanori; Shinmura, Kazuya; Ozawa, Takachika; Tanioka, Fumihiko; Sato, Naomi; Matsushima, Yoshitaka; Kageyama, Shinji; Funai, Kazuhito; Chou, Pei-Hsin; Matsuda, Tomonari

2011-01-01

10

Genetic Susceptibility to Pancreatic Cancer  

PubMed Central

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.

2013-01-01

11

Genetic variation in Drosophila melanogaster pathogen susceptibility  

E-print Network

Genetic variation in Drosophila melanogaster pathogen susceptibility M. C. TINSLEY*, S. BLANFORD: Drosophila melanogaster, Beauveria bassiana, immunity, genetic variation, malaria, resistance evolution). Drosophila melanogaster is the principal model system for study of the invertebrate immune system and has

Jiggins, Francis

12

Genetic Architecture of Intrinsic Antibiotic Susceptibility  

PubMed Central

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

Tavazoie, Saeed

2009-01-01

13

Genetics 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. PMID:22929093

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

2012-01-01

14

Genetic susceptibility to breast cancer  

Microsoft Academic Search

Deleterious mutations in two breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2 have been identified in breast and ovarian cancer families. Women with a BRCA1 or BRCA2 mutation are candidates for additional risk reduction measures such as intensive screening, prophylactic surgery or chemoprevention.\\u000a Additional susceptibility genes have been identified, including PTEN, ATM, TP53, CHEK2, CASP8, PBRL and BRIP1. Yet,

Angela R. Bradbury; Olufunmilayo I. Olopade

2007-01-01

15

Understanding Cancer Series: Patient's Genetic Background  

Cancer.gov

While attention must be paid to the changes discovered within the genomic profile of a cancerous growth, equal attention must be paid to the intrinsic genetic background of each patient. Cancer does not develop in a vacuum, but within a patient, and each patient's distinctive genetic background results from both intrinsic and extrinsic factors.

16

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. PMID:7613325

Clarke, A.

1995-01-01

17

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. PMID:21929748

2011-01-01

18

Personalized genetic testing and norovirus susceptibility  

PubMed Central

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

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

2014-01-01

19

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

20

RESEARCH ARTICLE Open Access Genetic susceptibility to Chagas disease  

E-print Network

RESEARCH ARTICLE Open Access Genetic susceptibility to Chagas disease cardiomyopathy: involvement cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical

Paris-Sud XI, Université de

21

Genetic Susceptibility to Triple Negative Breast Cancer  

PubMed Central

Triple negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression, account for 12-24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16-23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC but not other forms of breast cancer suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiological data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through development of risk prediction models. PMID:23536562

Stevens, Kristen N.; Vachon, Celine M.; Couch, Fergus J.

2013-01-01

22

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

Microsoft Academic Search

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

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

2009-01-01

23

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. PMID:23637549

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

2013-01-01

24

Genetic susceptibility in ecosystems: the challenge for ecotoxicology.  

PubMed Central

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

Evenden, A J; Depledge, M H

1997-01-01

25

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

E-print Network

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

Matuszek, Gregory; Talebizadeh, Zohreh

2009-09-24

26

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...

27

Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility  

PubMed Central

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

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

2014-01-01

28

Phenotypic variability and genetic susceptibility to genomic disorders  

PubMed Central

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

Girirajan, Santhosh; Eichler, Evan E.

2010-01-01

29

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. PMID:20519223

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

2010-01-01

30

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.

31

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

Microsoft Academic Search

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

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

2009-01-01

32

Genetic susceptibility to coronary artery disease: from promise to progress  

Microsoft Academic Search

Family history is an important independent risk factor for coronary artery disease (CAD), and identification of susceptibility genes for this common, complex disease is a vital goal. Although there has been considerable success in identifying genetic variants that influence well-known risk factors, such as cholesterol levels, progress in unearthing novel CAD genes has been slow. However, advances are now being

Martin Farrall; Hugh Watkins

2006-01-01

33

Genetic Susceptibility and Survival: Application to Breast Cancer  

E-print Network

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

West, Mike

34

Genetic polymorphisms and lung cancer susceptibility: a review  

Microsoft Academic Search

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

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

2002-01-01

35

Chloroquine Susceptibility and Reversibility in a Plasmodium falciparum Genetic Cross  

PubMed Central

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

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

2011-01-01

36

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

2010-04-01

37

Genetic susceptibility testing for neurodegenerative diseases: Ethical and practice issues  

PubMed Central

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

Roberts, J. Scott; Uhlmann, Wendy R.

2013-01-01

38

Genetic Algorithms To provide a background and understanding of basic genetic  

E-print Network

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

Qu, Rong

39

Genetic Risk Profiles for Cancer Susceptibility and Therapy Response  

Microsoft Academic Search

Cells in the body are permanently attacked by DNA-reactive species, both from intracellular and environmental sources. Inherited\\u000a and acquired deficiencies in host defense mechanisms against DNA damage (metabolic and DNA repair enzymes) can modify cancer\\u000a susceptibility as well as therapy response. Genetic profiles should help to identify high-risk individuals who subsequently\\u000a can be enrolled in preventive measures or treated by

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

40

Radiation-sensitive genetically susceptible pediatric sub-populations  

Microsoft Academic Search

Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged\\u000a about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients\\u000a with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to\\u000a multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni

Ruth A. Kleinerman

2009-01-01

41

DA rats from two colonies differ genetically and in their arthritis susceptibility.  

PubMed

The arthritis-susceptible DA rat is one of the most commonly used rat strains for genetic linkage analysis and is instrumental for the identification of many genetic loci. Even though DA rats were kept as inbred lines at different institutes and suppliers, it became obvious that the various breeding stocks differed genetically. To be able to compare the results from different linkage studies it is very import to verify the genetic background of the substrains used in those studies. We performed a genetic and phenotypic analysis of two DA substrains, DA/ZtmRhd and DA/OlaHsd, and found several genetic differences. One of the allelic differences between the DA/ZtmRhd and the DA/OlaHsd strain was located at rat chromosome 3, a 17-Mb large fragment, including the peak marker of a previously identified quantitative trait locus (QTL) for collagen-induced arthritis, Cia11. In addition, the substrains exhibited a significant difference in the susceptibility to pristane-induced arthritis (PIA) and disease severity of collagen-induced arthritis and PIA. However, by generating and testing a congenic line, we could demonstrate that phenotypic differences were not due to the contaminating fragment on chromosome 3. Nevertheless, we conclude that DA substrains show distinct genetic differences and caution should be taken when comparing arthritis data from different DA substrains. PMID:18668290

Rintisch, Carola; Holmdahl, Rikard

2008-06-01

42

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

PubMed Central

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

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

2012-01-01

43

Genetic variation and shared biological susceptibility underlying comorbidity in neuropsychiatry.  

PubMed

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

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

2007-07-01

44

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

45

Evidence for a Shared Genetic Susceptibility to Migraine and Epilepsy  

PubMed Central

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

Winawer, Melodie R.; Connors, Robert

2012-01-01

46

Association of susceptible genetic markers and autoantibodies in rheumatoid arthritis.  

PubMed

Rheumatoid arthritis (RA) is a chronic autoimmune disorder of unknown aetiology resulting in inflammation of the synovium, cartilage and bone. The disease has a heterogeneous character, consisting of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although, the pathogenesis of RA is incompletely understood, genetic factors play a vital role in susceptibility to RA as the heritability of RA is between 50 and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. Non-HLA genes, i.e. tumour necrosis factor-? (TNF-?) within the MHC (major histocompatibility complex) have also been investigated for association with RA. Although, some contradictory results have originated from several studies on TNF-? gene, the data published so far indicate the possible existence of TNF-? gene promoter variants that act as markers for disease severity and response to treatment in RA. The correlation of HLA and non-HLA genes within MHC region is apparently interpreted. A considerable number of confirmed associations with RA and other autoimmune disease susceptibility loci including peptidylarginine deiminase type 4 (PADI4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), signal transducer and activator of transcription (STAT4), cluster of differentiation 244 (CD244) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), located outside the MHC have been reported recently. In this review, we aim to give an update on recent progress in RA genetics, the importance of the combination of HLA-DRB1 alleles, non-HLA gene polymorphism, its detection and autoantibodies as susceptibility markers for early RA disease. PMID:25189266

Mohan, Vasanth Konda; Ganesan, Nalini; Gopalakrishnan, Rajasekhar

2014-08-01

47

Clinical features, treatment and genetic background of Treacher Collins syndrome  

Microsoft Academic Search

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development. The major features of the disease include midface hypoplasia, micrognathia, microtia, conductive hearing loss and cleft palate. Current procedures of surgical treatment of TCS are discussed and novel findings concerning the genetic background of TCS are described. The TCS locus has been mapped to chro- mosome 5q31.3-32. The

Piotr WÓJCICKI; Kazimierz KOBUS

2002-01-01

48

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

PubMed Central

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

Gundel, Pedro E; Martinez-Ghersa, Maria A; Omacini, Marina; Cuyeu, Romina; Pagano, Elba; Rios, Raul; Ghersa, Claudio M

2012-01-01

49

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

PubMed

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

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

2012-12-01

50

Genetic Variability in Susceptibility to Occupational Respiratory Sensitization  

PubMed Central

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

Yucesoy, Berran; Johnson, Victor J.

2011-01-01

51

Copyright 2001 by the Genetics Society of America Genetic Loci Controlling Breast Cancer Susceptibility in the Wistar-Kyoto Rat  

E-print Network

Copyright © 2001 by the Genetics Society of America Genetic Loci Controlling Breast Cancer of Mcs), which had no significant main effect on mammary cancer susceptibility in this genetic analysis that are rare in a population but have a high genetic pene- breast cancer, on the basis of family linkage

Gould, Michael N.

52

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

53

Genetic susceptibility to triple-negative breast cancer.  

PubMed

Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models. PMID:23536562

Stevens, Kristen N; Vachon, Celine M; Couch, Fergus J

2013-04-01

54

Sendai virus infection in genetically resistant and susceptible mice.  

PubMed Central

The pathogenesis of Sendai virus infection in genetically resistant (C57Bl/6) and susceptible (DBA/2) nonimmune adult mice was investigated. Rising serum complement-fixation (CF) antibody titers were delayed in DBA/2 mice as compared with C57Bl/6 mice. C57Bl/6 mice developed descending desquamative endobronchiolitis, and DBA/2 mice developed descending proliferative endobronchiolitis and bronchogenic alveolitis. Peribronchiolar lymphoid cuffs that formed in C57Bl/6 mice were thicker and more densely populated than those of DBA/2 mice. Immunofluorescence demonstrated viral antigens confined to the epithelial lining of conducting airways in C57Bl/6 mice but extending to alveolar corner cells in DBA/2 mice. Studies with a transmission electron microscope confirmed that Type II pneumocytes were infected only in DBA/2 mice. IgG-containing cells selectively accumulated along the airways of both strains, but fewer were recruited by DBA/2 mice. These results suggest that genetic resistance to Sendai virus is expressed through the immune system. Images Figure 4 Figure 5 Figure 6 Figure 7 PMID:6271017

Brownstein, D. G.; Smith, A. L.; Johnson, E. A.

1981-01-01

55

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. PMID:19397823

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

2009-01-01

56

Genetic susceptibility to non-polyposis colorectal cancer  

PubMed Central

Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APC gene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for approximately 5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1, MSH2, MSH6, PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still molecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example.?Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (1) tumours that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor ? type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such as K-ras, APC, and p53, and behave aggressively, of which FAP is an example.?This review focuses most heavily on the clinical features, pathology, molecular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a detailed differential diagnosis of the several hereditary CRC variants is provided. The extant genetic and phenotypic heterogeneity in CRC leads to the conclusion that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Therefore, it is important to ascertain cancer of all anatomical sites, as well as non-cancer phenotypic stigmata (such as the perioral and mucosal pigmentations in Peutz-Jeghers syndrome), when taking a family cancer history.???Keywords: colorectal cancer; hereditary non-polyposis colorectal cancer; genetic susceptibility PMID:10544223

Lynch, H.; de la Chapelle, A.

1999-01-01

57

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

E-print Network

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

Antonovics, Janis

58

The genetics of complex autoimmune diseases: non-MHC susceptibility genes  

Microsoft Academic Search

Susceptibility to complex autoimmune diseases (AIDs) is a multigenic phenotype affected by a variety of genetic and environmental or stochastic factors. After over a decade of linkage analyses, the identification of non-major histocompatibility complex (non-MHC) susceptibility alleles has proved to be difficult, predominantly because of extensive genetic heterogeneity and possible epistatic interactions among the multiple genes required for disease development.

Amy Wanstrat; Edward Wakeland

2001-01-01

59

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

PubMed

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

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

2014-07-01

60

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

PubMed Central

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

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

2013-01-01

61

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. PMID:23128497

Giudicessi, John R.; Ackerman, Michael J.

2013-01-01

62

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

63

Genetic selection for coping style predicts stressor susceptibility.  

PubMed

Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LAL male was living in sensory contact (except tactile contact) with a dominant SAL male for 25 days (sensory contact stress). In the second paradigm, a SAL or LAL male was, in addition to the first paradigm, defeated by a SAL male for 21 consecutive days (defeat stress). The sensory contact stressor induced in LAL mice chronic body weight loss and increased plasma adrenocorticotropic hormone levels compared to SAL mice and increased corticosterone levels, thymus involution and lower hippocampal mineralocorticoid receptor (MR) : glucocorticoid receptor (GR) ratio compared to LAL controls. The defeat stressor increased corticosterone secretion and caused adrenal hypertrophy and thymus involution in both mouse lines. Defeated LAL mice showed long-lasting body weight loss and higher corticosterone concentrations than SAL mice and lower hippocampal MR : GR ratio and decreased immobility behaviour in the forced swimming test than LAL controls. Hypothalamic corticotropin-releasing hormone mRNA expression was higher in defeated SAL than in controls. The present data show that both stress paradigms induced line-dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only. This latter stress paradigm therefore seems promising to analyse the role of genetic factors in the individual differences in stress-related psychopathology. PMID:12588514

Veenema, A H; Meijer, O C; de Kloet, E R; Koolhaas, J M

2003-03-01

64

Effect of excess body weight on the genetic susceptibility to cancer.  

PubMed

Excess body weight and genetics play important roles in cancer susceptibility. Although several studies have reported on obesity and genetic variants as separate risk factors for cancer, very few studies have investigated the interaction between excess body weight and genetic variants in cancer susceptibility. In this review, we focus on the interplay between these 2 risk factors, which are a major determinant of the individual risk of cancer onset. PMID:25291134

Burza, Maria A; Spagnuolo, Rocco; Montalcini, Tiziana; Doldo, Patrizia; Pujia, Arturo; Romeo, Stefano

2014-01-01

65

COMT Contributes to Genetic Susceptibility Shared Among Anxiety Spectrum Phenotypes  

PubMed Central

Background Catechol-O-methyl transferase (COMT) has been investigated for its possible role in a wide range of psychiatric phenotypes. In particular, several studies support association of this gene with panic disorder and other anxiety-related traits. Methods We examined the COMT gene for association with genetic risk across a range of anxiety spectrum phenotypes. We used multivariate structural equation modeling to select twin pairs scoring at the extremes of a latent genetic risk factor shared by neuroticism, several anxiety disorders, and major depression from a large population-based twin sample. Using one member from each of these pairs, the resulting sample of 589 cases and 539 controls were entered into a two-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2. Results The functional val158met polymorphism (rs4680) plus nine other SNP markers selected to capture the major allelic variation across the COMT locus were analyzed for differences between cases and controls. While the val (G) allele of rs4680 showed marginally significant association in our combined stage 1 plus stage 2 sample, a high-risk haplotype of this allele with the A allele of rs165599 was significantly over-represented in cases (p=1.97e-5, OR=1.95). This haplotype also predicted individual differences in neuroticism and risk for several anxiety disorders and major depression. Consistent with prior studies, our findings are female specific. Conclusions Variations in the COMT gene contribute to genetic risk shared across a range of anxiety-related phenotypes. PMID:18436194

Hettema, John M.; An, Seon-Sook; Bukszar, Jozsef; van den Oord, Edwin J.C.G.; Neale, Michael C.; Kendler, Kenneth S.; Chen, Xiangning

2008-01-01

66

Clinical features, treatment and genetic background of Treacher Collins syndrome.  

PubMed

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development. The major features of the disease include midface hypoplasia, micrognathia, microtia, conductive hearing loss and cleft palate. Current procedures of surgical treatment of TCS are discussed and novel findings concerning the genetic background of TCS are described. The TCS locus has been mapped to chromosome 5q31.3-32. The TCOF1 gene contains 26 exons and encodes a 1411 amino acid protein named treacle. In the TCOF1 gene 51 mutations have been identified. Most of these mutations are insertions or deletions, which result in an introduction of a premature termination codon into the reading frame. Mutational spectra support the hypothesis that TCS results from haploinsufficiency of treacle. PMID:12080178

Marsza?ek, Bozena; Wójcicki, Piotr; Kobus, Kazimierz; Trzeciak, Wies?aw H

2002-01-01

67

Genetic susceptibility, smoking, obesity and risk of venous thromboembolism.  

PubMed

The F5 G1691A (Factor V Leiden) and F2 G20210A (prothrombin) mutations are linked to an increase in the incidence rate of venous thromboembolism (VTE), but their effects are highly variable. We investigated whether the effects of smoking and obesity might explain this variability. In a case-cohort study including the participants of the Danish Diet, Cancer and Health study, we computed incidence rates and Cox proportional hazard ratios for VTE in individuals with and without the mutations, categorized by weight and tobacco consumption. The sole effect of heavy smoking was 128 extra VTE events per 100,000 person years in individuals with the F5 G1691A mutation versus 59 in individuals without. The sole effect of obesity was 222 extra VTE events per 100,000 person years in individuals with the F5 G1691A mutation, versus 103 in individuals without this mutation; and 705 extra VTE events per 100,000 person years in individuals with the F2 G20210A mutation versus 107 in individuals without this mutation. The F5 G1691A and F2 G20210A mutations conferred increased susceptibility to the unfavourable effects of smoking and obesity on the risk for VTE. Thus, individuals with genetic risk factors for VTE might benefit from maintaining a healthy lifestyle. PMID:20148880

Severinsen, Marianne T; Overvad, Kim; Johnsen, Søren P; Dethlefsen, Claus; Madsen, Poul H; Tjønneland, Anne; Kristensen, Søren R

2010-04-01

68

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

69

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

PubMed Central

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

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

2011-01-01

70

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

E-print Network

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

Rieseberg, Loren

71

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

PubMed Central

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

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

2014-01-01

72

Genetic differences in susceptibility to chemically induced myelotoxicity and leukemia.  

PubMed Central

The Ah locus represents a complex "cluster" of genese controlling the induction of numerous drug-metabolizing enzyme "activities" by polycyclic aromatic compounds. Allelic differences at the Ah locus are reflected in the large differences in inducibility of cytochrome P1-450 and benzo[a]pyrene metabolism in numerous tissues when the mice receive the chemical daily in their diet. This experimental model system offers to the hematologist and clinical pharmacologist a means to study genetic differences in toxic chemical depression of the bone marrow, as well as a potential model to study aplastic anemia and leukemia explainable on a single-gene basis. The genetically "responsive" individual who is at increased risk for cancer caused by subcutaneous or topical or intratracheal polycyclic hydrocarbons is at decreased risk for toxicity of the bone marrow and leukemia caused by oral benzo[a]pyrene (when compared with the genetically "nonresponsive" individual receiving the same dose of the same xenobiotic). In other words, tissue sites in direct contact with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dct with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dct with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dose but the route of administration and the tissue in which the malignancy or toxicity develops are therefore very important in the interpretation of data from tumorigenesis or toxicity experiments involving P1-450 inducers such as polycyclic hydrocarbons. There exists sufficient evidence that heritable variation of the Ah locus occurs in man. Growing evidence indicates that persons with higher aryl hydrocarbon hydroxylase inducibility in their cultured mitogen-activated lymphocytes may have a statistically significantly increased risk for certain types of cancer and drug toxicity. It remains to be determined at the present time, however, whether this genotype can be used as a biochemical marker in the individual patient for predicting increased susceptibility to certain types of environmentally caused cancers or toxicity in man. PMID:7016519

Nebert, D W

1981-01-01

73

Genetic polymorphism of cytochrome P450 as a biomarker of susceptibility to environmental toxicity.  

PubMed Central

Cytochrome P450 (CYP) enzymes are responsible for the metabolism of numerous xenobiotics and endogenous compounds, including the metabolic activation of most environmental toxic chemicals and carcinogens. Both metabolic and genetic polymorphisms have been identified for human CYP enzymes. The association of CYP genetic polymorphism and human cancer risk, and susceptibility to environmental hazards, have received increasing attention. This article briefly reviews the approaches and methods currently used in CYP genetic polymorphism studies. In addition, the current status and perspectives of using CYP genetic polymorphism as a biomarker of individual susceptibility to cancer and environmental toxicity are discussed. PMID:9255558

Hong, J Y; Yang, C S

1997-01-01

74

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

75

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

PubMed Central

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

Waits, Eric R.; Nebert, Daniel W.

2011-01-01

76

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

PubMed Central

Summary 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

2006-01-01

77

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

78

Genetic analysis of the susceptibility of mouse cytomegalovirus to acyclovir.  

PubMed Central

Eight independently derived mouse cytomegalovirus (MCMV) mutants resistant to acyclovir (ACV) were obtained by the sequential plating of wild-type virus in increasing concentrations of ACV. Results of complementation studies among these eight mutants suggest that all had mutations within the same or closely associated genes. A ninth MCMV mutant resistant to phosphonoacetate (PAA) derived by plating wild-type virus in the presence of 100 micrograms of PAA per ml displayed coresistance to ACV and was unable to complement any of the ACV-derived mutants. Recombination experiments among all combinations of the nine MCMV mutants were performed and supported the complementation data in that no recombination could be detected. Seven of the eight ACV-resistant mutants demonstrated cross-resistance to PAA and hypersensitivity to aphidicolin. The one mutant not coresistant to PAA was more susceptible to PAA than was the parent virus. Only a few mutants demonstrated coresistance when the mutants were tested against 9-beta-D-arabinofuranosyladenine (ara-A). The ACV mutant that demonstrated increased susceptibility to PAA was 30-fold more susceptible to ara-A but remained unchanged in susceptibility to aphidicolin. Two of the parent-mutant combinations were selected for DNA synthesis analysis in the presence of ACV (5 microM). A significant decrease in DNA synthesis was demonstrated for both parent viruses, and there was little effect on mutant virus DNA synthesis at the same drug concentration. These results suggest that susceptibility of MCMV to ACV is confined to a product of a single gene and that a mutation of this gene can lead to an altered phenotype when compared with parent virus in susceptibility of DNA synthesis to PAA, ara-A, and aphidicolin, drugs that are known to inhibit DNA polymerase activity. Images PMID:2983107

Sandford, G R; Wingard, J R; Simons, J W; Staal, S P; Saral, R; Burns, W H

1985-01-01

79

A Combinatorial Method for Predicting Genetic Susceptibility to Complex Diseases  

E-print Network

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

Zelikovsky, Alexander

80

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

SciTech Connect

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

Balmain, Allan [University of California, San Francisco; Song, Ihn Young [University of California, San Francisco

2013-05-15

81

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.

82

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

SciTech Connect

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

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

2006-11-22

83

Genetic variability in susceptibility and response to toxicants  

Microsoft Academic Search

Everyone has a unique combination of polymorphic traits that modify susceptibility and response to drugs, chemicals and carcinogenic exposures. The metabolism of exogenous and endogenous chemical toxins may be modified by inherited and induced variation in CYP (P450), acetyltransferase (NAT) and glutathione S-transferase (GST) genes. We observe that specific ‘at risk’ genotypes for GSTM1 and NAT1\\/2 increase risk for bladder

Merrill C. Miller; Harvey W. Mohrenweiser; Douglas A. Bell

2001-01-01

84

Genetically susceptible mice remain proportionally more susceptible to tuberculosis after vaccination  

PubMed Central

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

Medina, E; North, R J

1999-01-01

85

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

86

Connecting the dots between genes, biochemistry, and disease susceptibility: systems biology modeling in human genetics.  

PubMed

Understanding how DNA sequence variations impact human health through a hierarchy of biochemical and physiological systems is expected to improve the diagnosis, prevention, and treatment of common, complex human diseases. We have previously developed a hierarchical dynamic systems approach based on Petri nets for generating biochemical network models that are consistent with genetic models of disease susceptibility. This modeling approach uses an evolutionary computation approach called grammatical evolution as a search strategy for optimal Petri net models. We have previously demonstrated that this approach routinely identifies biochemical network models that are consistent with a variety of genetic models in which disease susceptibility is determined by nonlinear interactions between two or more DNA sequence variations. We review here this approach and then discuss how it can be used to model biochemical and metabolic data in the context of genetic studies of human disease susceptibility. PMID:15670716

Moore, Jason H; Boczko, Erik M; Summar, Marshall L

2005-02-01

87

Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis  

PubMed Central

Background Sporotrichosis is a chronic subcutaneous mycosis of humans and animals, which is typically acquired by traumatic inoculation of plant material contaminated with Sporothrix propagules, or via animals, mainly felines. Sporothrix infections notably occur in outbreaks, with large epidemics currently taking place in southeastern Brazil and northeastern China. Pathogenic species include Sporothrix brasiliensis, Sporothrix schenckii s. str., Sporothrix globosa, and Sporothrix luriei, which exhibit differing geographical distribution, virulence, and resistance to antifungals. The phylogenetically remote species Sporothrix mexicana also shows a mild pathogenic potential. Methods We assessed a genetically diverse panel of 68 strains. Susceptibility profiles of medically important Sporothrix species were evaluated by measuring the MICs and MFCs for amphotericin B (AMB), fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), posaconazole (PCZ), flucytosine (5FC), and caspofungin (CAS). Haplotype networks were constructed to reveal interspecific divergences within clinical Sporothrix species to evaluate genetically deviant isolates. Results ITC and PCZ were moderately effective against S. brasiliensis (MIC90?=?2 and 2 ?g/mL, respectively) and S. schenckii (MIC90?=?4 and 2 ?g/mL, respectively). PCZ also showed low MICs against the rare species S. mexicana. 5FC, CAS, and FLC showed no antifungal activity against any Sporothrix species. The minimum fungicidal concentration ranged from 2 to >16 ?g/mL for AMB against S. brasiliensis and S. schenckii, while the MFC90 was >16 ?g/mL for ITC, VRC, and PCZ. Conclusion Sporothrix species in general showed high degrees of resistance against antifungals. Evaluating a genetically diverse panel of strains revealed evidence of multidrug resistant phenotypes, underlining the need for molecular identification of etiologic agents to predict therapeutic outcome. PMID:24755107

2014-01-01

88

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

PubMed Central

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

Li, Jun

2014-01-01

89

Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics  

Microsoft Academic Search

Summary We previously have described a group of patients with gluten sensitivity presenting with ataxia (gluten ataxia) and suggested that this disease entity may account for a large number of patients with sporadic idiopathic ataxia. We have therefore investigated the prevalence of gluten sensitivity amongst a large cohort of patients with sporadic and familial ataxia and looked at possible genetic

Marios Hadjivassiliou; Richard Grunewald; Basil Sharrack; David Sanders; Alan Lobo; Clare Williamson; Nicola Woodroofe; Nicholas Wood; Aelwyn Davies-Jones

2003-01-01

90

Association studies for finding cancer-susceptibility genetic variants  

Microsoft Academic Search

Cancer is the result of complex interactions between inherited and environmental factors. Known genes account for a small proportion of the heritability of cancer, and it is likely that many genes with modest effects are yet to be found. Genetic-association studies have been widely used in the search for such genes, but success has been limited so far. Increased knowledge

Paul D. P. Pharoah; Alison M. Dunning; Douglas F. Easton; Bruce A. J. Ponder

2004-01-01

91

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

Microsoft Academic Search

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

Li-Jun Ma; Agnes B. Fogo

2003-01-01

92

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

Microsoft Academic Search

In an attempt to identify the genetic basis for susceptibility to non-insulin-dependent diabetes mellitus within the context of obesity, we generated 401 genetically obeseLeprfa\\/LeprfaF2 WKY13M intercross rats that demonstrated wide variation in multiple phenotypic measures related to diabetes, including plasma glucose concentration, percentage of glycosylated hemoglobin, plasma insulin concentration, and pancreatic islet morphology. Using selective genotyping genome scanning approaches, we

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

1997-01-01

93

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

Microsoft Academic Search

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

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

2007-01-01

94

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

PubMed

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

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

2010-08-01

95

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

PubMed

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

Monteleone, Palmiero; Maj, Mario

2008-10-01

96

Genetic variants at 6p21.33 are associated with susceptibility  

E-print Network

psoriasis susceptibility region 1 (PSORS1). Non-Hodgkin lymphoma (NHL) is a heterogeneous group of neo- plasms of B- and T-cells that vary in their causes and molecular profiles1. NHL is the fifth most common that environmental and genetic risk factors differ for the common NHL subtypes: FL, diffuse large B-cell (DLBCL

California at Berkeley, University of

97

[Genetic base of esophageal squamous cell carcinoma susceptibility].  

PubMed

The esophageal squamous cell carcinoma is multifactorial disease involving genetic and environmental factors. The paper presents most important human data on the polymorphisms of selected genes that have been linked with higher risk of the neoplasm. The most widely studied group were genes encoded molecules engaged in biotransformations of xenobiotics, in particular potential carcinogens, like alcohol (ADH2) and aldehyde (ALDH2) dehydrogenases, various isoenzymes of cytochrome P450 (CYP1A1, CYP2E1) and glutathione S-transferase (GSTM1, GSTT1, GSTP1). High interest was also put for polymorphism in DNA repair genes, i.e., OGG1, XRCC1, XPD, XPG and MGMT as well as genes associated with nucleotide biosyntesis like methylenotetrahydrofolate reductase and thymidylate synthase and in control of cell cycle and apoptosis e.g., p53, Fas, FasL or TNF. Furthermore, it was revealed that predisposition to cancer in certain individual could be determined by coexistence of unprofitable allele of a few genes. Introduction of genetic screening test allows effective, purpose-oriented methods of prevention and in patients suffered from the cancer--application of optimal therapy and minimization of side-effects. PMID:19388510

Szumi?o, Justyna; Marzec, Barbara; Szumi?o, Micha?; Korobowicz, Agnieszka; Burdan, Franciszek

2009-02-01

98

Salmonella penetration through eggshells of chickens of different genetic backgrounds.  

PubMed

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

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

2013-09-01

99

Targeted Disruption of Mouse EGF Receptor: Effect of Genetic Background on Mutant Phenotype  

Microsoft Academic Search

Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129\\/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the

David W. Threadgill; Andrzej A. Dlugosz; Laura A. Hansen; Tamar Tennenbaum; Ulrike Lichti; Della Yee; Christian Lamantia; Tracy Mourton; Karl Herrup; Raymond C. Harris; John A. Barnard; Stuart H. Yuspa; Robert J. Coffey; Terry Magnuson

1995-01-01

100

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. PMID:23087704

Mao, Lei

2012-01-01

101

Genetic Background Affects Human Glial Fibrillary Acidic Protein Promoter Activity  

PubMed Central

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

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

2013-01-01

102

Effects of the genetic background on cognitive performances of TG2576 mice  

Microsoft Academic Search

Animal models of genetic diseases obtained by transferring human mutated genes in the mouse are widely used in biomedical based research. They constitute efficient tools to study mechanisms underlying abnormal phenotypes. Unfortunately, the phenotype of the transgene is often obscured by the genetic background of the embryonic stem cells and that of the recipient strain used to create the transgenic

Jean Michel Lassalle; Hélène Halley; Stéphanie Daumas; Laure Verret; B. Frances

2008-01-01

103

SEPTIN12 Genetic Variants Confer Susceptibility to Teratozoospermia  

PubMed Central

It is estimated that 10–15% of couples are infertile and male factors account for about half of these cases. With the advent of intracytoplasmic sperm injection (ICSI), many infertile men have been able to father offspring. However, teratozoospermia still remains a big challenge to tackle. Septins belong to a family of cytoskeletal proteins with GTPase activity and are involved in various biological processes e.g. morphogenesis, compartmentalization, apoptosis and cytokinesis. SEPTIN12, identified by c-DNA microarray analysis of infertile men, is exclusively expressed in the post meiotic male germ cells. Septin12+/+/Septin12+/? chimeric mice have multiple reproductive defects including the presence of immature sperm in the semen, and sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make SEPTIN12 a potential sterile gene in humans. In this study, we sequenced the entire coding region of SEPTIN12 in infertile men (n?=?160) and fertile controls (n?=?200) and identified ten variants. Among them is the c.474 G>A variant within exon 5 that encodes part of the GTP binding domain. The variant creates a novel splice donor site that causes skipping of a portion of exon 5, resulting in a truncated protein lacking the C-terminal half of SEPTIN12. Most individuals homozygous for the c.474 A allele had teratozoospermia (abnormal sperm <14%) and their sperm showed bent tail and de-condensed nucleus with significant DNA damage. Ex vivo experiment showed truncated SEPT12 inhibits filament formation in a dose-dependent manner. This study provides the first causal link between SEPTIN12 genetic variant and male infertility with distinctive sperm pathology. Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development. PMID:22479503

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

2012-01-01

104

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

PubMed Central

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

2014-01-01

105

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

PubMed Central

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

2013-01-01

106

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

PubMed Central

For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our understanding of gene function. In this review we summarize the uses and advantages of animal studies in identification of disease susceptibility genes, focusing on rheumatoid arthritis. We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future. PMID:19490601

Ahlqvist, Emma; Hultqvist, Malin; Holmdahl, Rikard

2009-01-01

107

Genetic Testing for TMEM154 Mutations Associated with Lentivirus Susceptibility in Sheep  

PubMed Central

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

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

2013-01-01

108

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. PMID:20927378

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

109

Variation in Short Tandem Repeats Is Deeply Structured by Genetic Background on the Human Y Chromosome  

PubMed Central

Summary Eleven biallelic polymorphisms and seven short-tandem-repeat (STR) loci mapping on the nonrecombining portion of the human Y chromosome have been typed in men from northwestern Africa. Analysis of the biallelic markers, which represent probable unique events in human evolution, allowed us to characterize the stable backgrounds or haplogroups of Y chromosomes that prevail in this geographic region. Variation in the more rapidly mutating genetic markers (STRs) has been used both to estimate the time to the most recent common ancestor for STR variability within these stable backgrounds and to explore whether STR differentiation among haplogroups still retains information about their phylogeny. When analysis of molecular variance was used to study the apportionment of STR variation among both genetic backgrounds (i.e., those defined by haplogroups) and population backgrounds, we found STR variability to be clearly structured by haplogroups. More than 80% of the genetic variance was found among haplogroups, whereas only 3.72% of the genetic variation could be attributed to differences among populations—that is, genetic variability appears to be much more structured by lineage than by population. This was confirmed when two population samples from the Iberian Peninsula were added to the analysis. The deep structure of the genetic variation in old genealogical units (haplogroups) challenges a population-based perspective in the comprehension of human genome diversity. A population may be better understood as an association of lineages from a deep and population-independent gene genealogy, rather than as a complete evolutionary unit. PMID:10577916

Bosch, Elena; Calafell, Francesc; Santos, Fabricio R.; Perez-Lezaun, Anna; Comas, David; Benchemsi, Noufissa; Tyler-Smith, Chris; Bertranpetit, Jaume

1999-01-01

110

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

PubMed Central

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

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

2013-01-01

111

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...

112

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

Microsoft Academic Search

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

Kerry E. Leslie; Susan M. Koger

113

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

PubMed Central

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

Das, Swapan Kumar; Sharma, Neeraj Kumar

2014-01-01

114

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

PubMed

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

Das, Swapan Kumar; Sharma, Neeraj Kumar

2014-04-15

115

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

PubMed Central

Background Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a critical negative regulator of the T-cell response, has been considered a candidate for many autoimmune diseases. Evidence from Caucasians supported a genetic predisposition of CTLA4 to myasthenia gravis (MG), but the contribution in East Asians has not been established. Objectives To investigate the role of CTLA4 variants in the susceptibility to MG and the contribution to subtypes of MG. Methods Six autoimmune disease-related risk alleles of CTLA4 (rs1863800, rs733618, rs4553808, rs5742909, rs231775, and rs3087243) were investigated for MG in northern Chinese. 168 patients with MG (mean age 37.1±20.5 years, 64 men and 104 women) and 233 healthy controls (mean age 53.3±8.7 years, 96 men and 137 women) were screened, and the contribution of CTLA4 to the general risk of MG and each subgroup was explored. Results rs1863800*C, rs733618*C, and rs231775*G were significantly associated with the whole cohort of patients with MG after permutation correction for multiple-testing adjustment (P?=?0.027, 0.001, and 0.032, respectively). A risk haplotype (CCACG) [odds ratio (OR)?=?1.535, range?=?1.150–2.059, P?=?0.004)] was also identified. The stratified subtype analysis indicated that the positive contribution was possibly derived from early onset MG (EOMG), seropositive MG (SPMG), female patients, and MG without thymoma. No association was observed in juvenile MG/LOMG, and MG coupled with thymoma. Conclusion A predisposing effect of rs1863800*C, rs733618*C, and rs231775*G of CTLA4 gene to general risk of MG in Chinese was demonstrated for the first time, which was likely derived from EOMG, SPMG, MG without thymoma and the female patients. PMID:25003519

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

2014-01-01

116

Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility  

PubMed Central

Background Genetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual’s susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development. Methods We genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case–control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform. Results In the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers. Conclusions These results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas. PMID:23663450

2013-01-01

117

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

PubMed

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

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

2014-08-01

118

Validation of six genetic determinants of susceptibility to estrogen-induced mammary cancer in the rat and assessment of their relevance to breast cancer risk in humans.  

PubMed

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

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

2014-08-01

119

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

PubMed Central

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

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

2014-01-01

120

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

PubMed

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

Mulvey, Lorna; Sinclair, Amy; Selman, Colin

2014-09-20

121

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...

122

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

PubMed Central

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

2011-01-01

123

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

124

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

E-print Network

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

Cox, Nancy J.

125

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

Microsoft Academic Search

BACKGROUND: Arabidopsis thaliana is the main model species for plant molecular genetics studies and world-wide efforts are devoted to identify the function of all its genes. To this end, reverse genetics by TILLING (Targeting Induced Local Lesions IN Genomes) in a permanent collection of chemically induced mutants is providing a unique resource in Columbia genetic background. In this work, we

Beatriz Martín; Mercedes Ramiro; José M Martínez-Zapater; Carlos Alonso-Blanco

2009-01-01

126

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

PubMed Central

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

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

2013-01-01

127

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

PubMed

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

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

2013-02-01

128

Effects of genetic background and dietary immunomodulators on chicken heterophil function and Salmonella resistance  

Microsoft Academic Search

Immune responses in poultry can be influenced by genetic background, nutrition, environment and management, or any combination of the above. Chicken heterophils are the first line of defense that can launch a series of intra- and extracellular antimicrobial mechanisms. Salmonella enterica serovar Enteritidis (SE) is a causative agent of a bacterial foodborne illness, commonly occurring after consumption of contaminated eggs

Phongsakorn Chuammitri

2010-01-01

129

Population synthesis modeling of the X-ray background with genetic algorithm - based optimization method  

E-print Network

We present population synthesis modeling of the X-ray background with genetic algorithm - based optimization method. In our models the best fit could be achieved for lower values of high-energy exponential cut-off (~ 170 keV) and larger amount of the highly obscured (log N_H=25.5) AGNs.

Alexander V. Halevin

2003-09-05

130

Genetic Background May Contribute to PAM50 Gene Expression Breast Cancer Subtype Assignments  

PubMed Central

Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of “snapshot” expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer. PMID:24015230

Hu, Ying; Bai, Ling; Geiger, Thomas; Goldberger, Natalie; Walker, Renard C.; Green, Jeffery E.; Wakefield, Lalage M.; Hunter, Kent W.

2013-01-01

131

Genetic background may contribute to PAM50 gene expression breast cancer subtype assignments.  

PubMed

Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer. PMID:24015230

Hu, Ying; Bai, Ling; Geiger, Thomas; Goldberger, Natalie; Walker, Renard C; Green, Jeffery E; Wakefield, Lalage M; Hunter, Kent W

2013-01-01

132

The impact of familial environment on depression scores after genetic testing for cancer susceptibility.  

PubMed

The associations between characteristics of family relationships and family trends in cancer worry and the psychological adjustment of recipients of genetic testing for cancer susceptibility were investigated. Data provided by 178 individuals from 24 families with Lynch syndrome who participated in a cohort study investigating psychological and behavioral outcomes of genetic testing were used. Responses from multiple family members were aggregated to construct family trends representing norms and departure from norms in cancer worry. Lower perceived family cohesion at baseline and decrease in this variable at 6 months after receipt of test results were associated with higher depression scores at 12 months. More variability in cancer worry among family members at baseline was also associated with higher depression scores at 12 months. Increase in family conflict was associated with decrease in depression scores among individuals from families with higher levels of cancer worry on average and less variability among the members. Family relationships and family trends in levels of cancer worry may play important roles in the psychological adjustment of genetic test recipients. The findings highlight the complexity of familial environment surrounding individuals that undergo genetic testing and suggest the benefits of considering these factors when providing genetic services. PMID:19021640

Ashida, S; Hadley, D W; Vaughn, B K; Kuhn, N R; Jenkins, J F; Koehly, L M

2009-01-01

133

The impact of familial environment on depression scores after genetic testing for cancer susceptibility  

PubMed Central

Purpose The associations between characteristics of family relationships and family trends in cancer worry and the psychological adjustment of recipients of genetic testing for cancer susceptibility were investigated. Methods Data provided by 178 individuals from 24 families with Lynch syndrome who participated in a cohort study investigating psychological and behavioral outcomes of genetic testing were used. Responses from multiple family members were aggregated to construct family trends representing norms and departure from norms in cancer worry. Results Lower perceived family cohesion at baseline and decrease in this variable at 6-months after receipt of test results were associated with higher depression scores at 12-months. More variability in cancer worry among family members at baseline was also associated with higher depression scores at 12-months. Increase in family conflict was associated with decrease in depression scores among individuals from families with higher levels of cancer worry on average and less variability among the members. Conclusions Family relationships and family trends in levels of cancer worry may play important roles in the psychological adjustment of genetic test recipients. The findings highlight the complexity of familial environment surrounding individuals that undergo genetic testing and suggest the benefits of considering these factors when providing genetic services. PMID:19021640

Ashida, Sato; Hadley, Donald W.; Vaughn, Brandon K.; Kuhn, Natalia R.; Jenkins, Jean F.; Koehly, Laura M.

2008-01-01

134

Cancer genetic testing panels for inherited cancer susceptibility: the clinical experience of a large adult genetics practice.  

PubMed

Next-generation sequencing genetic testing panels for cancer susceptibility (cancer panels) have recently become clinically available. At present, clinical utility is unknown and there are no set criteria or guidelines established for whom to offer such testing. Although it may be a cost-effective method to test multiple cancer susceptibility genes concurrently, the rate of finding variants of unknown significance (VUS) may be high and testing may yield mutations in genes with no established management recommendations. We describe our Center's experience over a 14-month period (April 2012-June 2013) for patient interest and uptake in cancer panel testing and whether there were predictors of pursuing testing or identifying mutations. Using a clinical ranking system, patients' family histories were ranked from 0 to 3 (low likelihood to high likelihood for underlying genetic susceptibility). The clinical ranking system was assessed to determine its predictability of finding mutations. Of the 689 patients who met inclusion criteria, the option of pursuing a cancer panel was discussed with 357 patients; 63 (17.6 %) patients pursued testing. Those who pursued testing were more likely to be older, male, affected with cancer, affected with multiple primary cancers, and had a higher clinical rank than non-pursuers. There were no significant predictors of finding a mutation on panel testing. Of the 61 patients who have received results, there was a 6.6 % mutation rate and 19.7 % VUS rate. The yield of cancer panels in clinical practice is low and the strength of family history alone may not predict likelihood of finding a mutation. PMID:25117502

Selkirk, Christina G; Vogel, Kristen J; Newlin, Anna C; Weissman, Scott M; Weiss, Shelly M; Wang, Chi-Hsiung; Hulick, Peter J

2014-12-01

135

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

PubMed Central

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

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

2010-01-01

136

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

PubMed

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

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

2014-01-01

137

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

PubMed Central

Background Leptospirosis is a worldwide zoonotic and recognized neglected infectious disease. It has been observed that only a proportion of individuals exposed to pathogenic species of Leptospira become infected and develop clinically evident disease. Moreover, little information is available in subsequent reinfections. In the present study, we determine if a first infection with leptospirosis protects against subsequent reinfection, and investigate which of the host genetic factors are involved in the susceptibility and resistance to leptospirosis. Methodology and Findings We conducted, in 2011, a retrospective hospital-based case-control study in the São Miguel Island population (Azores archipelago). In order to determine the seropositivity against pathogenic Leptospira after the first episode of leptospirosis, we performed a serological evaluation in 97 unrelated participants diagnosed with leptospirosis between 1992 and 2011. The results revealed that 46.4% of the 97 participants have circulating anti-Leptospira antibodies, and from these participants 35.6% maintained the seroprevalence for the same serogroup. Moreover, three of them were reinfected with unrelated Leptospira serovars. The genetic study was carried out by adding a control group composed of 470 unrelated healthy blood donors, also from São Miguel Island. Twenty five SNPs among twelve innate immune genes – IL1?, IL1?, IL6, IL10, IL12RB1, TLR2, TLR4, TLR9, CD14, CISH, LTA and TNF – were genotyped, as well as HLA class I (–A and –B) genes. Association analysis indicates that genotypes -511GG (OR?=?1.6, 95%CI 1.01-2.56, p?=?0.04) in IL1?, +1196CG (OR?=?2.0, 95%CI 1.26-3.27, p?=?0.003) in IL12RB1, -292TA (OR?=?1.8, 95% CI 1.06–2.1, p?=?0.03) and +3415CG (OR?=?1.8, 95% CI 1.08–3.08, p?=?0.02), both in CISH confer susceptibility to pathogenic Leptospira. Conclusion The present study suggests some degree of long-term protection against leptospires with an attenuation of symptoms in case of reinfection. Moreover, our data supports the genetic influence of IL1?, IL12RB1 and CISH genes and the susceptibility to leptospirosis infection. PMID:25255143

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

2014-01-01

138

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

PubMed Central

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

2013-01-01

139

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

PubMed Central

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

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

2014-01-01

140

Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility.  

PubMed

NACHT leucine-rich repeat- and PYD-containing (NLRP)3 protein controls the inflammasome by regulating caspase-1 activity and interleukin (IL)-1? processing. The contribution of IL-1? in the pathogenesis of psoriasis is well recognized. Polymorphisms in NLRP3 and caspase recruitment domain-containing protein (CARD)8, a negative regulator of caspase-1 activity, have been associated with susceptibility to common inflammatory diseases, such as Crohn's disease and rheumatoid arthritis. To investigate the role for genetic variants in the NLRP3 inflammasome in psoriasis susceptibility. In a patient sample comprising 1988 individuals from 491 families and 1002 healthy controls, genotypes for four selected single-nucleotide polymorphisms (SNPs) in NLRP3 (three SNPs) and CARD8 (one SNP) were determined by TaqMan(®) Allelic Discrimination. Using the transmission disequilibrium test (TDT), a significant increase in the transmission of the NLRP3 rs10733113G genotype to a subgroup of patients with more widespread psoriasis was demonstrated (P = 0.015). Using logistic regression analysis in 741 patients with psoriasis and 1002 controls, the CARD8 rs2043211 genotype was significantly different in cases and controls in overall terms [OR 1.3 (1.1-1.5), P = 0.004] and for both genders. Our data support the hypothesis that the inflammasome plays a role in psoriasis susceptibility. PMID:23171454

Carlström, Maria; Ekman, Anna-Karin; Petersson, Stina; Söderkvist, Peter; Enerbäck, Charlotta

2012-12-01

141

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

PubMed Central

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

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

2011-01-01

142

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

PubMed Central

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

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

2014-01-01

143

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. PMID:24167503

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

144

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

PubMed Central

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

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

2009-01-01

145

Genetic Background Comparison Using Distance-based Regression, with Applications in Population Stratification Evaluation and Adjustment  

PubMed Central

Population stratification (PS) can lead to an inflated rate of false positive findings in genome-wide association studies (GWAS). A commonly used approach is to adjust for a fixed number of principal components (PCs) in GWAS but this approach could have a deleterious impact on power when the cases and controls are equally distributed along selected PCs, or if the adjustment of certain covariates, such as self-identified ethnicity or recruitment center, already included in the association analyses, correctly map to major axes of genetic heterogeneity. We propose a computationally efficient procedure, PC-Finder, to identify a minimal set of PCs while permitting an effective correction for PS. A general pseudo F statistic, derived from a non-parametric multivariate regression model, can be used to assess whether PS exists or has been adequately corrected by a set of selected PCs. Empirical data from two GWAS conducted as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project demonstrate the application of the procedure. Furthermore, simulation studies show the power advantage of the proposed procedure in GWAS over currently used PS correction strategies, particularly when the PCs with substantial genetic variation are distributed similarly in cases and controls and therefore do not induce PS. PMID:19140130

Li, Qizhai; Wacholder, Sholom; Hunter, David J.; Hoover, Robert N.; Chanock, Stephen; Thomas, Gilles; Yu, Kai

2009-01-01

146

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

PubMed Central

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

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

2014-01-01

147

Histopathogenesis of malignant skin melanoma induced in genetically susceptible transgenic mice.  

PubMed Central

Animal models of human malignant skin melanoma were created in melanoma-susceptible inbred-strain transgenic mice by grafting skin from donors of high-susceptibility lines to hosts of a low-susceptibility line, thereby overcoming the problem of early death of the more susceptible animals from eye melanomas. As already described [Mintz, B. & Silvers, W. K. (1993) Proc. Natl. Acad. Sci. USA 90, 8817-8821], melanocytes within the grafts selectively proliferated in close proximity to areas of greatest wound healing, presumably in response to mitogenic factors from cells contributing to wound repair. An orderly sequence of externally visible events culminated in malignant melanoma. We examine here the histogenetic concomitants of these changes and find that they define a stepwise sequence strikingly comparable to that leading to human cutaneous melanoma. Moreover, the histological details suggest some of the underlying mechanisms. While the early lesions are first seen in the superficial dermis in the mouse, and in the basal layer of the epidermis in the human, both progress by radial growth followed by vertical growth. Melanocytic hyperplasia resulted in nests of densely melanized fusiform cells which were losing their dendrites. Some discrete lesions in the deep dermis appeared as blue nevi. As radial proliferation advanced, cellular atypia increased and the previously independent melanocytes cohered closely and formed a small solid tumor; the cells were usually then hypomelanotic or amelanotic. Ulceration of tumor through the epidermis occurred early. The tumor mass grew rapidly in the deep dermis and invaded and destroyed subcutaneous tissue and muscle. Primary tumors in the skin were often heterogeneous, with lobules or regions differing in pigmentation or atypia. However, the cells in circulating emboli, or in metastases in lymph nodes and lungs, appeared relatively homogeneous. These genetically uniform transgenic mouse models provide experimental access to the multistage genesis of melanoma. Images Fig. 1 Fig. 2 PMID:8415614

Mintz, B; Silvers, W K; Klein-Szanto, A J

1993-01-01

148

Genetic testing for cardiovascular disease susceptibility: a useful clinical management tool or possible misinformation?  

PubMed

Genetic susceptibility tests are already advertised on the Internet to identify individuals at above average risk for cardiovascular disease (CVD), such as deep vein thrombosis, hyperlipidemia, or atherosclerosis, whereas other tests claim to predict response to a particular drug treatment. Some kits are available to the public directly, bypassing a doctor. Their value, however, must be considered carefully, because although a genotype may be strongly and consistently associated with an intermediate trait, and because the intermediate trait is a strong predictor of CVD risk, there may be little or no association of genotype with risk over and above that of the measured trait. This is because multigenic effects and environmental modification (context dependency) of genotype effects determine CVD risk. An individual's personal characteristics and plasma risk-trait levels (which reflect both genotype and exposure) at present are the best predictors of clinical outcome. Only when genetic tests surpass this, possibly by the inclusion of many functional common variants, in conjunction with their context-dependent effects on risk, might their usefulness in clinical management be realized. Here we review some of the particular issues and concerns raised by CVD-risk genetic testing, and suggest areas of further research to address these issues. PMID:14715642

Humphries, Steve E; Ridker, Paul M; Talmud, Philippa J

2004-04-01

149

Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility  

PubMed Central

Objective The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). Patients and methods The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. Results We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). Conclusions These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases. PMID:23172754

Diaz-Gallo, Lina-Marcela; Simeon, Carmen P; Broen, Jasper C; Ortego-Centeno, Norberto; Beretta, Lorenzo; Vonk, Madelon C; Carreira, Patricia E; Vargas, Sofia; Roman-Ivorra, Jose Andres; Gonzalez-Gay, Miguel A; Tolosa, Carlos; Lopez-Longo, Francisco Javier; Espinosa, Gerard; Vicente, Esther F; Hesselstrand, Roger; Riemekasten, Gabriela; Witte, Torsten; Distler, Jorg H W; Voskuyl, Alexandre E; Schuerwegh, Annemie J; Shiels, Paul G; Nordin, Annika; Padyukov, Leonid; Hoffmann-Vold, Anna-Maria; Scorza, Raffaella; Lunardi, Claudio; Airo, Paolo; van Laar, Jacob M; Hunzelmann, Nicolas; Gathof, Birgit S; Kreuter, Alexander; Herrick, Ariane; Worthington, Jane; Denton, Christopher P; Zhou, Xiaodong; Arnett, Frank C; Fonseca, Carmen; Koeleman, Bobby PC; Assasi, Shervin; Radstake, Timothy R D J; Mayes, Maureen D; Martin, Javier

2013-01-01

150

The contribution of the genetic variations of the matrix metalloproteinase-1 gene to the genetic susceptibility of gastric cancer.  

PubMed

Matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, is responsible for the proteolytic degradation of basement membrane and extracellular matrix. MMP-1 plays a major role in the invasion of gastric cancer (GC). The role of the genetic polymorphisms in the functional regions of MMP-1 on the risk of GC remains unclear. To identify the markers that contribute to the genetic susceptibility to GC, we examined the potential association between GC and nine single-nucleotide polymorphisms (rs1799750, rs498186, rs475007, rs514921, rs494379, rs996999, rs2071232, rs1938901, and rs2239008) of the MMP-1 gene using the MassARRAY system in this study. The participants enrolled in this study included 422 patients with GC and 428 healthy subjects as the healthy controls from a Chinese Han population. The analysis revealed a weak association between the rs1799750 (in the promoter region) genotype distribution and GC (p=0.020). The frequency of the 2G allele was significantly higher in the patients with GC than in the healthy controls (p=0.005, odds ratio [OR]=1.324, 95% confidence interval [CI]: 1.087-1.613). Moreover, the patients with the 2G/2G genotype of rs1799750 had a significantly increased risk of cancer invasion compared with patients with the 1G/1G+1G/2G genotype (p=0.001, OR=0.505, 95% CI: 0.331-0.771). Strong linkage disequilibrium was observed in three blocks (D'>0.9). Significantly, more C-2G haplotypes (block 3) (p=0.0005 after Bonferroni correction) were found in GC subjects. These findings point to a role for MMP-1 promoter polymorphism in GC among a Han Chinese population, and may be informative for future genetic or biological studies on GC. PMID:25148204

Dedong, He; Bin, Zhang; Peisheng, Sun; Hongwei, Xu; Qinghui, Yang

2014-10-01

151

Arsenic-Induced Genotoxicity and Genetic Susceptibility to Arsenic-Related Pathologies  

PubMed Central

The arsenic (As) exposure represents an important problem in many parts of the World. Indeed, it is estimated that over 100 million individuals are exposed to arsenic, mainly through a contamination of groundwaters. Chronic exposure to As is associated with adverse effects on human health such as cancers, cardiovascular diseases, neurological diseases and the rate of morbidity and mortality in populations exposed is alarming. The purpose of this review is to summarize the genotoxic effects of As in the cells as well as to discuss the importance of signaling and repair of arsenic-induced DNA damage. The current knowledge of specific polymorphisms in candidate genes that confer susceptibility to arsenic exposure is also reviewed. We also discuss the perspectives offered by the determination of biological markers of early effect on health, incorporating genetic polymorphisms, with biomarkers for exposure to better evaluate exposure-response clinical relationships as well as to develop novel preventative strategies for arsenic- health effects. PMID:23583964

Faita, Francesca; Cori, Liliana; Bianchi, Fabrizio; Andreassi, Maria Grazia

2013-01-01

152

Arsenic-induced genotoxicity and genetic susceptibility to arsenic-related pathologies.  

PubMed

The arsenic (As) exposure represents an important problem in many parts of the World. Indeed, it is estimated that over 100 million individuals are exposed to arsenic, mainly through a contamination of groundwaters. Chronic exposure to As is associated with adverse effects on human health such as cancers, cardiovascular diseases, neurological diseases and the rate of morbidity and mortality in populations exposed is alarming. The purpose of this review is to summarize the genotoxic effects of As in the cells as well as to discuss the importance of signaling and repair of arsenic-induced DNA damage. The current knowledge of specific polymorphisms in candidate genes that confer susceptibility to arsenic exposure is also reviewed. We also discuss the perspectives offered by the determination of biological markers of early effect on health, incorporating genetic polymorphisms, with biomarkers for exposure to better evaluate exposure-response clinical relationships as well as to develop novel preventative strategies for arsenic-health effects. PMID:23583964

Faita, Francesca; Cori, Liliana; Bianchi, Fabrizio; Andreassi, Maria Grazia

2013-04-01

153

Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes.  

PubMed

The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary beta-cell promoter P2 of hepatocyte nuclear factor-4 alpha (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06-1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1-3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes. PMID:15047633

Silander, Kaisa; Mohlke, Karen L; Scott, Laura J; Peck, Erin C; Hollstein, Pablo; Skol, Andrew D; Jackson, Anne U; Deloukas, Panagiotis; Hunt, Sarah; Stavrides, George; Chines, Peter S; Erdos, Michael R; Narisu, Narisu; Conneely, Karen N; Li, Chun; Fingerlin, Tasha E; Dhanjal, Sharanjeet K; Valle, Timo T; Bergman, Richard N; Tuomilehto, Jaakko; Watanabe, Richard M; Boehnke, Michael; Collins, Francis S

2004-04-01

154

Tumor necrosis factor B (TNFB) genetic variants and its increased expression are associated with vitiligo susceptibility.  

PubMed

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

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

2013-01-01

155

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

PubMed Central

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

FENG, MAOHUI; FANG, XIPING; YANG, QIAN; OUYANG, GANG; CHEN, DAPING; MA, XIANG; LI, HUACHI; XIE, WEI

2014-01-01

156

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. PMID:9584103

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

157

Genetic background matters: a plant-virus gene-for-gene interaction is strongly influenced by genetic contexts.  

PubMed

Evolutionary processes responsible for parasite adaptation to their hosts determine our capacity to manage sustainably resistant plant crops. Most plant-parasite interactions studied so far correspond to gene-for-gene models in which the nature of the alleles present at a plant resistance locus and at a pathogen pathogenicity locus determine entirely the outcome of their confrontation. The interaction between the pepper pvr2 resistance locus and Potato virus Y (PVY) genome-linked protein VPg locus obeys this kind of model. Using synthetic chimeras between two parental PVY cDNA clones, we showed that the viral genetic background surrounding the VPg pathogenicity locus had a strong impact on the resistance breakdown capacity of the virus. Indeed, recombination of the cylindrical inclusion (CI) coding region between two PVY cDNA clones multiplied by six the virus capacity to break down the pvr2(3) -mediated resistance. High-throughput sequencing allowed the exploration of the diversity of PVY populations in response to the selection pressure of the pvr2(3) resistance. The CI chimera, which possessed an increased resistance breakdown capacity, did not show an increased mutation accumulation rate. Instead, selection of the most frequent resistance-breaking mutation seemed to be more efficient for the CI chimera than for the parental virus clone. These results echoed previous observations, which showed that the plant genetic background in which the pvr2(3) resistance gene was introduced modified strongly the efficiency of selection of resistance-breaking mutations by PVY. In a broader context, the PVY CI coding region is one of the first identified genetic factors to determine the evolvability of a plant virus. PMID:21726391

Montarry, Josselin; Doumayrou, Juliette; Simon, Vincent; Moury, Benoìt

2011-12-01

158

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. PMID:22008150

2011-01-01

159

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

PubMed Central

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

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

2012-01-01

160

Genetic background of nonmutant Piebald-Virol-Glaxo rats does not influence nephronophthisis phenotypes  

PubMed Central

Background Nephronophthisis (NPHP), which affects multiple organs, is a hereditary cystic kidney disease (CKD), characterized by interstitial fibrosis and numerous fluid-filled cysts in the kidneys. It is caused by mutations in NPHP genes, which encode for ciliary proteins known as nephrocystins. The disorder affects many people across the world and leads to end-stage renal disease. The aim of this study was to determine if the genetic background of the nonmutant female Piebald-Virol-Glaxo (PVG/Seac–/–) rat influences phenotypic inheritance of NPHP from mutant male Lewis polycystic kidney rats. Methods Mating experiments were performed between mutant Lewis polycystic kidney male rats with CKD and nonmutant PVG and Wistar Kyoto female rats without cystic kidney disease to raise second filial and backcross 1 progeny, respectively. Rats that developed cystic kidneys were identified. Systolic blood pressure was determined in each rat at 12 weeks of age using the tail and cuff method. After euthanasia, blood samples were collected and chemistry was determined. Histological examination of the kidneys, pancreas, and liver of rats with and without cystic kidney disease was performed. Results It was established that the genetic background of nonmutant female PVG rats did not influence the phenotypic inheritance of the CKD from mutant male Lewis polycystic kidney rats. The disease arose as a result of a recessive mutation in a single gene (second filial generation, CKD = 13, non-CKD = 39, ?2 = 0.00, P ? 0.97; backcross 1 generation, CKD = 67, non-CKD = 72, ?2 = 0.18, P > 0.05) and inherited as NPHP. The rats with CKD developed larger fluid-filled cystic kidneys, higher systolic blood pressure, and anemia, but there were no extrarenal cysts and disease did not lead to early pup mortality. Conclusion The genetic background of the nonmutant PVG rats does not influence the genetic and phenotypic inheritance of CKD from mutant Lewis polycystic kidney rats. A single recessive mutation incapacitated the gene, which relaxed its functional constraints, and led to formation of multiple cysts in the kidneys of the homozygous mutant rats. PMID:23549608

Yengkopiong, Jada Pasquale; Lako, Joseph Daniel Wani

2013-01-01

161

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

2013-09-15

162

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. PMID:18518925

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

163

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

PubMed Central

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

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

2003-01-01

164

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

Microsoft Academic Search

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

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

1997-01-01

165

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

PubMed Central

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

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

2014-01-01

166

Genetic Background Drives Transcriptional Variation in Human Induced Pluripotent Stem Cells  

PubMed Central

Human iPS cells have been generated using a diverse range of tissues from a variety of donors using different reprogramming vectors. However, these cell lines are heterogeneous, which presents a limitation for their use in disease modeling and personalized medicine. To explore the basis of this heterogeneity we generated 25 iPS cell lines under normalised conditions from the same set of somatic tissues across a number of donors. RNA-seq data sets from each cell line were compared to identify the majority contributors to transcriptional heterogeneity. We found that genetic differences between individual donors were the major cause of transcriptional variation between lines. In contrast, residual signatures from the somatic cell of origin, so called epigenetic memory, contributed relatively little to transcriptional variation. Thus, underlying genetic background variation is responsible for most heterogeneity between human iPS cell lines. We conclude that epigenetic effects in hIPSCs are minimal, and that hIPSCs are a stable, robust and powerful platform for large-scale studies of the function of genetic differences between individuals. Our data also suggest that future studies using hIPSCs as a model system should focus most effort on collection of large numbers of donors, rather than generating large numbers of lines from the same donor. PMID:24901476

de Brito, Miguel Cardoso; Bradley, Allan; Vallier, Ludovic; Gaffney, Daniel

2014-01-01

167

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

PubMed Central

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

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

2012-01-01

168

Genetic Variants in Toll-Like Receptors Are Not Associated with Rheumatoid Arthritis Susceptibility or Anti-Tumour Necrosis Factor Treatment Outcome  

PubMed Central

Background Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication. Methodology and Principal Findings 22 single nucleotide polymorphisms (SNPs) in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls). 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients) we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. Conclusion We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population. PMID:21179534

Barrera, Pilar; Schijvenaars, Mascha M. V. A. P.; Toonen, Erik J. M.; Scheffer, Hans; Padyukov, Leonid; Kastbom, Alf; Klareskog, Lars; Barton, Anne; Kievit, Wietske; Rood, Maarten J.; Jansen, Tim L.; Swinkels, Dorine; van Riel, Piet L. C. M.; Franke, Barbara; Bendtzen, Klaus; Radstake, Timothy R. D. J.

2010-01-01

169

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

PubMed Central

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

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

1999-01-01

170

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

PubMed Central

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; Passini, B; Radice, P; Manoukian, S; Eccles, D M; Tang, N; Olah, E; Anton-Culver, H; Warner, E; Lubinski, J; Gronwald, J; Gorski, B; Tryggvadottir, L; Syrjakoski, K; Kallioniemi, O-P; Eerola, H; Nevanlinna, H; Pharoah, P D P; Easton, D F

2008-01-01

171

Correlations of IFN-? genetic polymorphisms with susceptibility to breast cancer: a meta-analysis.  

PubMed

The meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in the IFN-? gene and susceptibility to breast cancer. The following electronic databases were searched without language restrictions: MEDLINE (1966 ~ 2013), the Cochrane Library Database (issue 12, 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), Web of Science (1945 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). Meta-analysis was performed with the use of the STATA statistical software. Odds ratios (OR) with their 95 % confidence intervals (95 % CIs) were calculated. Nine clinical case-control studies met all the inclusion criteria and were included in this meta-analysis. A total of 1,182 breast cancer patients and 1,525 healthy controls were involved in this meta-analysis. Three functional polymorphisms were assessed, including rs2069705 C>T, rs2430561 T>A, and CA repeats 2/X. Our meta-analysis results indicated that IFN-? genetic polymorphisms might be significantly associated with an increased risk of breast cancer (allele model: OR = 1.37, 95 % CI = 1.03 ~ 1.83, P = 0.031; dominant model: OR = 1.55, 95 % CI = 1.01 ~ 2.37, P = 0.046; homozygous model: OR = 2.23, 95 % CI = 1.30 ~ 3.82, P = 0.004; respectively), especially the rs2430561 T>A polymorphism. Subgroup analysis based on ethnicity suggested that genetic polymorphisms in the IFN-? gene were closely correlated with increased breast cancer risk among Asians (allele model: OR = 1.21, 95 % CI = 1.02 ~ 1.58, P = 0.017; dominant model: OR = 3.44, 95 % CI = 2.07 ~ 5.71, P < 0.001; recessive model: OR = 1.58, 95 % CI = 1.06 ~ 2.37, P = 0.025; homozygous model: OR = 1.83, 95 % CI = 1.19 ~ 2.80, P = 0.006; respectively), but not among Caucasians (all P > 0.05). Our meta-analysis supported the hypothesis that IFN-? genetic polymorphisms may contribute to an increased risk of breast cancer, especially the rs2430561 T>A polymorphism among Asians. PMID:25051917

Li, Chun-Jiang; Dai, Yue; Fu, Yan-Jun; Tian, Jia-Ming; Li, Jin-Lun; Lu, Hong-Jun; Duan, Feng; Li, Qing-Wang

2014-07-01

172

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

PubMed

Esophageal cancer (EC) is the sixth leading cause of cancer-associated death worldwide and the incidence and mortality in China are the highest. The single nucleotide polymorphisms (SNPs) related to microRNAs could lead to alteration in microRNA expression and contribute to the susceptibility of cancer. To evaluate the association between microRNA-related SNPs and EC, a case-control study including 381 patients with esophageal squamous cell carcinoma (ESCC) and 426 gender, age-matched controls was carried out to investigate the genetic susceptibility of five microRNA-related SNPs (rs2910164 in microRNA-146a, rs11614913 in microRNA-196a-2, rs7813 in GEMIN4, rs1595066 and rs16845990 in ErbB4) as well as the interactions of gene-gene and gene-environment in the development of ESCC. Variant homozygote genotype of rs11614913 in microRNA-196a-2 and rs1595066 in ErbB4 were significantly associated with reduced ESCC risk (ORadjusted: 0.62, 95 % CI: 0.39-0.99 and ORadjusted: 0.38, 95 % CI: 0.24-0.61). The analysis of haplotypes in ErbB4 gene showed significant increased ESCC risk in Grs1595066Crs16845990 and Grs1595066Trs16845990 haplotypes (ORadjusted: 1.46, 95 % CI: 1.08-1.99 and ORadjusted: 1.33, 95 % CI: 1.10-1.62), and inversely reduced ESCC risk in Ars1595066Crs16845990 and Ars1595066Trs16845990 haplotypes with OR (95 % CI) of 0.75 (0.60-0.94) and 0.65 (0.49-0.86), respectively. These findings suggest that the polymorphisms in the microRNA-related genes may affect susceptibility of ESCC in Chinese Han population and the gene-gene interactions play vital roles in the progression on esophageal cancer. Future studies with larger sample and different ethnic populations are required to support and validate our findings. PMID:24916311

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

2014-12-01

173

Genetic-Background Modulation of Core and Variable Autistic-Like Symptoms in Fmr1 Knock-Out Mice  

E-print Network

Genetic-Background Modulation of Core and Variable Autistic-Like Symptoms in Fmr1 Knock-Out Mice of autism spectrum disorders (ASD) with good construct validity are currently available; using genetic of activity, epileptic events). Results: Fmr1-KO mice displayed autistic-like core symptoms of altered social

Boyer, Edmond

174

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

PubMed

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

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

1998-01-01

175

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

PubMed Central

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

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

2014-01-01

176

Genetic Variation in CLDN1 and Susceptibility to Hepatitis C Virus Infection  

PubMed Central

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

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

2010-01-01

177

Genetic susceptibility to hip arthroplasty failure--association with the RANK/OPG pathway  

PubMed Central

The OPG/RANK/RANKL system has been implicated in the biological cascade of events initiated by particulate wear debris and bacterial infection resulting in periprosthetic bone loss around total hip arthroplasties (THA). Individual responses to such stimuli may be dictated by genetic variation caused by single nucleotide polymorphisms (SNPs). Case control study of the osteoprotegerin and RANK genes for possible association with deep sepsis or aseptic loosening. All patients were Caucasian and had had a cemented Charnley THA and polyethylene acetabular cup. Cases consisted of 91 patients with early aseptic loosening and 71 patients with deep infection. Controls were 150 clinically and radiologically well-fixed THAs. DNA samples were genotyped using Taqman allelic discrimination. The A allele (p<0.001) and genotype A/A (p<0.001) for the OPG-163 SNP were associated with aseptic failure. Additionally, the RANK +575 (C/T SNP) T allele (p=0.004) and T/T genotype (p=0.008) frequencies were associated with aseptic failure. Comparing the septic group with the controls, the frequency of the A allele (p<0.001) and the genotype A/A (p<0.001) for the OPG-163 SNP were statistically significant. Aseptic loosening and deep infection of THA may be under the influence of susceptibility genes. SNP markers may serve as predictors of implant survival. PMID:16583245

Bayat, A.; Jury, F.; Ollier, W. E.R.; Kay, P. R.

2006-01-01

178

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

2009-05-01

179

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

PubMed Central

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

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

2014-01-01

180

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

PubMed

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

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

2014-10-01

181

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

PubMed

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

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

2014-10-01

182

Effect of Mutation and Genetic Background on Drug Resistance in Mycobacterium tuberculosis  

PubMed Central

Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter ?15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P < 0.0001). Lineage 1 was associated with inhA promoter ?15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P < 0.0001). In conclusion, M. tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance. PMID:22470121

Egger, Matthias; Bodmer, Thomas; Altpeter, Ekkehardt; Zwahlen, Marcel; Jaton, Katia; Pfyffer, Gaby E.; Borrell, Sonia; Dubuis, Olivier; Bruderer, Thomas; Siegrist, Hans H.; Furrer, Hansjakob; Calmy, Alexandra; Fehr, Jan; Stalder, Jesica Mazza; Ninet, Beatrice; Bottger, Erik C.; Gagneux, Sebastien

2012-01-01

183

Molecular Markers Allow to Remove Introgressed Genetic Background: A Simulation Study  

PubMed Central

The maintenance of genetically differentiated populations can be important for several reasons (whether for wild species or domestic breeds of economic interest). When those populations are introgressed by foreign individuals, methods to eliminate the exogenous alleles can be implemented to recover the native genetic background. This study used computer simulations to explore the usefulness of several molecular based diagnostic approaches to recover of a native population after suffering an introgression event where some exogenous alleles were admixed for a few generations. To remove the exogenous alleles, different types of molecular markers were used in order to decide which of the available individuals contributed descendants to next generation and their number of offspring. Recovery was most efficient using diagnostic markers (i.e., with private alleles) and least efficient when using alleles present in both native and exogenous populations at different frequencies. The increased inbreeding was a side-effect of the management strategy. Both values (% of native alleles and inbreeding) were largely dependent on the amount of exogenous individuals entering the population and the number of generations of admixture that occurred prior to management. PMID:23152901

Amador, Carmen; Toro, Miguel Angel; Fernandez, Jesus

2012-01-01

184

Quantitative trait loci for life span in Drosophila melanogaster: interactions with genetic background and larval density.  

PubMed Central

The genetic architecture of variation in adult life span was examined for a population of recombinant inbred lines, each of which had been crossed to both inbred parental strains from which the lines were derived, after emergence from both high and low larval density. QTL affecting life span were mapped within each sex and larval density treatment by linkage to highly polymorphic roo-transposable element markers, using a composite interval mapping method. We detected a total of six QTL affecting life span; the additive effects and degrees of dominance for all were highly sex- and larval environment-specific. There were significant epistatic interactions between five of the life span QTL, the effects of which also differed according to genetic background, sex, and larval density. Five additional QTL were identified that contributed to differences among lines in their sensitivity to variation in larval density. Further fine-scale mapping is necessary to determine whether candidate genes within the regions to which the QTL map are actually responsible for the observed variation in life span. PMID:10924473

Leips, J; Mackay, T F

2000-01-01

185

[Genetic background of ADHD: genes of the serotonergic system, other candidate genes, endophenotype].  

PubMed

Recent studies have shown that in the aetiology of attention-deficit hyperactivity disorder (ADHD) genetic factors may be of importance. Biochemical and pharmacological studies reveal a connection between abnormalities of dopaminergic, adrenergic and serotonergic system and ADHD. Therefore genes for enzymes synthesizing or degrading proper neurotransmitters, genes for adequate transporters and receptors and genes for other substances, which altered the level of neurotransmitters, are studied. Many authors describe the connection between ADHD development and the synaptosomal-associated protein 25 (SNAP-25) gene. This protein plays a role in catecholamine secretion. Its higher expression is specific for neurones. SNAP-25 gene mutation may change this protein level, function of synapse and neurotransmitters storage. Acetylcholine receptor alpha4 subunit gene stimulation increases the dopamine level. Therefore this receptor gene may be important in the aetiology of ADHD studies. Other possible factors in ADHD background are substance influence on brain maturation, including N-methyl-D aspartate glutamate receptor 2A gene polymorphism (GRIN2A) and brain derived neurotrophic factor (BDNF) gene. One of the greatest challenges in studying the genetic basis of psychiatric disorders is to find appropriate ways to define the relevant endophenotype. ADHD often coexists with other psychiatric disorders, including specific developmental disorders, conduct disorders, obsessive-compulsive disorder and early onset of bipolar disorder. PMID:16756026

S?opie?, Agnieszka; Dmitrzak-Weglarz, Monika; Rybakowski, Filip; Rajewski, Andrzej; Hauser, Joanna

2006-01-01

186

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

PubMed

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

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

2014-06-01

187

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

188

Genetic variations in EGFR and ERBB4 increase susceptibility to cervical cancer  

PubMed Central

Objectives Inherited genetic variability contributes to susceptibility to cervical cancer. We investigated the association of single nucleotide polymorphisms (SNPs) in the human epidermal growth factor receptor (ErbB) family with cervical cancer. Methods We used the transmission disequilibrium test (TDT) to look for excessive transmission of tag single nucleotide polymorphisms (tSNPs) in ERBB family members EGFR, ERBB2, ERBB3, and ERBB4 in a large sample of women with invasive and in situ cervical cancer and their biological parents (628 trios). The study used a discovery set of trios (244) analyzed by Ilumina GoldenGate in which SNPs reaching a P< .05 were re-tested by TaqMan in the combined set of 628. We also explored collaborative effects of different ERBB alleles. Results Based on single SNP TDT tests we identified 16 SNPs significant in the discover stage and six of 14 SNPs that could be assayed by TaqMan were significantly overtransmitted in women with cervical cancer in the combined replication set. Four SNPs were located in intron 1 of EGFR and two SNPs in intron 24 of ERBB4 The EGFR variants are located near multiple enhancers, silencers, and the previously identified functional common polymorphisms in intron 1. Conclusions Our data provide evidence for the involvement of intron 1 EGFR variants and intron 24 ERBB4 variants in modulating risk for the development of in situ and invasive cervical cancer. These variants should be examined in additional populations and functional studies would be needed to confirm this hypothesis. PMID:23927961

Ma, Duanduan; Hovey, Raymond L.; Zhang, Zhengyan; Fye, Samantha; Huettner, Phyllis C; Borecki, Ingrid B.; Rader, Janet S.

2013-01-01

189

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. PMID:23967108

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

190

Insufficiently Defined Genetic Background Confounds Phenotypes in Transgenic Studies As Exemplified by Malaria Infection in Tlr9 Knockout Mice  

Microsoft Academic Search

The use of genetically modified mice, i.e. transgenic as well as gene knockout (KO) and knock-in mice, has become an established tool to study gene function in many animal models for human diseases . However, a gene functions in a particular genomic context. This implies the importance of a well-defined homogenous genetic background for the analysis and interpretation of phenotypes

Nathalie Geurts; Erik Martens; Sebastien Verhenne; Natacha Lays; Greet Thijs; Stefan Magez; Bénédicte Cauwe; Sandra Li; Hubertine Heremans; Ghislain Opdenakker; Philippe E. Van den Steen

2011-01-01

191

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

PubMed Central

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

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

2014-01-01

192

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

PubMed

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. PMID:23066103

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

2012-12-01

193

Genetic variations in the KIR gene family may contribute to susceptibility to ankylosing spondylitis: a meta-analysis.  

PubMed

The present meta-analysis of relevant case-control studies was conducted to investigate the possible relationships between genetic variations in the killer cell immunoglobulin-like receptor (KIR) gene clusters of the human KIR gene family and susceptibility to ankylosing spondylitis (AS). The following electronic databases were searched for relevant articles without language restrictions: the Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, the Chinese Biomedical Database (CBM) and Chinese National Knowledge Infrastructure (CNKI) databases, covering all papers published until 2013. STATA statistical software was adopted in this meta-analysis as well. We also calculated the crude odds ratios (OR) and its 95% confidence intervals (95 % CI). Seven case-control studies with 1,004 patients diagnosed with AS and 2,138 healthy cases were implicated in our meta-analysis, and 15 genes in the KIR gene family were also evaluated. The results of our meta-analysis show statistical significance between the genetic variations in the KIR2DL1, KIR2DS4, KIR2DS5 and KIR3DS1 genes and an increased susceptibility to AS (KIR2DL1: OR 7.82, 95% CI 3.87-15.81, P< 0.001; KIR2DS4: OR 1.91, 95% CI 1.16-3.13, P = 0.010; KIR2DS5: OR1.51, 95% CI 1.14-2.01, P = 0.004; KIR3DS1: OR 1.58, 95% CI 1.34-1.86, P< 0.001; respectively). However, we failed to found positive correlations between other genes and susceptibility to AS (all P >0.05). The current meta-analysis provides reliable evidence that genetic variations in the KIR gene family may contribute to susceptibility to AS, especially for the KIR2DL1, KIR2DS4, KIR2DS5 and KIR3DS1 genes. PMID:24880650

Zuo, Hai-Ning; Wang, Zhi-Long; Cui, Dao-Ran; Xin, Da-Jiang

2014-08-01

194

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

PubMed

Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrP(C)) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C) protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter. PMID:23236380

Stewart, Paula; Campbell, Lauren; Skogtvedt, Susan; Griffin, Karen A; Arnemo, Jon M; Tryland, Morten; Girling, Simon; Miller, Michael W; Tranulis, Michael A; Goldmann, Wilfred

2012-01-01

195

Genetic susceptibility loci for subtypes of breast cancer in an African American population  

PubMed Central

Background Most genome-wide association scans (GWAS) have been carried out in European ancestry populations; no risk variants for breast cancer have been identified solely from African ancestry GWAS data. Few GWAS hits have replicated in African ancestry populations. Methods In a nested case-control study of breast cancer in the Black Women’s Health Study (1,199 cases/1,948 controls), we evaluated index SNPs in 21 loci from GWAS of European or Asian ancestry populations, overall, in subtypes defined by estrogen (ER) and progesterone (PR) receptor status (ER+/PR+, n=336; ER?/PR?, n=229), and in triple-negative breast cancer (TNBC, N=81). To evaluate the contribution of genetic factors to population differences in breast cancer subtype, we also examined global percent African ancestry. Results Index SNPs in five loci were replicated, including three associated with ER?/PR? breast cancer (TERT rs10069690 in 5p15.33, rs704010 in 10q22.3, and rs8170 in 19p13.11): per allele odds ratios were 1.29 (95% confidence interval (CI) 1.04–1.59), p=0.02, 1.52 (95% CI 1.12–2.08), p=0.01, and 1.30 (95% CI 1.01–1.68), p=0.04, respectively. Stronger associations were observed for TNBC. Furthermore, cases in the highest quintile of percent African ancestry were three times more likely to have TNBC than ER+/PR+ cancer. Conclusions These findings provide the first confirmation of the TNBC SNP rs8170 in an African ancestry population, and independent confirmation of the TERT ER? SNP. Further, the risk of developing ER? breast cancer, particularly TNBC, increased with increasing proportion of global African ancestry. Impact The findings demonstrate the importance of genetic factors in the disproportionately high occurrence of TNBC in African American women. PMID:23136140

Palmer, Julie R.; Ruiz-Narvaez, Edward A.; Rotimi, Charles N.; Cupples, L. Adrienne; Cozier, Yvette C.; Adams-Campbell, Lucile L.; Rosenberg, Lynn

2012-01-01

196

Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies  

PubMed Central

Type 2 diabetes (2DM), obesity, and coronary artery disease (CAD) are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI)-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA), which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30?cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants. PMID:22697793

2012-01-01

197

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

PubMed Central

The genetic variants linked with the susceptibility of individuals to VTE are well known; however, the studies explaining the ethnicity based difference in susceptibility to VTE are limited. Present study assesses mutations in six candidate genes contributing to the etiology of VTE in Indian subjects. The study comprised 93 VTE patients and 102 healthy controls. A PCR-RFLP based analysis was performed for nine mutations in the following genes associated with VTE: favtor V Leiden (FVL), prothrombin, tissue factor pathway inhibitor (TFPI), fibrinogen-beta, plasminogen activator inhibitor 1 (PAI-1), and methylene tetrahydrofolatereductase (MTHFR). All the subjects were found to be monomorphic for FVL 1691G/A, prothrombin 20210G/A and TFPI ?536C/T mutations. The mutation in the MTHFR gene (677C/T) was observed only in patients. Contrarily, higher frequency of mutation in the PAI-1 ?844G/A and the fibrinogen-? ?455G/A was observed in controls in comparison to the patients. This study suggests that the PAI-1 ?844G/A and fibrinogen-? ?455G/A could be protective variants against VTE in Indians. While MTHFR 677C/T mutation was found to be associated, in contrast to other populations, the established genetic variants FVL 1691G/A, prothrombin 20210G/A, and TFPI ?536C/T may not be associated with VTE in Indians thus revealing the basis of ethnicity related differences in susceptibility of Indians to VTE. PMID:25349733

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

2014-01-01

198

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

PubMed Central

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

2014-01-01

199

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. PMID:23738324

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

2013-01-01

200

Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension.  

PubMed

Background. Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. Material and methods. PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. Results. Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). Conclusion. Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9. PMID:25332267

Seyfarth, Hans-Jürgen; Favreau, Nadine; Tennert, Carsten; Ruffert, Claudia; Halank, Michael; Wirtz, Hubert; Mössner, Joachim; Rosendahl, Jonas; Kovacs, Peter; Wittenburg, Henning

2014-01-01

201

A matrilineal genetic legacy from the last glacial maximum confers susceptibility to schizophrenia in Han Chinese.  

PubMed

Mitochondrial dysfunction has been widely reported in schizophrenia patients. To dissect the matrilineal structure of Han Chinese with or without schizophrenia and to decipher the maternal influence and evolutionary history of schizophrenia, a total of 1212 schizophrenia patients and 1005 matched healthy controls, all of Han Chinese origin, were recruited in Hunan Province, China. We classified haplogroup for each individual based on mitochondrial DNA (mtDNA) sequence variations and compared the haplogroup distribution pattern between cases and controls. Haplogroup B5a presented a higher frequency in cases than in controls (P = 0.02, OR = 1.67, 95% CI = [1.09, 2.56]), and this result could be confirmed by permutation analysis. Age estimation of haplogroup B5a in cases revealed a much younger age than that of controls, which was coincident with the Northern Hemisphere deglaciation at the end of the Last Glacial Maximum. Analysis of complete mtDNA in five patients belonging to haplogroup B5a showed that this background effect might be caused by haplogroup-defining variants m.8584G>A and m.10398A>G. Our results showed that matrilineal risk factor for schizophrenia had an ancient origin and might acquire a predisposing effect on schizophrenia due to the environment change and/or orchestration with other nuclear genetic factors appeared recently in human evolutionary history. PMID:25064678

Zhang, Wen; Tang, Jinsong; Zhang, A-Mei; Peng, Min-Sheng; Xie, Hai-Bing; Tan, Liwen; Xu, Lin; Zhang, Ya-Ping; Chen, Xiaogang; Yao, Yong-Gang

2014-07-20

202

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

PubMed Central

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

Chari, Sudarshan; Dworkin, Ian

2013-01-01

203

Resistance/susceptibility to lethal Sendai virus infection genetically linked to a mucociliary transport polymorphism.  

PubMed Central

Linkage was tested between a mucociliary transport polymorphism and resistance/susceptibility to lethal Sendai virus infection in segregant hybrid mice of C57BL/6J and DBA/2J parents. The distribution of paired phenotypes for tracheal mucociliary transport rates and susceptibility to lethal Sendai virus infection in 171 F1 X DBA/2J mice showed strong interaction of the parental phenotypes. PMID:3033294

Brownstein, D G

1987-01-01

204

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

2013-05-10

205

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

206

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

E-print Network

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

Abney, Mark

207

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

PubMed Central

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

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

2014-01-01

208

Genetic Variants in the Promoter Region of the ALOX5AP Gene and Susceptibility of Ischemic Stroke  

Microsoft Academic Search

Background: Despite accumulating evidence supporting the association between variants of the ALOX5AP gene and atherosclerotic vascular events, the precise mechanism is still unclear. No variants in the coding sequence that lead to amino acid substitution have been found. We investigated genetic variants in the promoter region of the ALOX5AP gene and the association with ischemic stroke in a north Chinese

Ruijun Ji; Jianping Jia; Xin Ma; Jian Wu; Yanli Zhang; Liqing Xu

2011-01-01

209

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. PMID:22606226

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

210

Testing the role of genetic background in parallel evolution using the comparative experimental evolution of antibiotic resistance.  

PubMed

Parallel evolution is the independent evolution of the same phenotype or genotype in response to the same selection pressure. There are examples of parallel molecular evolution across divergent genetic backgrounds, suggesting that genetic background may not play an important role in determining the outcome of adaptation. Here, we measure the influence of genetic background on phenotypic and molecular adaptation by combining experimental evolution with comparative analysis. We selected for resistance to the antibiotic rifampicin in eight strains of bacteria from the genus Pseudomonas using a short term selection experiment. Adaptation occurred by 47 mutations at conserved sites in rpoB, the target of rifampicin, and due to the high diversity of possible mutations the probability of within-strain parallel evolution was low. The probability of between-strain parallel evolution was only marginally lower, because different strains substituted similar rpoB mutations. In contrast, we found that more than 30% of the phenotypic variation in the growth rate of evolved clones was attributable to among-strain differences. Parallel molecular evolution across strains resulted in divergent phenotypic evolution because rpoB mutations had different effects on growth rate in different strains. This study shows that genetic divergence between strains constrains parallel phenotypic evolution, but had little detectable impact on the molecular basis of adaptation in this system. PMID:25228081

Vogwill, Tom; Kojadinovic, Mila; Furió, Victoria; MacLean, R Craig

2014-12-01

211

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

PubMed Central

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

Belinsky, Steven A.

2013-01-01

212

Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma.  

PubMed

We conducted genome-wide association studies of non-Hodgkin lymphoma using Illumina HumanHap550 BeadChips to identify subtype-specific associations in follicular, diffuse large B-cell and chronic lymphocytic leukemia/small lymphocytic lymphomas. We found that rs6457327 on 6p21.33 was associated with susceptibility to follicular lymphoma (FL; N = 189 cases, 592 controls) with validation in another 456 FL cases and 2,785 controls (combined allelic P = 4.7 x 10(-11)). The region of strongest association overlapped C6orf15 (STG), located near psoriasis susceptibility region 1 (PSORS1). PMID:19620980

Skibola, Christine F; Bracci, Paige M; Halperin, Eran; Conde, Lucia; Craig, David W; Agana, Luz; Iyadurai, Kelly; Becker, Nikolaus; Brooks-Wilson, Angela; Curry, John D; Spinelli, John J; Holly, Elizabeth A; Riby, Jacques; Zhang, Luoping; Nieters, Alexandra; Smith, Martyn T; Brown, Kevin M

2009-08-01

213

Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma  

PubMed Central

We conducted genome-wide association studies of non-Hodgkin lymphoma using Illumina HumanHap550 BeadChips to identify subtype-specific associations in follicular, diffuse large B-cell and chronic lymphocytic leukemia/small lymphocytic lymphomas. We found that rs6457327 on 6p21.33 was associated with susceptibility to follicular lymphoma (FL, N=189 cases/592 controls) with validation in an additional 456 FL cases and 2,785 controls (combined allelic p-value=4.7×10?11). The region of strongest association overlaps C6orf15(STG), located near psoriasis susceptibility region 1(PSORS1). PMID:19620980

Skibola, Christine F.; Bracci, Paige M.; Halperin, Eran; Conde, Lucia; Craig, David W.; Agana, Luz; Iyadurai, Kelly; Becker, Nikolaus; Brookes-Wilson, Angela; Curry, John D.; Spinelli, John J.; Holly, Elizabeth A.; Riby, Jacques; Zhang, Luoping; Nieters, Alexandra; Smith, Martyn T.; Brown, Kevin M.

2010-01-01

214

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

215

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

Microsoft Academic Search

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

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

1997-01-01

216

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

PubMed Central

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

Christiani, David C.

2013-01-01

217

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

218

Genetic susceptibility to nosocomial pneumonia, acute respiratory distress syndrome and poor outcome in patients at risk of critical illness.  

PubMed

Genetic susceptibility may partially explain the clinical variability observed during the course of similar infections. To establish the contribution of genetic host factors in the susceptibility to critical illness, we genotyped 750 subjects (419 at high risk of critical illness) for 14 single nucleotide polymorphisms (SNPs) in the xenobiotics detoxification/oxidative stress and vascular homeostasis metabolic pathways. In the group of nosocomial pneumonia (NP; 268 patients) the risk of acute respiratory distress syndrome (ARDS) is significantly higher for the carriers of CYP1A1 rs2606345 T/T genotypes and AhR rs2066853 G/A-A/A genotypes. AGTR1 rs5186 allele C is more common among NP non-survivors. The duration of stay in intensive care units (ICU) is higher for NP patients with ABCB1 rs1045642-T allele. The cumulative effect of the risk alleles in the genes comprising two sets of genes partners (xenobiotics detoxification: CYP1A1, AhR and RAS family: ACE, AGT, AGTR1) is associated with the development of both NP and ARDS. PMID:24127120

Salnikova, Lyubov E; Smelaya, Tamara V; Vesnina, Irina N; Golubev, Arkadiy M; Moroz, Viktor V

2014-04-01

219

Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis  

PubMed Central

BACKGROUND & AIMS Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10?8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10?8). We also found evidence for 3 additional loci with P values less than 5.0 × 10?7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10?8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10?8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10?7). CONCLUSIONS In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to ?-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation. PMID:23266556

Peters, Ulrike; Jiao, Shuo; Schumacher, Fredrick R.; Hutter, Carolyn M.; Aragaki, Aaron K.; Baron, John A.; Berndt, Sonja I.; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Lin S.; Coetzee, Gerhard A.; Coetzee, Simon G.; Conti, David V.; Curtis, Keith R.; Duggan, David; Edwards, Todd; Fuchs, Charles S.; Gallinger, Steven; Giovannucci, Edward L.; Gogarten, Stephanie M.; Gruber, Stephen B.; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Henderson, Brian E.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Hunter, David J.; Jackson, Rebecca D.; Jee, Sun Ha; Jenkins, Mark A.; Jia, Wei-Hua; Kolonel, Laurence N.; Kooperberg, Charles; Kury, Sebastien; Lacroix, Andrea Z.; Laurie, Cathy C.; Laurie, Cecelia A.; Le Marchand, Loic; Lemire, Mathieu; Levine, David; Lindor, Noralane M.; Liu, Yan; Ma, Jing; Makar, Karen W.; Matsuo, Keitaro; Newcomb, Polly A.; Potter, John D.; Prentice, Ross L.; Qu, Conghui; Rohan, Thomas; Rosse, Stephanie A.; Schoen, Robert E.; Seminara, Daniela; Shrubsole, Martha; Shu, Xiao-Ou; Slattery, Martha L.; Taverna, Darin; Thibodeau, Stephen N.; Ulrich, Cornelia M.; White, Emily; Xiang, Yongbing; Zanke, Brent W.; Zeng, Yi-Xin; Zhang, Ben; Zheng, Wei; Hsu, Li

2013-01-01

220

Resistance and susceptibility of mice to bacterial infection: genetics of listeriosis.  

PubMed

A survey of various strains of mice showed distinct differences in resistance or susceptibility to Listeria monocytogenes. C57B1, related sublines, NZB, and SJL were resistant to Listeria, whereas BALB/c, CBA, A, DBA/1, C3H, LP.RIII, 129, and WB were susceptible. The gene(s) responsible for resistance and susceptibility to Listeria were studied in detail. C57BL6/6, B10.D2, and B10.A mice were 100 times more resistant than were BALB/c, CBA, and A. Resistance of the (C57B1/6 X BALB/C)F1 was intermediate between the two parents, suggesting partial penetration of a dominant gene. Backcross studies in which the (C57B1/6 X BALB/c)F1 were crossed with the susceptible BALB/c parent suggested that a single gene or group of linked genes were the major determinant of resistance, although the possibility that other genes exerted a modifying influence was not excluded. By using the backcross and various congenic and recombinant mice, linkage of the genes involved to the H-1, H-2, H-3, H-4, H-7, or H-8 loci, to the immunoglobulin allotype, to the Thy-1 gene, to the Hc gene specifying C5, or to coat color genes (B, c) was excluded. There was no difference in the response of males and females. In all studies, the powerful overriding influence of the C57B1 genome was evident. PMID:305895

Cheers, C; McKenzie, I F

1978-03-01

221

Genetic Background Determines the Extent of Atherosclerosis in ApoE-Deficient Mice  

Microsoft Academic Search

Two strains of ApoE-deficient mice were found to have markedly different plasma lipoprotein profiles and susceptibility to atherosclerosis when fed either a low-fat chow or a high-fat Western-type diet. FVB\\/NJ ApoE-deficient (FVB E0) mice had higher total cholesterol, HDL cholesterol, ApoA1, and ApoA2 levels when compared with C57BL\\/6J ApoE-deficient (C57 E0) mice. At 16 weeks of age, mean aortic root

Hayes M. Dansky; Sherri A. Charlton; John L. Sikes; Simon C. Heath; Ronit Simantov; Lawrence F. Levin; Pei Shu; Karen J. Moore; Jan L. Breslow; Jonathan D. Smith

2010-01-01

222

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

PubMed

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

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

2014-11-01

223

Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus  

PubMed Central

Mouse strains AcB55 and AcB61 are resistant to malaria by virtue of a mutation in erythrocyte pyruvate kinase (PklrI90N). Linkage analysis in [AcB55 × A/J] F2 mice detected a second locus (Char9; logarithm of odds = 4.74) that regulates the blood-stage replication of Plasmodium chabaudi AS independently of Pklr. We characterized the 77 genes of the Char9 locus for tissue-specific expression, strain-specific alterations in gene expression, and polymorphic variants that are possibly associated with differential susceptibility. We identified Vnn1/Vnn3 as the likely candidates responsible for Char9. Vnn3/Vnn1 map within a conserved haplotype block and show expression levels that are strictly cis-regulated by this haplotype. The absence of Vnn messenger RNA expression and lack of pantetheinase protein activity in tissues are associated with susceptibility to malaria and are linked to a complex rearrangement in the Vnn3 promoter region. The A/J strain also carries a unique nonsense mutation that leads to a truncated protein. Vanin genes code for a pantetheinase involved in the production of cysteamine, a key regulator of host responses to inflammatory stimuli. Administration of cystamine in vivo partially corrects susceptibility to malaria in A/J mice, as measured by reduced blood parasitemia and decreased mortality. These studies suggest that pantetheinase is critical for the host response to malaria. PMID:17312006

Min-Oo, Gundula; Fortin, Anny; Pitari, Giuseppina; Tam, Mifong; Stevenson, Mary M.; Gros, Philippe

2007-01-01

224

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

PubMed Central

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

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

2014-01-01

225

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] [Univ. of Adelaide (Australia); and others

1996-07-12

226

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

PubMed Central

Purpose Prevalence rates for primary open-angle glaucoma (POAG) are significantly higher in Africans than in European or Asians. It has been reported recently that mitochondrial DNA (mtDNA) lineages of African origin, excluding L2, conferred susceptibility to POAG in Saudi Arabia. This prompted us to test the role of mtDNA haplogroups in the incidence of POAG in the Ghanaian population who has a high frequency of L2 lineages. Methods DNA was extracted from two independent cohorts of clinically diagnosed POAG patients (n=373) and healthy controls (n=451). All patients and controls were from Accra and Tema (the southern region of Ghana). The hypervariable region-I (HVS-I) and coding regions comprising mtDNA haplogroup diagnostic polymorphisms were polymerase chain reaction (PCR) amplified and sequenced in all patients and controls and the haplotypes obtained were assorted into haplogroups and their frequencies compared between cohorts. Results No statistically significant differences were found in mtDNA haplogroup frequencies between POAG patients and matched controls in this cohort for the various mtDNA haplogroups tested. Conclusions In this Ghanaian cohort, mtDNA haplogroups do not seem to confer susceptibility to POAG. PMID:22876121

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

2012-01-01

227

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

PubMed Central

Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context. PMID:24719615

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

2014-01-01

228

Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium.  

PubMed

Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going. PMID:23206934

Campa, Daniele; Rizzato, Cosmeri; Capurso, Gabriele; Giese, Nathalia; Funel, Niccola; Greenhalf, William; Soucek, Pavel; Gazouli, Maria; Pezzilli, Raffaele; Pasquali, Claudio; Talar-Wojnarowska, Renata; Cantore, Maurizio; Andriulli, Angelo; Scarpa, Aldo; Jamroziak, Krzysztof; Delle Fave, Gianfranco; Costello, Eithne; Khaw, Kay-Tee; Heller, Anette; Key, Tim J; Theodoropoulos, George; Malecka-Panas, Ewa; Mambrini, Andrea; Bambi, Franco; Landi, Stefano; Pedrazzoli, Sergio; Bassi, Claudio; Pacetti, Paola; Piepoli, Ada; Tavano, Francesca; di Sebastiano, Pierluigi; Vodickova, Ludmila; Basso, Daniela; Plebani, Mario; Fogar, Paola; Büchler, Markus W; Bugert, Peter; Vodicka, Pavel; Boggi, Ugo; Neoptolemos, John P; Werner, Jens; Canzian, Federico

2013-02-01

229

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

PubMed Central

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

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

2014-01-01

230

Genetic factors influence level of proteinuria in cationic antigen-induced immune complex glomerulonephritis in the rat.  

PubMed Central

The influence of genetic factors on the susceptibility of the rat to cationic antigen-induced in situ immune complex glomerulonephritis was investigated. The levels of proteinuria developing in 11 inbred strains of rats differing in MHC and in genetic background varied markedly. Susceptibility was not MHC associated but resided in the genetic background. PMID:3159528

Kato, A; Thaiss, F; Oite, T; Gunther, E; Batsford, S; Vogt, A

1985-01-01

231

Impact of gene patents and licensing practices on access to genetic testing for inherited susceptibility to cancer: comparing breast and ovarian cancers with colon cancers.  

PubMed

Genetic testing for inherited susceptibility to breast and ovarian cancer can be compared with similar testing for colorectal cancer as a "natural experiment." Inherited susceptibility accounts for a similar fraction of both cancers and genetic testing results guide decisions about options for prophylactic surgery in both sets of conditions. One major difference is that in the United States, Myriad Genetics is the sole provider of genetic testing, because it has sole control of relevant patents for BRCA1 and BRCA2 genes, whereas genetic testing for familial colorectal cancer is available from multiple laboratories. Colorectal cancer-associated genes are also patented, but they have been nonexclusively licensed. Prices for BRCA1 and 2 testing do not reflect an obvious price premium attributable to exclusive patent rights compared with colorectal cancer testing, and indeed, Myriad's per unit costs are somewhat lower for BRCA1/2 testing than testing for colorectal cancer susceptibility. Myriad has not enforced patents against basic research and negotiated a Memorandum of Understanding with the National Cancer Institute in 1999 for institutional BRCA testing in clinical research. The main impact of patenting and licensing in BRCA compared with colorectal cancer is the business model of genetic testing, with a sole provider for BRCA and multiple laboratories for colorectal cancer genetic testing. Myriad's sole-provider model has not worked in jurisdictions outside the United States, largely because of differences in breadth of patent protection, responses of government health services, and difficulty in patent enforcement. PMID:20393305

Cook-Deegan, Robert; DeRienzo, Christopher; Carbone, Julia; Chandrasekharan, Subhashini; Heaney, Christopher; Conover, Christopher

2010-04-01

232

Ethical, legal and social implications of prenatal and preimplantation genetic testing for cancer susceptibility  

Microsoft Academic Search

With the progress in cancer genetics and assisted reproductive technologies, it is now possible for cancer gene mutation carriers not only to reduce cancer mortality through the targeting of surveillance and preventive therapies, but also to avoid the birth of at-risk babies through the choice of different means of reproduction. Thus, the incidence of hereditary cancer syndromes may be decreased

C-W Wang; EC Hui

2009-01-01

233

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

Microsoft Academic Search

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

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

2004-01-01

234

Joint effects of genetic hitchhiking and background selection on neutral variation.  

PubMed Central

Due to relatively high rates of strongly selected deleterious mutations, directional selection on favorable alleles (causing hitchhiking effects on linked neutral polymorphisms) is expected to occur while a deleterious mutation-selection balance is present in a population. We analyze this interaction of directional selection and background selection and study their combined effects on neutral variation, using a three-locus model in which each locus is subjected to either deleterious, favorable, or neutral mutations. Average heterozygosity is measured by simulations (1) at the stationary state under the assumption of recurrent hitchhiking events and (2) as a transient level after a single hitchhiking event. The simulation results are compared to theoretical predictions. It is shown that known analytical solutions describing the hitchhiking effect without background selection can be modified such that they accurately predict the joint effects of hitchhiking and background on linked, neutral variation. Generalization of these results to a more appropriate multilocus model (such that background selection can occur at multiple sites) suggests that, in regions of very low recombination rates, stationary levels of nucleotide diversity are primarily determined by hitchhiking, whereas in regions of high recombination, background selection is the dominant force. The implications of these results on the identification and estimation of the relevant parameters of the model are discussed. PMID:10880499

Kim, Y; Stephan, W

2000-01-01

235

Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse.  

PubMed

Alzheimer's disease (AD) is a multigenic neurodegenerative disorder characterized by distinct neuropathological hallmarks including deposits of the beta-amyloid (A beta) peptide. A beta is a 39- to 43-amino acid peptide derived from the proteolytic processing of the amyloid precursor protein (APP). While increasing evidence suggests that altered APP processing and A beta metabolism is a common feature of AD, the relationship between the levels of A beta and various APP products and the onset of AD remains unclear. We have undertaken a screen to characterize genetic factors that modify APP processing, A beta metabolism and A beta deposition in a genomic-based yeast artificial chromosome (YAC) transgenic mouse model of AD. A mutant human APP YAC transgene was transferred to three inbred mouse strains. Despite similar levels of holo-APP expression in the congenic strains, the levels of APP C-terminal fragments as well as brain and plasma A beta in young animals varied by genetic background. Furthermore, we demonstrate that age-dependent A beta deposition in the APP YAC transgenic model is dramatically altered depending on the congenic strain examined. These studies demonstrate that APP processing, A beta metabolism and A beta deposition are regulated by genetic background and that analysis of these phenotypes in mice should provide new insights into the factors that regulate AD pathogenesis. PMID:14506131

Lehman, Emily J H; Kulnane, Laura Shapiro; Gao, Yuan; Petriello, Michelle C; Pimpis, Karen M; Younkin, Linda; Dolios, Georgia; Wang, Rong; Younkin, Steven G; Lamb, Bruce T

2003-11-15

236

Cerebral Blood Volume Calculated by Dynamic Susceptibility Contrast-Enhanced Perfusion MR Imaging: Preliminary Correlation Study with Glioblastoma Genetic Profiles  

PubMed Central

Purpose To evaluate the usefulness of dynamic susceptibility contrast (DSC) enhanced perfusion MR imaging in predicting major genetic alterations in glioblastomas. Materials and Methods Twenty-five patients (M:F?=?13?12, mean age: 52.1±15.2 years) with pathologically proven glioblastoma who underwent DSC MR imaging before surgery were included. On DSC MR imaging, the normalized relative tumor blood volume (nTBV) of the enhancing solid portion of each tumor was calculated by using dedicated software (Nordic TumorEX, NordicNeuroLab, Bergen, Norway) that enabled semi-automatic segmentation for each tumor. Five major glioblastoma genetic alterations (epidermal growth factor receptor (EGFR), phosphatase and tensin homologue (PTEN), Ki-67, O6-methylguanine-DNA methyltransferase (MGMT) and p53) were confirmed by immunohistochemistry and analyzed for correlation with the nTBV of each tumor. Statistical analysis was performed using the unpaired Student t test, ROC (receiver operating characteristic) curve analysis and Pearson correlation analysis. Results The nTBVs of the MGMT methylation-negative group (mean 9.5±7.5) were significantly higher than those of the MGMT methylation-positive group (mean 5.4±1.8) (p?=?.046). In the analysis of EGFR expression-positive group, the nTBVs of the subgroup with loss of PTEN gene expression (mean: 10.3±8.1) were also significantly higher than those of the subgroup without loss of PTEN gene expression (mean: 5.6±2.3) (p?=?.046). Ki-67 labeling index indicated significant positive correlation with the nTBV of the tumor (p?=?.01). Conclusion We found that glioblastomas with aggressive genetic alterations tended to have a high nTBV in the present study. Thus, we believe that DSC-enhanced perfusion MR imaging could be helpful in predicting genetic alterations that are crucial in predicting the prognosis of and selecting tailored treatment for glioblastoma patients. PMID:23977117

Ryoo, Inseon; Choi, Seung Hong; Kim, Ji-Hoon; Sohn, Chul-Ho; Kim, Soo Chin; Shin, Hwa Seon; Yeom, Jeong A.; Jung, Seung Chai; Lee, A. Leum; Yun, Tae Jin; Park, Chul-Kee; Park, Sung-Hye

2013-01-01

237

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

PubMed Central

The major histocompatibility complex class III tumor necrosis factor-lymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 "shared epitope" (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, B8, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR. PMID:8751869

Mulcahy, B.; Waldron-Lynch, F.; McDermott, M. F.; Adams, C.; Amos, C. I.; Zhu, D. K.; Ward, R. H.; Clegg, D. O.; Shanahan, F.; Molloy, M. G.; O'Gara, F.

1996-01-01

238

Genetic resistance to murine cryptococcosis: increased susceptibility in the CBA/N XID mutant strain of mice.  

PubMed Central

In a survey of 301 normocomplementemic inbred mice (belonging to nine different strains: BALB/cN nu/nu and nu/+, CBA/N, C57BL/KsJ, C57BR/cdJ, CBA/CaJ, BRVR, DW/+, and C57BL/6J) for natural resistance to Cryptococcus neoformans, cumulative survival values were found to range from 12 to 22 days. When the average organ weights of infected animals were compared with reference values obtained in uninfected mice of the same age and genetic lineage, the following changes were documented. In the CBA/N strain, the mean spleen and brain weights increased 313 and 13.5%, respectively, whereas the mean liver weight remained unchanged. In the CBA/Ca strain, cerebral cryptococcosis was the dominant clinical feature, and a 54% increase in mean brain weight was recorded at the time of death. The averaged liver weight was drastically lower, whereas spleen weight values evinced a biphasic pattern of transient splenomegaly followed by involution. At the median time of death, CBA/N mice had significantly more cryptococci in the liver and spleen than corresponding CBA/Ca mice. In the (CBA/N X CBA/Ca)F1 mice, susceptibility to C. neoformans segregated according to the sex-linked inheritance of the X-linked immunodeficiency (xid) gene. It is concluded that (i) susceptibility to cryptococcosis is under multigenic control, (ii) the xid locus on the X chromosome influences susceptibility to cryptococcosis, and (iii) xid mice behave differently than CBA/Ca mice in their organ response during the course of the infection. Images PMID:3880724

Marquis, G; Montplaisir, S; Pelletier, M; Mousseau, S; Auger, P

1985-01-01

239

Evaluation of Genetic Susceptibility to Childhood Allergy and Asthma in an African American Urban Population  

EPA Science Inventory

Background: Asthma and allergy represent complex phenotypes, which disproportionately burden ethnic minorities in the United States. Strong evidence for genomic factors predisposing subjects to asthma/allergy is available. However, methods to utilize this information to identify ...

240

Common Variations in BMP4 Confer Genetic Susceptibility to Sporadic Congenital Heart Disease in a Han Chinese Population.  

PubMed

Congenital heart disease (CHD) is the most common birth defect in humans. The genetic causes of sporadic CHD remain largely unknown. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor-? (TGF-?) family, is required for normal heart development. Loss of BMP4 gene expression in mice is associated with septal defects, defective endocardial cushion remodeling, and abnormal semilunar valve formation. This study evaluated the contribution of single nucleotide polymorphisms (SNPs) in BMP4 to CHD susceptibility in a case-control study of 575 patients with CHD and 844 non-CHD control subjects in a Chinese population. The BMP4 SNP rs762642 was associated with CHD in an additive model (odds ratio [OR]add 1.22; 95 % confidence interval [CI] 1.04-1.43; P add = 0.02). Stratified analysis by CHD subtypes showed a significant association only between rs762642 and atrial septal defect (ORadd 1.33; 95 % CI 1.04-1.72; P add = 0.03) in the additive model. This study was the first to indicate that a common variant of BMP4 may contribute to susceptibility to sporadic CHD in a Chinese population. PMID:25022354

Qian, Bo; Mo, Ran; Da, Min; Peng, Wei; Hu, Yuanli; Mo, Xuming

2014-12-01

241

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

PubMed Central

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

Muller, Erinn M.; van Woesik, Robert

2014-01-01

242

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

PubMed

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

Muller, Erinn M; van Woesik, Robert

2014-01-01

243

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

PubMed Central

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

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

2012-01-01

244

Susceptibility to childhood onset rheumatoid arthritis: Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci  

PubMed Central

Objectives Children with rheumatoid-factor or anti-citrullinated peptide antibody positive juvenile idiopathic arthritis represent the childhood onset of RA (CORA). To test the hypothesis that adult-onset RA-associated variants are also associated with CORA, we investigated RA-associated variants at five loci in our CORA cohort. We also assessed the cumulative association of these variants in the susceptibility to CORA using a weighted genetic risk score (wGRS). Methods 155 children with CORA and 684 healthy controls were genotyped for five variants in PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with CORA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios for the alleles investigated, and used logistic regression to test the wGRS for association with CORA. Results CORA was associated with TNFAIP3-rs10499194 [OR 0.60 (95%CI 0.44–0.83)], PTPN22-rs2476601 [OR 1.61 (1.11–2.31)], and STAT4-rs7574865 [OR 1.41 (1.06–1.87)] variants. The wGRS was significantly different between cases and controls (P<2×10?16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to the baseline. Higher wGRS associated with increased risk of CORA, especially among males. Conclusions TNFAIP3, STAT4 and PTPN22 variants are associated with CORA in a similar magnitude and direction as in RA, suggesting that adult-onset RA and CORA share common genetic risk factors. Utilizing a wGRS, we have demonstrated the cumulative association of RA-associated variants in the susceptibility to CORA. PMID:23450725

Prahalad, Sampath; Conneely, Karen N.; Jiang, Yunxuan; Sudman, Marc; Wallace, Carol A.; Brown, Milton R.; Ponder, Lori A.; Rohani-Pichavant, Mina; Zwick, Michael E.; Cutler, David J.; Angeles-Han, Sheila T.; Vogler, Larry B.; Kennedy, Christine; Rouster-Stevens, Kelly; Wise, Carol A.; Punaro, Marilynn; Reed, Ann M.; Mellins, Elizabeth D.; Bohnsack, John F.; Glass, David N.; Thompson, Susan D.

2013-01-01

245

Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility  

Microsoft Academic Search

Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere-related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n=120) and population-based controls (n=110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in

H. Dean Hosgood III; Richard Cawthon; Xingzhou He; Stephen Chanock; Qing Lan

2009-01-01

246

Susceptibility and Prevention Recent Natural Selection Identifies a Genetic Variant in a Regulatory  

E-print Network

: Studies of human genetic variants in the p53 tumor suppressor gene and MDM2 oncogene have shown- ied are found in the p53 and MDM2 genes (p53 codon72; ref. 6, rs1042522, C/G; MDM2 SNP309; ref. 7, rs populations. For example, the G allele of MDM2 SNP309 was found to be at 10% in African Americans (8), 33

Vazquez, Alexei

247

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

PubMed

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

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

2014-11-01

248

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

PubMed Central

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

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

2014-01-01

249

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

PubMed

Detecting, characterizing, and interpreting gene-gene interactions or epistasis in studies of human disease susceptibility is both a mathematical and a computational challenge. To address this problem, we have previously developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension (i.e. constructive induction) thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe a comprehensive and flexible framework for detecting and interpreting gene-gene interactions that utilizes advances in information theory for selecting interesting single-nucleotide polymorphisms (SNPs), MDR for constructive induction, machine learning methods for classification, and finally graphical models for interpretation. We illustrate the usefulness of this strategy using artificial datasets simulated from several different two-locus and three-locus epistasis models. We show that the accuracy, sensitivity, specificity, and precision of a naïve Bayes classifier are significantly improved when SNPs are selected based on their information gain (i.e. class entropy removed) and reduced to a single attribute using MDR. We then apply this strategy to detecting, characterizing, and interpreting epistatic models in a genetic study (n = 500) of atrial fibrillation and show that both classification and model interpretation are significantly improved. PMID:16457852

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

2006-07-21

250

A Preliminary Study of Genetic Factors That Influence Susceptibility to Bovine Tuberculosis in the British Cattle Herd  

PubMed Central

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test (‘reactors’). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling. PMID:21533277

Driscoll, Erin E.; Hoffman, Joseph I.; Green, Laura E.; Medley, Graham F.; Amos, William

2011-01-01

251

Lifestyle, genetic susceptibility and future trends of breast cancer in Korea.  

PubMed

Not only the incidence but the mortality of breast cancer has been steadily increasing in Korea over the last twenty years, and it became the most common female neoplasm in 2002. In fact, the increase in the rate of breast cancer mortality in Korea over the past 10 years has been higher than anywhere else in the world, and it is particularly noteworthy that more than half of the incident cases occur among those younger than 50 years of age. The rapid westernization of dietary habits and changes in reproductive behavior of Korean women presumably played a central role in this extraordinary increase in breast cancer occurrence. A large-scale multi-center case-control analysis showed that an older age, a family history of breast cancer, early menarche, late menopause, late full-term pregnancy, never-having had a breast-fed child, and postmenopausal obesity are breast cancer risk factors in Korea. Environmental and genetic factors are known to play interactive roles in human carcinogenesis and recent studies have shown that genetic polymorphisms may predispose individuals to breast cancer via gene-to-environment or gene-to-gene interactions. Thus research into genetic variation in xenobiotic metabolism, estrogen metabolism, DNA repair, cytokine metabolism, or cell cycle control may give insights into both the etiology and prevention of breast cancer. Epidemiologic evidence obtained from migrant and lifestyle change studies and investigations of main risk factors strongly suggests that breast cancer will further increase in Korea. Future predictions point to a 2- to 3-fold increase in incidence by 2020. Here, we briefly introduce health education programs and breast cancer campaigns, in the broad context of the Korean National Cancer Control Program. PMID:17250452

Yoo, Keun-Young; Kim, Yeonju; Park, Sue Kyung; Kang, Daehee

2006-01-01

252

Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates  

PubMed Central

Amyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case–control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Zmax = 4.03) in our initial scan, with additional support in the complete case–control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Zmax = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS. PMID:19567404

Sieh, Weiva; Choi, Yoonha; Chapman, Nicola H.; Craig, Ulla-Katrina; Steinbart, Ellen J.; Rothstein, Joseph H.; Oyanagi, Kiyomitsu; Garruto, Ralph M.; Bird, Thomas D.; Galasko, Douglas R.; Schellenberg, Gerard D.; Wijsman, Ellen M.

2009-01-01

253

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

PubMed Central

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

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

2012-01-01

254

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

Microsoft Academic Search

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

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

2011-01-01

255

Genetic Susceptibility to Lupus: New Insights from fine mapping and genome-wide association studies  

PubMed Central

Genome-wide association studies and fine mapping of candidate regions have rapidly advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE or lupus). More than 20 robust associations have now been identified and confirmed, and have provided insights at the molecular level that refine our understanding of the involvement of processes involved in the host immune response. In addition, genes with as yet unknown roles in SLE pathophysiology have been identified. These findings provide new routes toward improved clinical management of this complex disease. PMID:19337289

Harley, Isaac T.W.; Kaufman, Kenneth M.; Langefeld, Carl D.; Harley, John B.; Kelly, Jennifer A.

2009-01-01

256

Genomewide Screen and Identification of Gene-Gene Interactions for Asthma-Susceptibility Loci in Three U.S. Populations: Collaborative Study on the Genetics of Asthma  

Microsoft Academic Search

The genomewide screen to search for asthma-susceptibility loci, in the Collaborative Study on the Genetics of Asthma (CSGA), has been conducted in two stages and includes 266 families (199 nuclear and 67 extended pedigrees) from three U.S. populations: African American, European American, and Hispanic. Evidence for linkage with the asthma phenotype was observed for multiple chromosomal regions, through use of

Jianfeng Xu; Deborah A. Meyers; Carole Ober; Malcolm N. Blumenthal; Beverly Mellen; Kathleen C. Barnes; Richard A. King; Lucille A. Lester; Timothy D. Howard; Julian Solway; Carl D. Langefeld; Terri H. Beaty; Stephen S. Rich; Eugene R. Bleecker; Nancy J. Cox

2001-01-01

257

234 VOLUME 46 | NUMBER 3 | MARCH 2014 Nature GeNetics The majority of GWAS of T2D susceptibility have been undertaken in  

E-print Network

234 VOLUME 46 | NUMBER 3 | MARCH 2014 Nature GeNetics The majority of GWAS of T2D susceptibility are less biased toward Europeans, and more recent T2D GWAS have been performed with great success- bility loci for the disease and enhance the fine-mapping resolution of causal variants by combining GWAS

Cai, Long

258

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

PubMed Central

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

Castillo-Rojas, Gonzalo; Mazari-Hiriart, Marisa; Ponce de Leon, Sergio; Amieva-Fernandez, Rosa I.; Agis-Juarez, Raul A.; Huebner, Johannes; Lopez-Vidal, Yolanda

2013-01-01

259

The role of genetic breast cancer susceptibility variants as prognostic factors  

PubMed Central

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

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

2012-01-01

260

Common Variation in ISL1 Confers Genetic Susceptibility for Human Congenital Heart Disease  

PubMed Central

Congenital heart disease (CHD) is the most common birth abnormality and the etiology is unknown in the overwhelming majority of cases. ISLET1 (ISL1) is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages. The fundamental role of ISL1 in cardiac morphogenesis makes this an exceptional candidate gene to consider as a cause of complex congenital heart disease. We evaluated whether genetic variation in ISL1 fits the common variant–common disease hypothesis. A 2-stage case-control study examined 27 polymorphisms mapping to the ISL1 locus in 300 patients with complex congenital heart disease and 2,201 healthy pediatric controls. Eight genic and flanking ISL1 SNPs were significantly associated with complex congenital heart disease. A replication study analyzed these candidate SNPs in 1,044 new cases and 3,934 independent controls and confirmed that genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease. Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations. PMID:20520780

Stevens, Kristen N.; Hakonarson, Hakon; Kim, Cecilia E.; Doevendans, Pieter A.; Koeleman, Bobby P. C.; Mital, Seema; Raue, Jennifer; Glessner, Joseph T.; Coles, John G.; Moreno, Victor; Granger, Anne; Gruber, Stephen B.; Gruber, Peter J.

2010-01-01

261

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

PubMed

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

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

2014-03-01

262

The genetic background of generalized pustular psoriasis: IL36RN mutations and CARD14 gain-of-function variants.  

PubMed

Generalized pustular psoriasis (GPP) is often present in patients with existing or prior psoriasis vulgaris (PV; "GPP with PV"). However, cases of GPP have been known to arise without a history of PV ("GPP alone"). There has long been debate over whether GPP alone and GPP with PV are distinct subtypes that are etiologically different from each other. We recently reported that the majority of GPP alone cases is caused by recessive mutations of IL36RN. In contrast, only a few exceptional cases of GPP with PV were found to have recessive IL36RN mutations. Very recently, we also reported that CARD14 p.Asp176His, a gain-of-function variant, is a predisposing factor for GPP with PV; in contrast, the variant is not associated with GPP alone in the Japanese population. These results suggest that GPP alone is genetically different from GPP with PV. IL36RN mutations are also found in some patients with severe acute generalized exanthematous pustulosis, palmar-plantar pustulosis, and acrodermatitis continua of hallopeau. CARD14 mutations and variants are causal or disease susceptibility factors of PV, GPP, or pityriasis rubra pilaris, depending on the mutation or variant position of CARD14. It is clinically important to analyze IL36RN mutations in patients with sterile pustulosis. For example, identifying recessive IL36RN mutations leads to early diagnosis of GPP, even at the first episode of pustulosis. In addition, individuals with IL36RN mutations are very susceptible to GPP or GPP-related generalized pustulosis induced by drugs (e.g., amoxicillin), infections, pregnancy, or menstruation. PMID:24656634

Sugiura, Kazumitsu

2014-06-01

263

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

PubMed Central

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

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

2013-01-01

264

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

PubMed

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

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

2012-12-01

265

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

PubMed Central

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

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

2010-01-01

266

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

PubMed Central

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

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

1991-01-01

267

PARAOXONASE 1 (PON1) AS A GENETIC DETERMINANT OF SUSCEPTIBILITY TO ORGANOPHOSPHATE TOXICITY  

PubMed Central

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

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

2012-01-01

268

Resampling-based analyses of the effects of combinations of HIV genetic mutations on drug susceptibility.  

PubMed

Viral genotype data aid in understanding the development of antiretroviral drug resistance and in identifying appropriate treatments. Using HIV-1 protease sequences and measures of in vitro sensitivity to the drug amprenavir, we develop a novel statistical approach that can be used to investigate combinations of mutations that alter drug susceptibility. Our method is based on the use of order statistics whose null distributions are estimated through resampling and used for formal hypothesis testing. We present a step-down testing method that preserves the overall family-wise error rate in finite samples via an application of the monotonicity condition of Romano and Wolf. Simulations demonstrate that the power of this new approach is comparable to a traditional resampling method; however, this approach can also be used as a visual diagnostic that may be informative even when specified hypotheses are not rejected, for example, in suggesting candidate regression models. Analysis of the data from the Stanford HIV database shows that while M46I/L mutations are associated with drug resistance, addition of the L88D/S mutation leads to hypersusceptible virus. Further addition of T90M/L mutations results in highly resistant virus. Use of this order statistics method allows the investigation of how mutations act in the presence of others and may suggest mechanisms by which resistance occurs or is reversed through the accumulation of mutations. PMID:18186529

Schumi, Jennifer; Degruttola, Victor

2008-10-15

269

Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia.  

PubMed

The glutathione S-transferase (GST) genes are involved in the metabolism of environmental carcinogens and of some classes of chemotherapy drugs. GSTM1 and GSTT1 genotypes are polymorphic in humans, and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. Previous, smaller studies of childhood acute lymphoblastic leukemia (ALL) provided contrasting data on the role of the GST genotype in susceptibility and treatment outcomes. We analyzed GST genotypes in 710 children with ALL treated by the Children's Cancer Group. Frequencies were compared with those of normal controls, and outcomes were analyzed according to genotype. Comparisons of gene frequencies in ALL case and control patients showed similar frequencies (54% vs 53% GSTM1 null in whites, P =.9; 40% versus 32% in blacks, P =.45; 16% versus 15% GSTT1 null in whites, P =.8; 17% versus 28% in blacks, P =.3). ALL was not associated with the GSTM1-null genotype or the double-null genotype in blacks or whites, in contrast to previous reports. Stratification of cases by age at diagnosis, sex, white blood cell count at diagnosis, B or T lineage, or cytogenetics revealed no differences in genotype frequencies. Analysis of treatment outcomes showed no differences in outcome according to GST genotype; in particular, there were no differences in frequencies of relapse at any site. These data, representing a larger series than any reported previously, suggest that GST genotype does not affect etiology or outcome of childhood ALL. PMID:12070010

Davies, Stella M; Bhatia, Smita; Ross, Julie A; Kiffmeyer, William R; Gaynon, Paul S; Radloff, Gretchen A; Robison, Leslie L; Perentesis, John P

2002-07-01

270

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. PMID:21930754

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

2011-01-01

271

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

Microsoft Academic Search

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

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

2006-01-01

272

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

2012-01-01

273

Genetic susceptibility and gastric cancer risk: the importance of meta-analyses as a statistical tool.  

PubMed

Gastric cancer (GC) is a complex disease and a worldwide health burden due to its high prevalence and poor prognosis. A deeper knowledge of the factors involved in the development and progression of GC could help to identify subpopulations at risk that therefore require surveillance or early treatment strategies. Current research is based on the study of genetic variants that confer a higher risk of GC and their interactions with environmental exposure. Recently, meta-analysis has emerged as an important statistical method involving pooling of data from individual association studies to increase statistical power and obtain more conclusive results. Given the importance of chronic inflammation in the process of gastric carcinogenesis, the present article reviews the most recent meta-analyses of the contribution of cytokine gene polymorphisms to GC risk. PMID:24661935

García-González, María Asunción; Lanas, Angel

2014-01-01

274

Parent-of-origin genetic background affects the transcriptional levels of circadian and neuronal plasticity genes following sleep loss.  

PubMed

Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico, specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects. PMID:24446504

Tinarelli, Federico; Garcia-Garcia, Celina; Nicassio, Francesco; Tucci, Valter

2014-03-01

275

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

PubMed Central

The Trypanosoma brucei complex contains a number of subspecies with exceptionally variable life histories, including zoonotic subspecies, which are causative agents of human African trypanosomiasis (HAT) in sub-Saharan Africa. Paradoxically, genomic variation between taxa is extremely low. We analyzed the whole-genome sequences of 39 isolates across the T. brucei complex from diverse hosts and regions, identifying 608,501 single nucleotide polymorphisms that represent 2.33% of the nuclear genome. We show that human pathogenicity occurs across a wide range of parasite genotypes, and taxonomic designation does not reflect genetic variation across the group, as previous studies have suggested based on a small number of genes. This genome-wide study allowed the identification of significant host and geographic location associations. Strong purifying selection was detected in genomic regions associated with cytoskeleton structure, and regulatory genes associated with antigenic variation, suggesting conservation of these regions in African trypanosomes. In agreement with expectations drawn from meiotic reciprocal recombination, differences in average linkage disequilibrium between chromosomes in T. brucei correlate positively with chromosome size. In addition to insights into the life history of a diverse group of eukaryotic parasites, the documentation of genomic variation across the T. brucei complex and its association with specific hosts and geographic localities will aid in the development of comprehensive monitoring tools crucial to the proposed elimination of HAT by 2020, and on a shorter term, for monitoring the feared merger between the two human infective parasites, T. brucei rhodesiense and T. b. gambiense, in northern Uganda. PMID:25287146

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

2014-01-01

276

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

PubMed

The Trypanosoma brucei complex contains a number of subspecies with exceptionally variable life histories, including zoonotic subspecies, which are causative agents of human African trypanosomiasis (HAT) in sub-Saharan Africa. Paradoxically, genomic variation between taxa is extremely low. We analyzed the whole-genome sequences of 39 isolates across the T. brucei complex from diverse hosts and regions, identifying 608,501 single nucleotide polymorphisms that represent 2.33% of the nuclear genome. We show that human pathogenicity occurs across a wide range of parasite genotypes, and taxonomic designation does not reflect genetic variation across the group, as previous studies have suggested based on a small number of genes. This genome-wide study allowed the identification of significant host and geographic location associations. Strong purifying selection was detected in genomic regions associated with cytoskeleton structure, and regulatory genes associated with antigenic variation, suggesting conservation of these regions in African trypanosomes. In agreement with expectations drawn from meiotic reciprocal recombination, differences in average linkage disequilibrium between chromosomes in T. brucei correlate positively with chromosome size. In addition to insights into the life history of a diverse group of eukaryotic parasites, the documentation of genomic variation across the T. brucei complex and its association with specific hosts and geographic localities will aid in the development of comprehensive monitoring tools crucial to the proposed elimination of HAT by 2020, and on a shorter term, for monitoring the feared merger between the two human infective parasites, T. brucei rhodesiense and T. b. gambiense, in northern Uganda. PMID:25287146

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

2014-01-01

277

Genetic Susceptibility to Experimental Autoimmune Glomerulonephritis in the Wistar Kyoto Rat  

PubMed Central

In experimental autoimmune glomerulonephritis (EAG), a model of Goodpasture's disease, Wistar Kyoto (WKY) rats immunized with collagenase-solubilized glomerular basement membrane (GBM) or the recombinant NC1 domain of the ?3 chain of type IV collagen [?3(IV)NC1] develop anti-GBM antibodies and focal necrotizing glomerulonephritis with crescent formation. However, Lewis (LEW) rats, which share the same major histocompatibility complex (MHC) haplotype, are resistant to EAG development. A genome-wide linkage analysis of backcrossed animals with EAG revealed a major quantitative trait locus (QTL) on rat chromosome 13 (LOD = 3.9) linked to the percentage of glomerular crescents. To investigate the role of this QTL in EAG induction, reciprocal congenic rats were generated (LEW.WCrgn1 congenic and WKY.LCrgn1 congenic), immunized with recombinant rat ?3(IV)NC1, and assessed for EAG development. WKY.LCrgn1 rats showed a marked reduction in albuminuria, severity of crescentic nephritis, and number of glomerular macrophages compared with WKY controls. No reduction in antibody levels was observed. However, LEW.WCrgn1 rats were resistant to EAG development, as were LEW controls. Macrophage activation in vitro was assessed in parental and congenic rat bone marrow–derived macrophages (BMDMs). WKY.LCrgn1 BMDMs showed a significant reduction in Fc receptor–mediated oxidative burst, phagocytosis of opsonised polystyrene beads, and LPS-induced levels of MCP-1 secretion and iNOS mRNA expression compared with WKY rats. These results confirm the importance of Crgn1 on chromosome 13 in EAG susceptibility, mediated partly through differences in Fc receptor-mediated macrophage activation. PMID:22445570

Reynolds, John; Cook, Paul R.; Behmoaras, Jacques; Smith, Jennifer; Bhangal, Gurjeet; Tadros, Susan; Tee, Jonathan; Salama, Alan D.; Evans, David J.; Aitman, Timothy J.; Cook, H. Terence; Pusey, Charles D.

2012-01-01

278

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

USGS Publications Warehouse

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

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

2012-01-01

279

Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.  

PubMed

It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case-control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility. PMID:23873044

Ansari, Morad; McKeigue, Paul M; Skerka, Christine; Hayward, Caroline; Rudan, Igor; Vitart, Veronique; Polasek, Ozren; Armbrecht, Ana-Maria; Yates, John R W; Vatavuk, Zoran; Bencic, Goran; Kolcic, Ivana; Oostra, Ben A; Van Duijn, Cornelia M; Campbell, Susan; Stanton, Chloe M; Huffman, Jennifer; Shu, Xinhua; Khan, Jane C; Shahid, Humma; Harding, Simon P; Bishop, Paul N; Deary, Ian J; Moore, Anthony T; Dhillon, Baljean; Rudan, Pavao; Zipfel, Peter F; Sim, Robert B; Hastie, Nicholas D; Campbell, Harry; Wright, Alan F

2013-12-01

280

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

PubMed Central

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

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

2014-01-01

281

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

PubMed

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

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

2014-01-01

282

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

PubMed

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

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

2013-12-01

283

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

PubMed

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

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

2014-08-01

284

Role of Genetic Susceptibility in Development of Treatment-related Adverse Outcomes in Cancer Survivors  

PubMed Central

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

Bhatia, Smita

2011-01-01

285

Leptin-Deficient Mice Backcrossed to the BALB\\/cJ Genetic Background Have Reduced Adiposity, Enhanced Fertility, Normal Body Temperature, and Severe Diabetes  

Microsoft Academic Search

A deficiency of leptin synthesis in mice results in a complex phenotype characterized by morbid obesity, diabetes, steril- ity, and defective thermogenesis. To determine whether the genetic background could alter the pleiotropic effects of lep- tin deficiency, we backcrossed the ob mutation for 10 gener- ations from the C57BL\\/6J to the BALB\\/cJ genetic background. Compared with C57BL\\/6J ob\\/ob mice, BALB\\/cJ

J. Qiu; S. OGUS; K. MOUNZIH; A. EWART-TOLAND; F. F. CHEHAB

2001-01-01

286

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

PubMed

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

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

2012-04-23

287

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

PubMed Central

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

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

2014-01-01

288

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

PubMed Central

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

2014-01-01

289

The Molecular through Ecological Genetics of Abnormal Abdomen in Drosophila Mercatorum. V. Female Phenotypic Expression on Natural Genetic Backgrounds and in Natural Environments  

PubMed Central

The abnormal abdomen (aa) syndrome in Drosophila mercatorum depends on the presence of R1 inserts in a third or more of the X-linked 28S rDNA genes and the absence of selective underreplication of inserted repeats in polytene tissues that is controlled by an X-linked locus (ur) half a map unit from the rDNA complex. This syndrome affects both life history and morphology in the laboratory. Because abnormal morphologies are rarely encountered in nature, the purpose of this study is to see if the female life history traits are still affected under more natural genetic backgrounds and environmental conditions. Two outbred stocks were extracted from the natural population living near Kamuela, Hawaii: KaaX that has only X chromosomes with ur(aa) alleles, and K+X that has only ur(+) alleles. These two stocks have nonoverlapping distributions of insert proportions, indicating strong disequilibrium between the ur locus and the rDNA complex. The KaaX stock had almost no morphological penetrance of ur(aa), indicating that genetic background is important. KaaX expressed longer female egg-to-adult developmental times, increased early adult female fecundity, and decreased female adult longevity compared with K+X. By bagging natural rots of the cactus Opuntia megacantha near Kamuela, Hawaii, it was shown that egg-to-adult developmental time is slowed down by 0.92 days in females bearing ur(aa) alleles in nature, with no detectable slowdown in ur(aa) males. The bagged rot data also indicate that females bearing ur(aa) alleles have a strong fecundity advantage in nature under some ecological conditions but not others. PMID:8325484

Templeton, A. R.; Hollocher, H.; Johnston, J. S.

1993-01-01

290

Virulence genotypes and phylogenetic background of fluoroquinolone-resistant and susceptible Escherichia coli urine isolates from dogs with urinary tract infection  

Microsoft Academic Search

The origins and virulence potential of fluoroquinolone-resistant (FQ-R) Escherichia coli from dogs with urinary tract infection (UTI) are undefined. Therefore, fluoroquinolone-resistant (n=38) or susceptible (n=62) E. coli urine isolates from dogs with UTI were characterized for phylogenetic group (A, B1, B2, D) and 61 virulence-associated genes by multiplex PCR, then were compared according to these characteristics. Compared with fluoroquinolone-susceptible (FQ-S)

James R. Johnson; Michael A. Kuskowski; Krista Owens; Connie Clabots; Randall S. Singer

2009-01-01

291

RET and PHOX2B Genetic Polymorphisms and Hirschsprung's Disease Susceptibility: A Meta-Analysis  

PubMed Central

Background Many publications have evaluated the correlation between RET, PHOX2B polymorphisms and Hirschsprung's disease with conflicting results. We performed this meta-analysis to clarify the association of RET, PHOX2B polymorphisms with HSCR. Methods We searched Pubmed, Elsevier Science Direct, China National Knowledge Infrastructure database, Chinese Biomedical database, Google scholar. The combined odds ratio (OR) with 95% CI was calculated to estimate the strength of the association. Heterogeneity and publication bias were also assessed. Results In total, 16 studies concerning RET and 4 studies concerning PHOX2B were included in the meta-analysis. The effects of five polymorphisms of RET (rs1800858, rs1800860, rs1800861, rs10900297, rs2435357) and one polymorphism (rs28647582) of PHOX2B were evaluated. We found a significant correlation between RET polymorphisms and HSCR. For rs1800858, the overall ORs (95% CI) of the A versus G, AA versus GG, AA/AG versus GG and AA versus GG/AG were 3.81 (2.28–6.35); 8.36 (3.45–20.25); 3.59 (1.83–7.02); and 6.60 (3.66–11.89). For rs1800861, the comparison of subjects in the G versus T, GG versus TT, GG/TG versus TT and GG versus TT/TG were 2.85(1.81–4.47); 5.38(2.68–10.80); 3.07(2.17–4.34) and 4.14(1.84–9.30) respectively. For rs10900297, the comparison results showed statistically significant. (ORC versus A?=?5.05,95%CI?=?4.16–6.13; ORCC versus AA?=?9.73, 95%CI?=?5.94–15.94; ORCC/AC versus AA?=?5.31, 95%CI?=?3.27–6.82; ORCC versus AC/AA?=?7.06,95%CI?=?5.60–8.91.) But, for rs1800860, the GG/GA versus AA did not reach statistical association (OR?=?3.77, 95% CI?=?0.94–15.07) and the G versus A, GG versus AA, GG versus GA/AA were 2.23 (1.60–3.11);4.56 (1.14–18.27); 2.38 (1.66–3.43) respectively. For rs2435357, the T versus C, TT versus CC, TT/TC versus CC and TT versus CC/TC were 4.53 (3.27–6.27); 11.44 (5.67–23.10); 4.04 (2.92–5.57), and 9.01(5.25–15.46).The single polymorphism of PHOX2B gene wasn't related to the risk for HSCR. Conclusions This meta-analysis shows a significant association between RET polymorphisms and HSCR. PMID:24651702

Yuan, Xu; Ren, Ling-ling; Shen, Juan; Zhang, Hai-yan

2014-01-01

292

Analysis of HLA-DRB1-related alleles in Japanese patients with lung cancer – relationship to genetic susceptibility and resistance to lung cancer  

Microsoft Academic Search

Purpose:   To investigate differences in HLA status among lung cancer patients, patients with hematological malignancies, and healthy\\u000a controls in order to determine the genetic susceptibility and resistance features of HLA-DRB1-related alleles in Japanese\\u000a patients with lung cancer. Methods: HLA class I (HLA-A, -B, and -C) antigens and HLA class II (HLA-DRB1) alleles were determined in 36 patients with lung cancer,

Hiroshi Tokumoto

1998-01-01

293

IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii.  

PubMed

The role for IL-10 in the immunopathogenesis of acute toxoplasmosis following peroral infection was examined in both genetically susceptible C57BL/6 and resistant BALB/c mice. C57BL/6-background IL-10-targeted mutant (IL-10-/-) mice all died in 2 wk after infection with 20 cysts of the ME49 strain, whereas only 20% of control mice succumbed. Histological studies revealed necrosis in the small and large intestines and livers of infected IL-10-/- mice. The necrosis in the small intestine was the most severe pathologic response and was not observed in control mice. Treatment of infected IL-10-/- mice with either anti-CD4 or anti-IFN-gamma mAb prevented intestinal pathology and significantly prolonged time to death. Treatment of these animals with anti-IL-12 mAb also prevented the pathology. Significantly greater amounts of IFN-gamma mRNA were detected in the lamina propria lymphocytes obtained from the small intestine of infected IL-10-/- mice than those from infected control mice. In common with C57BL/6-background IL-10-/- mice, BALB/c-background IL-10-/- mice all died developing intestinal pathology after infection. Control BALB/c mice all survived even after infection with 100 cysts and did not develop the intestinal lesions. Treatment with anti-IFN-gamma mAb prevented the pathology and prolonged time to death of the infected IL-10-/- mice. These results strongly suggest that IL-10 plays a critical role in down-regulating IFN-gamma production in the small intestine following sublethal peroral infection with Toxoplasma gondii and that this down-regulatory effect of IL-10 is required for prevention of development of IFN-gamma-mediated intestinal pathology and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice. PMID:10799901

Suzuki, Y; Sher, A; Yap, G; Park, D; Neyer, L E; Liesenfeld, O; Fort, M; Kang, H; Gufwoli, E

2000-05-15

294

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

PubMed

Mass mortality events in wild fish due to infectious diseases are troubling, especially given the potential for long-term, population-level consequences. Evolutionary theory predicts that populations with sufficient genetic variation will adapt in response to pathogen pressure. Chinook Salmon Oncorhynchus tshawytscha were introduced into Lake Michigan in the late 1960s from a Washington State hatchery population. In the late 1980s, collapse of the forage base and nutritional stress in Lake Michigan were thought to contribute to die-offs of Chinook Salmon due to bacterial kidney disease (BKD). Previously, we demonstrated that Lake Michigan Chinook Salmon from a Wisconsin hatchery have greater survival following BKD challenge relative to their progenitor population. Here, we evaluated whether the phenotypic divergence of these populations in BKD susceptibility was due to selection rather than genetic drift. Comparison of the overall magnitude of quantitative trait to neutral marker divergence between the populations suggested selection had occurred but a direct test of quantitative trait divergence was not significant, preventing the rejection of the null hypothesis of differentiation through genetic drift. Estimates of phenotypic variation (VP ), additive genetic variation (VA ) and narrow-sense heritability (h (2)) were consistently higher in the Wisconsin relative to the Washington population. If selection had acted on the Wisconsin population there was no evidence of a concomitant loss of genetic variation in BKD susceptibility. The Renibacterium salmoninarum exposures were conducted at both 14°C and 9°C; the warmer temperature accelerated time to death in both populations and there was no evidence of phenotypic plasticity or a genotype-by-environment (G × E) interaction. High h (2) estimates for BKD susceptibility in the Wisconsin population, combined with a lack of phenotypic plasticity, predicts that future adaptive gains in BKD resistance are still possible and that these adaptive gains would be stable under the temperature range evaluated here. PMID:24689954

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

2014-03-01

295

Individual Genetic Susceptibility  

SciTech Connect

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

Eric J. Hall

2008-12-08

296

INFLUENCE OF THE MUTATION "DIABETES" ON INSULIN RELEASE AND ISLET MORPHOLOGY IN MICE OF DIFFERENT GENETIC BACKGROUNDS  

PubMed Central

Mice, 7–8-mo old, of the C57BL/KsJ-db strain and homozygotic for the mutant gene db, exhibited marked hyperglycemia and moderately elevated serum insulin levels. Light and electron microscopy provided evidence of a slightly decreased proportion of ? cells in the pancreatic islets, irregular islet architecture with intraislet ducts, and degenerative as well as hypertrophic changes in the individual ? cells. As a rule, islets microdissected from these mice did not release insulin in response to glucose, theophylline, iodoacetamide, or chloromercuribenzene-p-sulphonic acid. The absence of secretory responses was not simply due to lack of insulin. Although the islet content of insulin was decreased in C57BL/KsJ-db/db mice, the remaining amount was severalfold larger than that released from stimulated islets of normal controls. Another mutation, db2J, an allele of db with identical phenotypic expressions in the C57BL/KsJ strain, was studied on the genetic background C57BL/6J. In contrast to the severely diabetic C57BL/KsJ-db/db animals, the C57BL/6J-db2J/db2J mice were characterized by highly elevated serum insulin levels and only moderate hyperglycemia. Their endocrine pancreas was enlarged and showed an increased proportion of ? cells. Like the islets of normal mice, those of C57BL/6J-db2J/db2J mice responded to glucose and chloromercuribenzene-p-sulphonic acid, the glucose-induced responses being potentiated by theophylline or iodoacetamide. C57BL/KsJ-db/db mice should provide a valuable model for studying defects in insulin secretion in relation to diabetes mellitus. Mice of the C57BL/6J strain offer a control material that may help to elucidate the dependence of the insulin secretory defect on the background genome. PMID:4135113

Boquist, L.; Hellman, B.; Lernmark, A.; Taljedal, I.-B.

1974-01-01

297

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

PubMed Central

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

Hirasawa, Tadashi

2014-01-01

298

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

EPA Science Inventory

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 ap...

299

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

PubMed

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

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

2014-02-25

300

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

SciTech Connect

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

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

1996-11-01

301

Phenolic Contents and Compositions in Skins of Red Wine Grape Cultivars among Various Genetic Backgrounds and Originations.  

PubMed

In order to analyze and compare the phenolic characteristics of red wine grapes with diverse genetic backgrounds, skin phenolics among 21 different cultivars belonging to Vitis vinifera L., East Asian and North American Vitis species and hybrids, as well as 2 varieties of muscadine grapes were estimated by HPLC-MS/MS. There were 45 anthocyanins, 28 flavonols, 8 flavan-3-ols, 9 cinnamic acids, 5 benzoic acids, 5 ellagic acids and 2 stilbenes detected in all the samples. Total contents of each phenolic type varied significantly among the different grape cultivars investigated. There was also a large variability in the phenolic compositions of different grape groups. The differences in anthocyanin composition were obvious between V. vinifera and non-V. vinifera grapes and also between the grapes originating from Eurasia and North America. Quercetin-3-glucuronide and quercetin-3-glucoside were marker flavonol compounds for Euvitis grape skins. Flavan-3-ol monomers were dominant in the skins of muscadine and non-V. amurensis East Asian grapes, whereas polymers were more common in V. vinifera and North American grapes. The muscadine grapes were very rich in flavonols, flavan-3-ols and ellagic acids. Via principal component analysis, these grape cultivars were clustered into three groups according to their characteristic phenolic content and composition. PMID:22489164

Zhu, Lei; Zhang, Yali; Lu, Jiang

2012-01-01

302

Genome-wide linkage analysis in families with infantile hypertrophic pyloric stenosis indicates novel susceptibility loci  

Microsoft Academic Search

Infantile hypertrophic pyloric stenosis (IHPS) is a common cause of upper gastrointestinal obstruction during infancy. A multifactorial background of the disease is well established. Multiple susceptibility loci including the neuronal nitric oxide synthase (NOS1) gene have previously been linked to IHPS, but contradictory results of linkage studies in different materials indicate genetic heterogeneity. To identify IHPS susceptibility loci, we conducted

Anna Svenningsson; Cilla Söderhäll; Sofia Persson; Fredrik Lundberg; Holger Luthman; Eddie Chung; Mark Gardiner; Ingrid Kockum; Agneta Nordenskjöld

2012-01-01

303

Genetic dissection of susceptibility genes for diabetes and related phenotypes on mouse chromosome 14 by means of congenic strains  

PubMed Central

Background A susceptibility locus, Nidd2n, for type 2 diabetes has been mapped to mouse chromosome 14 (Chr 14) and confirmed using the consomic strain (C3H-Chr 14NSY) of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes. The aim of this study was to localize and characterize Nidd2n. Results We constructed two novel congenic strains homozygous for different segments of NSY-Chr 14 on the control C3H/HeNcrj (C3H) background: R1 (C3H.NSY-(D14Mit206-D14Mit5)) possesses the proximal and middle segment, and R2 (C3H.NSY-(D14Mit206-D14Mit186)) possesses the most proximal segment of NSY-Chr 14. Diabetes-related phenotypes were studied in comparison with those of consomic C3H-Chr 14NSY (R0) and parental NSY and C3H strains. Congenic R1 and R2 showed significantly higher post-challenge glucose than that in C3H mice. Fasting glucose, in contrast, was significantly lower in R1 and R2 than in C3H mice. Insulin sensitivity was significantly impaired in R1 and R2 compared to C3H mice. R2 showed significantly higher body weight and fat-pad weight than those in C3H and R1. Leptin level was significantly higher in R0, R1 and R2 than in C3H mice, with R2 showing the highest level, similar to that in NSY mice. Serum adiponectin level was significantly lower in R0, R1 and R2 than in C3H mice, while it was significantly higher in NSY than in C3H mice. Conclusions These data indicate that Chr 14 harbors multiple genes for diabetes-related phenotypes. The original Nidd2n, which is located in the middle region of Chr 14, was divided into two segments; Nidd2.1n in proximal Chr 14 and Nidd2.2n in distal Chr 14. Nidd2.1n contributes to post-challenge hyperglycemia, insulin resistance and adiposity. Nidd2.2n contributes to fasting as well as post-challenge hyperglycemia and insulin resistance. Adp1n, which contributes to decreased adiposity and increased insulin sensitivity, rather than a diabetogenic gene, was mapped in the middle segment. PMID:25167881

2014-01-01

304

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons  

PubMed Central

Background?Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods?In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results?A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10?4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ?1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions?In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD. PMID:23532479

Rotger, Margalida; Glass, Tracy R.; Junier, Thomas; Lundgren, Jens; Neaton, James D.; Poloni, Estella S.; van 't Wout, Angelique B.; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Gunthard, Huldrych F.; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A.; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P.; Li, Xiuhong; Kingsley, Lawrence A.; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S.; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egana-Gorrono, Lander; Gatell, Jose M.; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jurgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H.; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Monica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, Jose R.; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fatkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A.; Reiss, Peter; Weber, Rainer; Bucher, Heiner C.; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E.

2013-01-01

305

Am. J. Hum. Genet. 70:10441048, 2002 A New Susceptibility Locus for Autosomal Dominant Pancreatic Cancer  

E-print Network

. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early cancer is relatively com- mon, very few dominant genetic or environmental risk factors have been of Human Genetics. All rights reserved. 0002-9297/2002/7004-0025$15.00 inherited pancreatic cancer

Kruglyak, Leonid

306

Developmental Analysis and Influence of Genetic Background on the Lhx3 W227ter Mouse Model of Combined Pituitary Hormone Deficiency Disease  

PubMed Central

Combined pituitary hormone deficiency (CPHD) diseases result in severe outcomes for patients including short stature, developmental delays, and reproductive deficiencies. Little is known about their etiology, especially the developmental profiles and the influences of genetic background on disease progression. Animal models for CPHD provide valuable tools to investigate disease mechanisms and inform diagnostic and treatment protocols. Here we examined hormone production during pituitary development and the influence of genetic background on phenotypic severity in the Lhx3W227ter/W227ter mouse model. Lhx3W227ter/W227ter embryos have deficiencies of ACTH, ?-glycoprotein subunit, GH, PRL, TSH?, and LH? during prenatal development. Furthermore, mutant mice have significant reduction in the critical pituitary transcriptional activator-1 (PIT1). Through breeding, the Lhx3W227ter/W227ter genotype was placed onto the 129/Sv and C57BL/6 backgrounds. Intriguingly, the genetic background significantly affected viability: whereas Lhx3W227ter/W227ter animals were found in the expected frequencies in C57BL/6, homozygous animals were not viable in the 129/Sv genetic environment. The hormone marker and PIT1 reductions observed in Lhx3W227ter/W227ter mice on a mixed background were also seen in the separate strains but in some cases were more severe in 129/Sv. To further characterize the molecular changes in diseased mice, we conducted a quantitative proteomic analysis of pituitary proteins. This showed significantly lower levels of PRL, pro-opiomelanocortin (ACTH), and ?-glycoprotein subunit proteins in Lhx3W227ter/W227ter mice. Together, these data show that hormone deficiency disease is apparent in early prenatal stages in this CPHD model system. Furthermore, as is noted in human disease, genetic background significantly impacts the phenotypic outcome of these monogenic endocrine diseases. PMID:23288907

Prince, Kelly L.; Colvin, Stephanie C.; Park, Soyoung; Lai, Xianyin; Witzmann, Frank A.

2013-01-01

307

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

EPA Science Inventory

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

308

Immune Responses of Mice with Different Genetic Backgrounds to Improved Multiepitope, Multitarget Malaria Vaccine Candidate Antigen FALVAC-1A ?  

PubMed Central

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

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

2008-01-01

309

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

PubMed

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

Ribeiro, Rui; Lopes, Isabel

2013-07-01

310

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

EPA Science Inventory

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

311

Genetic variants A1826H and D2937Y in GAG-? domain of versican influence susceptibility to intestinal-type gastric cancer  

Microsoft Academic Search

Purpose  Versican regulates adhesion, migration, proliferation, and survival of cells, and plays an important role in cancer development.\\u000a A case–control association study was performed to test genetic association of versican polymorphisms with susceptibility to\\u000a gastric cancer.\\u000a \\u000a \\u000a \\u000a Methods  In this study, 1,101 unrelated Korean subjects including 612 gastric cancer patients and 489 healthy controls were genotyped\\u000a for all 21 exonic polymorphisms in the

Hyoungseok Ju; Byungho Lim; Minjin Kim; Seung-Moo Noh; Dong Soo Han; Hang-Jong Yu; Bo Youl Choi; Yong Sung Kim; Woo Ho Kim; Chunhwa Ihm; Changwon Kang

2010-01-01

312

Assessment of the Genetic Susceptibility of Sheep to Scrapie by Protein Misfolding Cyclic Amplification and Comparison with Experimental Scrapie Transmission Studies ?  

PubMed Central

The susceptibility of sheep to scrapie is influenced mainly by the prion protein polymorphisms A136V, R154H, and Q171R/H. Here we analyzed the ability of protein misfolding cyclic amplification (PMCA) to model the genetic susceptibility of sheep to scrapie. For this purpose, we studied the efficiency of brain homogenates from sheep with different PrP genotypes to support PrPSc amplification by PMCA using an ARQ/ARQ scrapie inoculum. The results were then compared with those obtained in vivo using the same sheep breed, genotypes, and scrapie inoculum. Genotypes associated with susceptibility (ARQ/ARQ, ARQ/AHQ, and AHQ/ARH) were able to sustain PrPSc amplification in PMCA reactions, while genotypes associated with resistance to scrapie (ARQ/ARR and ARR/ARR) were unable to support the in vitro conversion. The incubation times of the experimental infection were then compared with the in vitro amplification factors. Linear regression analysis showed that the efficiency of in vitro PrPSc amplification of the different genotypes was indeed inversely proportional to their incubation times. Finally, the rare ARQK176/ARQK176 genotype, for which no in vivo data are available, was studied by PMCA. No amplification was obtained, suggesting ARQK176/ARQK176 as an additional genotype associated with resistance, at least to the isolate tested. Our results indicate a direct correlation between the ability of different PrP genotypes to undergo PrPC-to-PrPSc conversion by PMCA and their in vivo susceptibility and point to PMCA as an alternative to transmission studies and a potential tool to test the susceptibility of numerous sheep PrP genotypes to a variety of prion sources. PMID:21680531

Bucalossi, Cecilia; Cosseddu, GianMario; D'Agostino, Claudia; Di Bari, Michele Angelo; Chiappini, Barbara; Conte, Michela; Rosone, Francesca; De Grossi, Luigi; Scavia, Gaia; Agrimi, Umberto; Nonno, Romolo; Vaccari, Gabriele

2011-01-01

313

Direct-to-consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value.  

PubMed

Genetic research on addiction liability and pharmacogenetic research on treatments for addiction have identified some genetic variants associated with disease risk and treatment. Genetic testing for addiction liability and treatment response has not been used widely in clinical practice because most of the genes identified only modestly predict addiction risk or treatment response. However, many of these genetic tests have been commercialized prematurely and are available direct to the consumer (DTC). The easy availability of DTC tests for addiction liability and lack of regulation over their use raises a number of ethical concerns. Of paramount concern is the limited predictive power and clinical utility of these tests. Many DTC testing companies do not provide the consumer with the necessary genetic counselling to assist them in interpreting and acting on their test results. They may also engage in misleading marketing to entice consumers to purchase their products. Consumers' genetic information may be vulnerable to misuse by third parties, as there are limited standards to protect the privacy of the genetic information. Non-consensual testing and inappropriate testing of minors may also occur. The United States Food and Drug Administration plans to regulate DTC genetic tests. Based on the ethical concerns we discuss below, we believe there is a strong case for regulation of DTC genetic tests for addiction liability and treatment response. We argue that until this occurs, these tests have more potential to cause harm than to contribute to improved prevention and treatment of addiction. PMID:22510165

Mathews, Rebecca; Hall, Wayne; Carter, Adrian

2012-12-01

314

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

SciTech Connect

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

Hoff, R.J.; Minggao, S.

1994-02-01

315

Modelling decisions to undergo genetic testing for susceptibility to common health conditions: An ancillary study of the Multiplex Initiative  

Microsoft Academic Search

New genetic tests reveal risks for multiple conditions simultaneously, although little is understood about the psychological factors that affect testing uptake. We assessed a conceptual model called the multiplex genetic testing model (MGTM) using structural equation modelling. The MGTM delineates worry, perceived severity, perceived risk, response efficacy and attitudes towards testing as predictors of intentions and behaviour. Participants were 270

Christopher H. Wade; Shoshana Shiloh; Samuel W. Woolford; J. Scott Roberts; Sharon Hensley Alford; Theresa M. Marteau; Barbara B. Biesecker

2012-01-01

316

Modelling decisions to undergo genetic testing for susceptibility to common health conditions: An ancillary study of the Multiplex Initiative  

Microsoft Academic Search

New genetic tests reveal risks for multiple conditions simultaneously, although little is understood about the psychological factors that affect testing uptake. We assessed a conceptual model called the multiplex genetic testing model (MGTM) using structural equation modelling. The MGTM delineates worry, perceived severity, perceived risk, response efficacy and attitudes towards testing as predictors of intentions and behaviour. Participants were 270

Christopher H. Wade; Shoshana Shiloh; Samuel W. Woolford; J. Scott Roberts; Sharon Hensley Alford; Theresa M. Marteau; Barbara B. Biesecker

2011-01-01

317

The interferon gamma gene in celiac disease: augmented expression correlates with tissue damage but no evidence for genetic susceptibility  

Microsoft Academic Search

Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-?), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-?, either as a genetic factor in the etiology, or as a facilitator of disease initiation\\/progression. Duodenal biopsies were

Martin C. Wapenaar; Martine J. van Belzen; Justin H. Fransen; Aranzazu Fariña Sarasqueta; Roderick H. J. Houwen; Jos W. R. Meijer; Chris J. J. Mulder; Cisca Wijmenga

2004-01-01

318

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

Microsoft Academic Search

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

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

2004-01-01

319

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

PubMed Central

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

Janssen, I. Jana I.; Krucken, Jurgen; Demeler, Janina; Basiaga, Marta; Kornas, Slawomir; von Samson-Himmelstjerna, Georg

2013-01-01

320

Genetic variants conferring susceptibility to Alzheimer's disease in the general population; do they also predispose to dementia in Down's syndrome  

PubMed Central

Background Down’s syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer’s disease (DAD) compared with the general population. Recent collaborative genome-wide association studies of large case control data sets of individuals with and without Alzhemier’s disease (AD) have revealed new risk variants for dementia, as well as confirming previously identified risk variants. In this study, nine AD-derived SNPs, near or within the CR1 (rs3818361), BIN1 (rs744373), CD2AP (rs9349407), EPHA1 (rs11767557), CLU (rs1532278), MS4A6A/4A (rs610932), PICALM (rs561655), ABCA7 (rs3764650) and CD33 (rs3865444) genes were genotyped in 295 individuals with DS. Results There were no significant associations between these nine GWAS-derived SNPs and DAD in British Caucasian individuals with DS. Interestingly the CR1 rs3818361 variant appeared to be associated with mortality in our cohort, particularly in the subjects without dementia. To our knowledge, this is the first time that this variant has been implicated as a determinant of mortality and the finding warrants further investigation in other cohorts with DS. Conclusions This study shows negative associations of nine AD-derived SNPs with DAD in DS. This may be due to the modest size of our cohort, which may indicate that our study is insufficiently powered to pick up such associations. We cannot conclusively exclude a role for these SNPs in DAD in DS. Clearly, efforts to investigate genetic variants with small effects on disease risk require a much larger cohort of individuals with DS. In fact, we hypothesize that a sample size of 4465 individuals with DS would be needed to determine the role in DAD in DS of the nine AD-derived SNPs investigated in this study. We therefore recommend that all national and international clinics with access to individuals with DS should contribute DNA samples to form DS consortia. PMID:24438528

2014-01-01

321

Genetically reprogrammed, liver-derived insulin-producing cells are glucose-responsive, but susceptible to autoimmune destruction in settings of murine model of type 1 diabetes  

PubMed Central

Many previous studies demonstrate that hepatocytes can be reprogrammed into insulin-producing cells (IPCs) utilizing viral vector-mediated delivery of pancreatic transcription factors (PTFs). However, whether these liver-derived IPCs are susceptible to autoimmune attack in animal models of type 1 diabetes remains unclear, in part due to the immunogenicity of the viral vectors used to introduce PTF genes. Adeno-associated virus serotype 2 vector-expressing Pdx1-VP16 (Pdx1) and Ngn3 were prepared and injected into the portal vein of streptozotocin (Stz)/diabetic NOD/SCID mice. The presence of glucose-responsive liver-IPCs and their susceptibility to anti-beta cell autoimmunity were assessed by blood glucose levels, insulin content, IPC cell distribution, and intraperitoneal glucose tolerance test following subtotal pancreatectomy (Px) and passive transfer of diabetogenic splenocytes isolated from diabetic female NOD mice. A combination of two PTF genes (Pdx1/Ngn3) effectively reprogrammed liver cells into glucose-responsive IPCs. These IPCs corrected hyperglycemia in Stz/diabetic NOD/SCID mice and maintained normoglycemia following subtotal Px, indicating that liver-derived IPCs could maintain glucose homeostasis. Importantly, we also demonstrated that the glucose-responsive liver–derived IPCs were susceptible to autoimmune destruction by diabetogenic splenocytes, as indicated by progressive elevation in blood glucose levels as well as mixed T-, and B-lymphocytic infiltrates surrounding liver-IPCs 2~3 weeks following transferring of diabetogenic splenocytes into NOD/SCID mice, and confirmed by immunohistochemical studies. In conclusion, genetically reprogrammed liver-IPCs, like pancreatic islet beta-cells, are susceptible to autoimmune attack, suggesting that for cell-replacement therapy of treating type 1 diabetes, beta-cell surrogates may require concomitant immunotherapy to avoid autoimmune destruction. PMID:23573363

Tang, Dong-Qi; Shun, Lu; Koya, Vijay; Sun, Yuping; Wang, Qiwei; Wang, Hai; Li, Shi-Wu; Sun, Yu; Purich, Daniel L; Zhang, Clare; Hansen, Barbara; Qian, Keping; Atkinson, Mark; Phillips, M Ian; Yang, Li-Jun

2013-01-01

322

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

Cancer.gov

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

323

Hemizygous Le-Cre Transgenic Mice Have Severe Eye Abnormalities on Some Genetic Backgrounds in the Absence of LoxP Sites  

PubMed Central

Eye phenotypes were investigated in Le-CreTg/?; Pax6fl/+ mice, which were expected to show tissue-specific reduction of Pax6 in surface ectoderm derivatives. To provide a better comparison with our previous studies of Pax6+/? eye phenotypes, hemizygous Le-CreTg/? and heterozygous Pax6fl/+mice were crossed onto the CBA/Ca genetic background. After the Le-Cre transgene had been backcrossed to CBA/Ca for seven generations, significant eye abnormalities occurred in some hemizygous Le-CreTg/?; Pax6+/+ controls (without a floxed Pax6fl allele) as well as experimental Le-CreTg/?; Pax6fl/+ mice. However, no abnormalities were seen in Le-Cre?/?; Pax6fl/+ or Le-Cre?/?; Pax6+/+ controls (without the Le-Cre transgene). The severity and frequency of the eye abnormalities in Le-CreTg/?; Pax6+/+ control mice diminished after backcrossing Le-CreTg/? mice to the original FVB/N strain for two generations, showing that the effect was reversible. This genetic background effect suggests that the eye abnormalities are a consequence of an interaction between the Le-Cre transgene and alleles of unknown modifier genes present in certain genetic backgrounds. The abnormalities were also ameliorated by introducing additional Pax6 gene copies on a CBA/Ca background, suggesting involvement of Pax6 depletion in Le-CreTg/?; Pax6+/+ mice rather than direct action of Cre recombinase on cryptic pseudo-loxP sites. One possibility is that expression of Cre recombinase from the Pax6-Le regulatory sequences in the Le-Cre transgene depletes cofactors required for endogenous Pax6 gene expression. Our observation that eye abnormalities can occur in hemizygous Le-CreTg/?; Pax6+/+ mice, in the absence of a floxed allele, demonstrates the importance of including all the relevant genetic controls in Cre-loxP experiments. PMID:25272013

Dora, Natalie J.; Collinson, J. Martin; Hill, Robert E.; West, John D.

2014-01-01

324

Genetic Background (C57BL\\/6J Versus FVB\\/N) Strongly Influences the Severity of Diabetes and Insulin Resistance in ob\\/ob Mice  

Microsoft Academic Search

We studied the effects of genetic background on the pheno- type of ob\\/ob mice, a model of severe obesity, insulin resis- tance, and diabetes caused by leptin deficiency. Despite a comparable degree of obesity and hyperinsulinemia, C57BL\\/6J ob\\/ob mice had much milder hyperglycemia and, surprisingly, normal circulating adiponectin levels despite still-prominent signs of insulin resistance. Hyperinsulinemic- euglycemic clamp revealed relatively

MARTIN HALUZIK; CARLO COLOMBO; OKSANA GAVRILOVA; STREAMSON CHUA; NICOLE WOLF; MIN CHEN; BETHEL STANNARD; KELLY R. DIETZ; DEREK LE ROITH; MARC L. REITMAN

2004-01-01

325

Comparing self-reported ethnicity to genetic background measures in the context of the MultiEthnic Study of Atherosclerosis (MESA)  

Microsoft Academic Search

Background  Questions remain regarding the utility of self-reported ethnicity (SRE) in genetic and epidemiologic research. It is not clear\\u000a whether conditioning on SRE provides adequate protection from inflated type I error rates due to population stratification\\u000a and admixture. We address this question using data obtained from the Multi-Ethnic Study of Atherosclerosis (MESA), which enrolled\\u000a individuals from 4 self-reported ethnic groups. We

Jasmin Divers; David T Redden; Kenneth M Rice; Laura K Vaughan; Miguel A Padilla; David B Allison; David A Bluemke; Hunter J Young; Donna K Arnett

2011-01-01

326

Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease.  

PubMed

Increased dietary ratios of ?6/?3 polyunsaturated fatty acids have been implicated in the pathogenesis of Crohn's disease (CD), but epidemiologic data are limited. We investigated whether variants of genes that control polyunsaturated fatty acid metabolism (CYP4F3, FADS1, and FADS2), along with the dietary ratio of ?6/?3, confers susceptibility to CD. Based on data from 182 children newly diagnosed with CD and 250 controls, we found that children who consumed a higher dietary ratio of ?6/?3 were susceptible for CD if they were also carriers of specific variants of CYP4F3 and FADS2 genes. Our findings implicate diet-gene interactions in the pathogenesis of CD. PMID:24406470

Costea, Irina; Mack, David R; Lemaitre, Rozenn N; Israel, David; Marcil, Valerie; Ahmad, Ali; Amre, Devendra K

2014-04-01

327

Host Genetic Background Influences the Response to the Opportunistic Pseudomonas aeruginosa Infection Altering Cell-Mediated Immunity and Bacterial Replication  

PubMed Central

Pseudomonas aeruginosa is a common cause of healthcare-associated infections including pneumonia, bloodstream, urinary tract, and surgical site infections. The clinical outcome of P. aeruginosa infections may be extremely variable among individuals at risk and patients affected by cystic fibrosis. However, risk factors for P. aeruginosa infection remain largely unknown. To identify and track the host factors influencing P. aeruginosa lung infections, inbred immunocompetent mouse strains were screened in a pneumonia model system. A/J, BALB/cJ, BALB/cAnNCrl, BALB/cByJ, C3H/HeOuJ, C57BL/6J, C57BL/6NCrl, DBA/2J, and 129S2/SvPasCRL mice were infected with P. aeruginosa clinical strain and monitored for body weight and mortality up to seven days. The most deviant survival phenotypes were observed for A/J, 129S2/SvPasCRL and DBA/2J showing high susceptibility while BALB/cAnNCrl and C3H/HeOuJ showing more resistance to P. aeruginosa infection. Next, one of the most susceptible and resistant mouse strains were characterized for their deviant clinical and immunological phenotype by scoring bacterial count, cell-mediated immunity, cytokines and chemokines profile and lung pathology in an early time course. Susceptible A/J mice showed significantly higher bacterial burden, higher cytokines and chemokines levels but lower leukocyte recruitment, particularly neutrophils, when compared to C3H/HeOuJ resistant mice. Pathologic scores showed lower inflammatory severity, reduced intraluminal and interstitial inflammation extent, bronchial and parenchymal involvement and diminished alveolar damage in the lungs of A/J when compared to C3H/HeOuJ. Our findings indicate that during an early phase of infection a prompt inflammatory response in the airways set the conditions for a non-permissive environment to P. aeruginosa replication and lock the spread to other organs. Host gene(s) may have a role in the reduction of cell-mediated immunity playing a critical role in the control of P. aeruginosa infection. These results now provide a basis for mapping genomic regions underlying host susceptibility to P. aeruginosa infection. PMID:25268734

Lore, Nicola Ivan; Rossi, Giacomo; Cigana, Cristina; De Fino, Ida; Iraqi, Fuad A.; Bragonzi, Alessandra

2014-01-01

328

Genetic variation in natural populations of the cereal cyst nematode (Heterodera avenae Woll.) submitted to resistant and susceptible cultivars of cereals.  

PubMed

The purpose of the present work was to study the genetic characteristics of cereal cyst nematode (Heterodera avenae) populations re-established after the long-term use of resistant oat cultivars in field conditions. Population features were analyzed through fitness components and variation in enzymatic polymorphism (esterase and malate dehydrogenase loci). The longest (6 year) use of the same resistance genes (oat cv Panema) at high frequency (Rotation IB) led to the selection of a resistance-breaking pathotype and to a decrease in viability which suggested either a founder effect or a lower reproductive potential for the new pathotype. Analysis of esterase allelic frequencies led to the conclusions that: (1) the genetic constitution of this pathotype was different from the reference population maintained on the susceptible host (oat cv Peniarth), and (2) that the esterase locus may develop a disequilibrium linkage with loci involved in virulence Nematodes overcoming the resistance of cv Panema did not differ from H. avenae species following RFLPs in ribosomal DNA . Random mating was recorded at the whole-field level but not always at the single-plant level, suggesting that cultivation practices such as annual ploughing could play a major role in homogenizing subpopulations developed in the vicinity of a plant. These phenomena showed that the long-term use of highly effective resistance could provok marked genetic modifications in populations. These risks should be taken into account when deciding strategies for optimal use of resistance genes in nematode management programs. PMID:24162191

Lasserre, F; Gigault, F; Gauthier, J P; Henry, J P; Sandmeier, M; Rivoal, R

1996-07-01

329

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

PubMed Central

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

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

2013-01-01

330

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

Microsoft Academic Search

Background: Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1–3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided

Maria Karayiorgou; Christina Sobin; Maude L. Blundell; Brandi L. Galke; Lubomira Malinova; Pablo Goldberg; Jurg Ott; Joseph A. Gogos

1999-01-01

331

[Identification of susceptibility genes for age-related macular degeneration--a success story of molecular genetics].  

PubMed

The number of persons over 70 years of age with advanced age-related macular degeneration in Finland can be estimated to be approximately 50,000. Milder forms are additionally present in a considerably larger group. Smoking and age are undisputed non-genetic risk factors of age-related macular degeneration. Of the genetic factors, polymorphisms of the complement factor H (CFH) and LOC387715 genes have a strong impact on the risk of developing the disease, whereas alleles of the C3, CFB, and the C1 inhibitor SERPING1 genes of the complement system exhibit only minor effects. PMID:19999660

Seitsonen, Sanna; Onkamo, Päivi; Immonen, Ilkka; Järvelä, Irma

2009-01-01

332

Genetics of Crohn disease, an archetypal inflammatory barrier disease  

Microsoft Academic Search

Chronic inflammatory disorders such as Crohn disease, atopic eczema, asthma and psoriasis are triggered by hitherto unknown environmental factors that function on the background of some polygenic susceptibility. Recent technological advances have allowed us to unravel the genetic aetiology of these and other complex diseases. Using Crohn disease as an example, we show how the discovery of susceptibility genes furthers

Philip Rosenstiel; Mario Albrecht; Jochen Hampe; Michael Krawczak; Stefan Schreiber

2005-01-01

333

Genetic evidence for the neuronal nitric oxide synthase gene (NOS1) as a susceptibility locus for infantile pyloric stenosis  

SciTech Connect

The etiological role of the gene for neuronal nitric oxide synthase (NOS1) in infantile pyloric stenosis (PS) was investigated by analysis of two intragenic polymorphisms (NOS1a and NOS1b) in 27 families. There was significant overall transmission disequilibrium between PS and NOS1a (P=.006). Consideration of each allele independently revealed a highly significant tendency for allele 7 (210 bp) to be preferentially transmitted to the affected offspring (P=.0006). These observations suggest that NOS1 is a susceptibility locus for PS. 38 refs., 1 fig., 3 tabs.

Chung, E.; Chen, G.; Gardiner, M. [Rayne Inst., London (United Kingdom)] [and others

1996-02-01

334

Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis  

Microsoft Academic Search

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

Krzysztof Kiryluk; Yifu Li; Simone Sanna-Cherchi; Mersedeh Rohanizadegan; Hitoshi Suzuki; Frank Eitner; Holly J. Snyder; Murim Choi; Ping Hou; Francesco Scolari; Claudia Izzi; Maddalena Gigante; Loreto Gesualdo; Silvana Savoldi; Antonio Amoroso; Daniele Cusi; Pasquale Zamboli; Bruce A. Julian; Jan Novak; Robert J. Wyatt; Krzysztof Mucha; Markus Perola; Kati Kristiansson; Alexander Viktorin; Patrik K. Magnusson; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Kari Stefansson; Anne Boland; Marie Metzger; Lise Thibaudin; Christoph Wanner; Kitty J. Jager; Shin Goto; Dita Maixnerova; Hussein H. Karnib; Judit Nagy; Ulf Panzer; Jingyuan Xie; Nan Chen; Vladimir Tesar; Ichiei Narita; Francois Berthoux; Jürgen Floege; Benedicte Stengel; Hong Zhang; Richard P. Lifton; Ali G. Gharavi

2012-01-01

335

Overlap of genetic susceptibility to type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes in adults.  

PubMed

Despite the notion that there is a degree of commonality to the biological etiology of type 1 diabetes (T1D) and type 2 diabetes (T2D), the lack of overlap in the genetic factors underpinning each of them suggests very distinct mechanisms. A disorder considered to be at the "intersection" of these two diseases is "latent autoimmune diabetes in adults" (LADA). Interestingly, genetic signals from both T1D and T2D are also seen in LADA, including the key HLA and transcription factor 7-like 2 (TCF7L2) loci, but the magnitudes of these effects are more complex than just pointing to LADA as being a simple admixture of T1D and T2D. We review the current status of the understanding of the genetics of LADA and place it in the context of what is known about the genetics of its better-studied "cousins," T1D and T2D, especially with respect to the myriad of discoveries made over the last decade through genome-wide association studies. PMID:25189437

Basile, Kevin J; Guy, Vanessa C; Schwartz, Stanley; Grant, Struan F A

2014-11-01

336

Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility  

PubMed Central

Several neuroblastoma (NB) susceptibility loci have been identified within LINC00340, BARD1, LMO1, DUSP12, HSD17B12, DDX4, IL31RA, HACE1 and LIN28B by genome-wide association (GWA) studies including European American individuals. To validate and comprehensively evaluate the impact of the identified NB variants on disease risk and phenotype, we analyzed 16 single nucleotide polymorphisms (SNPs) in an Italian population (370 cases and 809 controls). We assessed their regulatory activity on gene expression in lymphoblastoid (LCLs) and NB cell lines. We evaluated the cumulative effect of the independent loci on NB risk and high-risk phenotype development in Italian and European American (1627 cases and 2575 controls) populations. All NB susceptibility genes replicated in the Italian dataset except for DDX4 and IL31RA, and the most significant SNP was rs6435862 in BARD1 (P = 8.4×10–15). BARD1 showed an additional and independent SNP association (rs7585356). This variant influenced BARD1 mRNA expression in LCLs and NB cell lines. No evidence of epistasis among the NB-associated variants was detected, whereas a cumulative effect of risk variants on NB risk (European Americans: P trend = 6.9×10–30, Italians: P trend = 8.55×1013) and development of high-risk phenotype (European Americans: P trend = 6.9×10–13, Italians: P trend = 2.2×10–1) was observed in a dose-dependent manner. These results provide further evidence that the risk loci identified in GWA studies contribute to NB susceptibility in distinct populations and strengthen the role of BARD1 as major genetic contributor to NB risk. This study shows that even in the absence of interaction the combination of several low-penetrance alleles has potential to distinguish subgroups of patients at different risks of developing NB. PMID:23222812

Capasso, Mario

2013-01-01

337

Genetic control in the susceptibility of germfree inbred mice to infection by Escherichia coli O115a,c:K(B).  

PubMed Central

We studied the susceptibility of five germfree inbred strains of mice to oral infection by murine pathogenic Escherichia coli O115a,c:K(B) (MPEC), the causative agent of mouse megaenteron. Although MPEC colonized all strains of mice at 10(9)/g of feces, the mouse strains could be divided into three groups according to their intestinal lesions. In CF1 and C3H/He mice, intestinal lesions were produced in the cecum and colon with hyperplasia of epithelial cells accompanied by severe inflammatory reactions and erosion. The lesions in NC and C57BL/6 mice were restricted to the tip of the cecum, and hyperplasia of epithelial cells was more severe in these mice than in CF1 or C3H/He mice. BALB/c mice had no lesions. Analysis of F1 hybrids of CF1, NC, and BALB/c mice and offsprings from backcrosses of F1 mice to parental strains showed that susceptibility to MPEC seemed to be controlled genetically by a single locus which may be related to the receptors on epithelial cells for MPEC adherence. However, the differences in lesions between CF1 and NC mice suggest that a combination of this locus and another locus to which it may be related regulates the hyperplasia of intestinal epithelial cells. Images PMID:3278987

Itoh, K; Matsui, T; Tsuji, K; Mitsuoka, T; Ueda, K

1988-01-01

338

Association between the Haptoglobin and Heme Oxygenase 1 Genetic Profiles and Soluble CD163 in Susceptibility to and Severity of Human Malaria  

PubMed Central

Intravascular hemolysis is a hallmark event in the immunopathology of malaria that results in increased systemic concentrations of free hemoglobin (Hb). The oxidation of Hb by free radicals causes the release of heme, which amplifies inflammation. To circumvent the detrimental effects of free heme, hosts have developed several homeostatic mechanisms, including the enzyme haptoglobin (Hp), which scavenges cell-free Hb, the monocyte receptor CD163, which binds to Hb-Hp complexes, and heme oxygenase-1 (HO-1), which degrades intracellular free heme. We tested the association between these three main components of the host response to hemolysis and susceptibility to malaria in a Brazilian population. The genetic profiles of the HMOX1 and Hp genes and the plasma levels of a serum inflammatory marker, the soluble form of the CD163 receptor (sCD163), were studied in 264 subjects, including 78 individuals with symptomatic malaria, 106 individuals with asymptomatic malaria, and 80 uninfected individuals. We found that long (GT)n repeats in the microsatellite polymorphism region of the HMOX1 gene, the Hp2 allele, and the Hp2.2 genotype were associated with symptomatic malaria. Moreover, increased plasma concentrations of heme, Hp, HO-1, and sCD163 were associated with susceptibility to malaria. The validation of these results could support the development of targeted therapies and aid in reducing the severity of malaria. PMID:22290142

Mendonça, Vitor R. R.; Luz, Nívea F.; Santos, Nadja J. G.; Borges, Valéria M.; Gonçalves, Marilda S.; Andrade, Bruno B.

2012-01-01

339

Intrinsic Susceptibility MRI Identifies Tumors with ALKF1174L Mutation in Genetically-Engineered Murine Models of High-Risk Neuroblastoma  

PubMed Central

The early identification of children presenting ALKF1174L-mutated neuroblastoma, which are associated with resistance to the promising ALK inhibitor crizotinib and a marked poorer prognosis, has become a clinical priority. In comparing the radiology of the novel Th-ALKF1174L/Th-MYCN and the well-established Th-MYCN genetically-engineered murine models of neuroblastoma using MRI, we have identified a marked ALKF1174L-driven vascular phenotype. We demonstrate that quantitation of the transverse relaxation rate R2* (s?1) using intrinsic susceptibility-MRI under baseline conditions and during hyperoxia, can robustly discriminate this differential vascular phenotype, and identify MYCN-driven tumors harboring the ALKF1174L mutation with high specificity and selectivity. Intrinsic susceptibility-MRI could thus potentially provide a non-invasive and clinically-exploitable method to help identifying children with MYCN-driven neuroblastoma harboring the ALKF1174L mutation at the time of diagnosis. PMID:24667968

Jamin, Yann; Glass, Laura; Hallsworth, Albert; George, Rani; Koh, Dow-Mu; Pearson, Andrew D. J.; Chesler, Louis; Robinson, Simon P.

2014-01-01

340

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

E-print Network

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

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

2008-08-20

341

Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background.  

PubMed

The significant worldwide health burden introduced by tobacco smoking highlights the importance of studying the genetic determinants of smoking behavior and the key factor sustaining compulsive smoking, that is, nicotine dependence (ND). We have here addressed the genetic background of smoking in a special study sample of twins, harmonized for early life events and specifically ascertained for smoking from the nationwide twin cohort of the genetically unique population of Finland. The twins and their families were carefully examined for extensive phenotype profiles and a genome-wide scan was performed to identify loci behind the smoking status, ND and the comorbid phenotype of ND and alcohol use in 505 individuals from 153 families. We replicated previous linkage findings on 10q (max logarithm of the odds (LOD) 3.12) for a smoker phenotype, and on 7q and 11p (max LOD 2.50, and 2.25, respectively) for the ND phenotype. The loci linked for ND also showed evidence for linkage for the comorbid phenotype. Our study provides confirmatory evidence for the involvement of these genome regions in the genetic etiology of smoking behavior and ND and for the first time associates drinking and smoking to a shared locus on 10q. PMID:17549066

Loukola, A; Broms, U; Maunu, H; Widén, E; Heikkilä, K; Siivola, M; Salo, A; Pergadia, M L; Nyman, E; Sammalisto, S; Perola, M; Agrawal, A; Heath, A C; Martin, N G; Madden, P A F; Peltonen, L; Kaprio, J

2008-06-01

342

Classification of educational backgrounds of students using musical intelligence and perception with the help of genetic neural networks  

Microsoft Academic Search

In this study we demonstrate that machine learning can be used to classify students who had backgrounds in positive sciences (including engineering, science and math disciplines) vs. social sciences (including arts and humanities disciplines) by the help of musical hearing and perception using artificial neural networks. Our 80 test subjects had an even mixture of both aforementioned disciplines. Each participant

Firat Hardalaç

2009-01-01

343

Skewed Helper T-Cell Responses to IL-12 Family Cytokines Produced by Antigen-Presenting Cells and the Genetic Background in Behcet's Disease  

PubMed Central

Behcet's disease (BD) is a multisystemic inflammatory disease and is characterized by recurrent attacks on eyes, brain, skin, and gut. There is evidence that skewed T-cell responses contributed to its pathophysiology in patients with BD. Recently, we found that Th17 cells, a new helper T (Th) cell subset, were increased in patients with BD, and both Th type 1 (Th1) and Th17 cell differentiation signaling pathways were overactivated. Several researches revealed that genetic polymorphisms in Th1/Th17 cell differentiation signaling pathways were associated with the onset of BD. Here, we summarize current findings on the Th cell subsets, their contribution to the pathogenesis of BD and the genetic backgrounds, especially in view of IL-12 family cytokine production and pattern recognition receptors of macrophages/monocytes. PMID:24490076

Shimizu, Jun; Kaneko, Fumio; Suzuki, Noboru

2013-01-01

344

Temporal and Anatomical Host Resistance to Chronic Salmonella Infection Is Quantitatively Dictated by Nramp1 and Influenced by Host Genetic Background  

PubMed Central

The lysosomal membrane transporter, Nramp1, plays a key role in innate immunity and resistance to infection with intracellular pathogens such as non-typhoidal Salmonella (NTS). NTS-susceptible C57BL/6 (B6) mice, which express the mutant Nramp1D169 allele, are unable to control acute infection with Salmonella enterica serovar Typhimurium following intraperitoneal or oral inoculation. Introducing functional Nramp1G169 into the B6 host background, either by constructing a congenic strain carrying Nramp1G169 from resistant A/J mice (Nramp-Cg) or overexpressing Nramp1G169 from a transgene (Nramp-Tg), conferred equivalent protection against acute Salmonella infection. In contrast, the contributions of Nramp1 for controlling chronic infection are more complex, involving temporal and anatomical differences in Nramp1-dependent host responses. Nramp-Cg, Nramp-Tg and NTS-resistant 129×1/SvJ mice survived oral Salmonella infection equally well for the first 2–3 weeks, providing evidence that Nramp1 contributes to the initial control of NTS bacteremia preceding establishment of chronic Salmonella infection. By day 30, increased host Nramp1 expression (Tg>Cg) provided greater protection as indicated by decreased splenic bacterial colonization (Tgsusceptible mice, 2) restriction of systemic bacterial growth in the spleens of NTS-susceptible mice is enhanced by Nramp1 expression and dose-dependent, and 3) host genes other than Nramp1 also contribute to the ability of NTS-resistant 129×1/SvJ mice to control bacterial replication during chronic infection. PMID:25350459

Loomis, Wendy P.; Johnson, Matthew L.; Brasfield, Alicia; Blanc, Marie-Pierre; Yi, Jaehun; Miller, Samuel I.; Cookson, Brad T.; Hajjar, Adeline M.

2014-01-01

345

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

Microsoft Academic Search

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

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

2010-01-01

346

The Epsin 4 Gene on Chromosome 5q, Which Encodes the Clathrin-Associated Protein Enthoprotin, Is Involved in the Genetic Susceptibility to Schizophrenia  

PubMed Central

Chromosome 5q33 is a region that has previously shown good evidence of linkage to schizophrenia, with four LOD scores >3.00 in independent linkage studies. We studied 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Four adjacent markers at the 5? end of the Epsin 4 gene showed significant evidence of linkage disequilibrium with schizophrenia. These included two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide–polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01). A series of different two- and three-marker haplotypes were also significantly associated with schizophrenia, as confirmed with a permutation test (HapA, P=.004; HapB, P=.0005; HapC, P=.007; and HapD, P=.01). The Epsin 4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. A genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3. PMID:15793701

Pimm, Jonathan; McQuillin, Andrew; Thirumalai, Srinivasa; Lawrence, Jacob; Quested, Digby; Bass, Nicholas; Lamb, Graham; Moorey, Helen; Datta, Susmita R.; Kalsi, Gursharan; Badacsonyi, Allison; Kelly, Katie; Morgan, Jenny; Punukollu, Bhaskar; Curtis, David; Gurling, Hugh

2005-01-01

347

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.  

PubMed

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ?2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior. PMID:21471458

Schumann, Gunter; Coin, Lachlan J; Lourdusamy, Anbarasu; Charoen, Pimphen; Berger, Karen H; Stacey, David; Desrivières, Sylvane; Aliev, Fazil A; Khan, Anokhi A; Amin, Najaf; Aulchenko, Yurii S; Bakalkin, Georgy; Bakker, Stephan J; Balkau, Beverley; Beulens, Joline W; Bilbao, Ainhoa; de Boer, Rudolf A; Beury, Delphine; Bots, Michiel L; Breetvelt, Elemi J; Cauchi, Stéphane; Cavalcanti-Proença, Christine; Chambers, John C; Clarke, Toni-Kim; Dahmen, Norbert; de Geus, Eco J; Dick, Danielle; Ducci, Francesca; Easton, Alanna; Edenberg, Howard J; Esko, Tõnu; Esk, Tõnu; Fernández-Medarde, Alberto; Foroud, Tatiana; Freimer, Nelson B; Girault, Jean-Antoine; Grobbee, Diederick E; Guarrera, Simonetta; Gudbjartsson, Daniel F; Hartikainen, Anna-Liisa; Heath, Andrew C; Hesselbrock, Victor; Hofman, Albert; Hottenga, Jouke-Jan; Isohanni, Matti K; Kaprio, Jaakko; Khaw, Kay-Tee; Kuehnel, Brigitte; Laitinen, Jaana; Lobbens, Stéphane; Luan, Jian'an; Mangino, Massimo; Maroteaux, Matthieu; Matullo, Giuseppe; McCarthy, Mark I; Mueller, Christian; Navis, Gerjan; Numans, Mattijs E; Núñez, Alejandro; Nyholt, Dale R; Onland-Moret, Charlotte N; Oostra, Ben A; O'Reilly, Paul F; Palkovits, Miklos; Penninx, Brenda W; Polidoro, Silvia; Pouta, Anneli; Prokopenko, Inga; Ricceri, Fulvio; Santos, Eugenio; Smit, Johannes H; Soranzo, Nicole; Song, Kijoung; Sovio, Ulla; Stumvoll, Michael; Surakk, Ida; Thorgeirsson, Thorgeir E; Thorsteinsdottir, Unnur; Troakes, Claire; Tyrfingsson, Thorarinn; Tönjes, Anke; Uiterwaal, Cuno S; Uitterlinden, Andre G; van der Harst, Pim; van der Schouw, Yvonne T; Staehlin, Oliver; Vogelzangs, Nicole; Vollenweider, Peter; Waeber, Gerard; Wareham, Nicholas J; Waterworth, Dawn M; Whitfield, John B; Wichmann, Erich H; Willemsen, Gonneke; Witteman, Jacqueline C; Yuan, Xin; Zhai, Guangju; Zhao, Jing H; Zhang, Weihua; Martin, Nicholas G; Metspalu, Andres; Doering, Angela; Scott, James; Spector, Tim D; Loos, Ruth J; Boomsma, Dorret I; Mooser, Vincent; Peltonen, Leena; Stefansson, Kari; van Duijn, Cornelia M; Vineis, Paolo; Sommer, Wolfgang H; Kooner, Jaspal S; Spanagel, Rainer; Heberlein, Ulrike A; Jarvelin, Marjo-Riitta; Elliott, Paul

2011-04-26

348

Gene expression profiling of the local cecal response of genetic chicken lines that differ in their susceptibility to Campylobacter jejuni colonization.  

PubMed

Campylobacter jejuni (C. jejuni) is one of the most common causes of human bacterial enteritis worldwide primarily due to contaminated poultry products. Previously, we found a significant difference in C. jejuni colonization in the ceca between two genetically distinct broiler lines (Line A (resistant) has less colony than line B (susceptible) on day 7 post inoculation). We hypothesize that different mechanisms between these two genetic lines may affect their ability to resist C. jejuni colonization in chickens. The molecular mechanisms of the local host response to C. jejuni colonization in chickens have not been well understood. In the present study, to profile the cecal gene expression in the response to C. jejuni colonization and to compare differences between two lines at the molecular level, RNA of ceca from two genetic lines of chickens (A and B) were applied to a chicken whole genome microarray for a pair-comparison between inoculated (I) and non-inoculated (N) chickens within each line and between lines. Our results demonstrated that metabolism process and insulin receptor signaling pathways are key contributors to the different response to C. jejuni colonization between lines A and B. With C. jejuni inoculation, lymphocyte activation and lymphoid organ development functions are important for line A host defenses, while cell differentiation, communication and signaling pathways are important for line B. Interestingly, circadian rhythm appears play a critical role in host response of the more resistant A line to C. jejuni colonization. A dramatic differential host response was observed between these two lines of chickens. The more susceptible line B chickens responded to C. jejuni inoculation with a dramatic up-regulation in lipid, glucose, and amino acid metabolism, which is undoubtedly for use in the response to the colonization with little or no change in immune host defenses. However, in more resistant line A birds the host defense responses were characterized by an up-regulation lymphocyte activation, probably by regulatory T cells and an increased expression of the NLR recognition receptor NALP1. To our knowledge, this is the first time each of these responses has been observed in the avian response to an intestinal bacterial pathogen. PMID:20676366

Li, Xianyao; Swaggerty, Christina L; Kogut, Michael H; Chiang, Hsin-I; Wang, Ying; Genovese, Kenneth J; He, Haiqi; Zhou, Huaijun

2010-01-01

349

Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease  

PubMed Central

Pre-eclampsia is an idiopathic pregnancy disorder promoting morbidity and mortality to both mother and child. Delivery of the fetus is the only means to resolve severe symptoms. Women with pre-eclamptic pregnancies demonstrate increased risk for later life cardiovascular disease (CVD) and good evidence suggests these two syndromes share several risk factors and pathophysiological mechanisms. To elucidate the genetic architecture of pre-eclampsia we have dissected our chromosome 2q22 susceptibility locus in an extended Australian and New Zealand familial cohort. Positional candidate genes were prioritized for exon-centric sequencing using bioinformatics, SNPing, transcriptional profiling and QTL-walking. In total, we interrogated 1598 variants from 52 genes. Four independent SNP associations satisfied our gene-centric multiple testing correction criteria: a missense LCT SNP (rs2322659, P = 0.0027), a synonymous LRP1B SNP (rs35821928, P = 0.0001), an UTR-3 RND3 SNP (rs115015150, P = 0.0024) and a missense GCA SNP (rs17783344, P = 0.0020). We replicated the LCT SNP association (P = 0.02) and observed a borderline association for the GCA SNP (P = 0.07) in an independent Australian case–control population. The LRP1B and RND3 SNP associations were not replicated in this same Australian singleton cohort. Moreover, these four SNP associations could not be replicated in two additional case–control populations from Norway and Finland. These four SNPs, however, exhibit pleiotropic effects with several quantitative CVD-related traits. Our results underscore the genetic complexity of pre-eclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVD-related risk factors. PMID:23420841

Johnson, Matthew P.; Brennecke, Shaun P.; East, Christine E.; Dyer, Thomas D.; Roten, Linda T.; Proffitt, J. Michael; Melton, Phillip E.; Fenstad, Mona H.; Aalto-Viljakainen, Tia; Makikallio, Kaarin; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Laivuori, Hannele; Austgulen, Rigmor; Blangero, John; Moses, Eric K.; Pouta, Anneli; Kivinen, Katja; Ekholm, Eeva; Hietala, Reija; Sainio, Susanna; Saisto, Terhi; Uotila, Jukka; Klemetti, Miira; Inkeri Lokki, Anna; Georgiadis, Leena; Huovari, Elina; Kortelainen, Eija; Leminen, Satu; Lahdesmaki, Aija; Mehtala, Susanna; Salmen, Christina

2013-01-01

350

Genetic polymorphisms in VDR, ESR1 and ESR2 genes may contribute to susceptibility to Parkinson's disease: a meta-analysis.  

PubMed

We conducted this meta-analysis of relevant case-control studies to investigate the relationships between genetic polymorphisms in VDR, ESR1 and ESR2 genes to the susceptibility of Parkinson's disease (PD). A search on electronic databases without any language restrictions was conducted: MEDLINE (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and the Chinese Biomedical Database (1982-2013). Meta-analysis was performed using the STATA statistical software. Crude odds ratio (OR) with their 95% confidence interval (95% CI) was calculated. Fourteen case-control studies with a total of 3,689 PD patients and 4,627 healthy subjects were included in our meta-analysis. The results of our meta-analysis demonstrated that the VDR genetic polymorphisms might be closely related to increased risks of PD (allele model: OR = 1.18, 95% CI 1.09-1.29, P < 0.001; dominant model: OR = 1.37, 95% CI 1.16-1.63, P < 0.001; respectively), especially for the polymorphisms rs7976091 and rs10735810. Our findings also illustrated that ESR1 genetic polymorphisms might increase the risk of PD (allele model: OR = 1.56, 95% CI 1.17-2.07, P = 0.002; recessive model: OR = 1.93, 95 % CI 1.33-2.80, P < 0.001; homozygous model: OR = 1.35, 95% CI 1.02-1.79, P = 0.038; heterozygous model: OR = 2.04, 95% CI 1.36-3.07, P = 0.001; respectively), especially for the polymorphisms rs2234693 and rs9340799. Furthermore, we found significant correlations of ESR2 genetic polymorphisms with the risk of PD (allele model: OR = 1.78, 95% CI 1.19-2.67, P = 0.005; recessive model: OR = 1.93, 95% CI 1.15-3.27, P = 0.014; homozygous model: OR = 1.77, 95% CI 1.09-2.89, P = 0.022; heterozygous model: OR = 1.88, 95% CI 1.08-3.27, P = 0.025; respectively), especially for the rs1256049 polymorphism. Our meta-analysis suggests that genetic polymorphisms in VDR, ESR1 and ESR2 genes may contribute to increased risks for PD. PMID:24595449

Gao, Zhan; Fu, Hong-Juan; Xue, Ju-Jun; Wu, Zhi-Xuan; Zhao, Li-Bo

2014-07-01

351

Impact of host genetics on susceptibility and resistance to Mycobacterium avium subspecies Paratuberculosis infection in domestic ruminants.  

PubMed

Johne's disease or Paratuberculosis has emerged as major infectious disease of animals in general and domestic livestock in particular on global basis. There have been major initiatives in developed countries for the control of this incurable malady of animals and human beings alike (inflammatory bowel disease or Crohn's disease). Disease has not received similar attention due to inherent complexities of disease, diagnosis and control, in resource poor counties around the world. However, the rich genetic diverstiy of the otherwise low productive animal population offers opportunity for the control of Johne's disease and improve per animal productivity. Present review aims to gather and compile information available on genetics or resistance to Johne's disease and its future exploitation by resource poor countries rich in animal diversity. This review will also help to create awareness and share knowledge and experience on prevalence and opportunities for control of Johne's disease in the livestock population to boost per animal productivity among developing and poor countries of the world. Breeding of animals for disease resistance provides good, safe, effective and cheaper way of controlling Johne's disease in animals, with especial reference to domestic livestock of developing and poor countries. Study will help to establish better understanding of the correlation between host cell factors and resistance to MAP infection which may have ultimately help in the control of Johne's disease in future. PMID:24498788

Vir Singh, Shoor; Dhama, Kuldeep; Chaubey, Kundan Kumar; Kumar, Naveen; Singh, Pravin Kumar; Sohal, Jagdip Singh; Gupta, Saurabh; Vir Singh, Ajay; Verma, Amit Kumar; Tiwari, Ruchi; Mahima; Chakraborty, S; Deb, Rajib

2013-03-15

352

Association of genetic variants of cancer stem cell gene CD44 haplotypes with gallbladder cancer susceptibility in North Indian population.  

PubMed

CD44 is an important marker for cancer stem cells. Germline variants in CD44 gene have been associated with susceptibility to breast and nasopharyngeal carcinomas but no study in gallbladder cancer (GBC) has been done yet. The present study included 405 GBC patients and 200 healthy controls from North India. Tagger SNPs for CD44 were selected from the GIH population data. Genotyping was carried out by PCR-RFLP and Taqman probes. Statistical analysis was done by SPSS. Bonferroni correction was applied in subgroup analysis. Logistic regression analysis showed no individual association of CD44 polymorphisms with GBC risk. However, [CCAT] haplotype was associated with overall reduced risk of GBC [P?=?0.04, odds ratios (OR)?=?0.47]. Gender stratification revealed that [CCAT] and [TAGT] haplotypes were significantly associated with decreased risk in female GBC patients [P?=?0.022, OR?=?0.38; P?=?0.011, OR?=?0.17, respectively]. The CAAT haplotype was marginally associated with low GBC risk in patients with co-existing gallstones [P?=?0.026, OR?=?0.53]. The cancer risk was not further modified with tobacco usage or age of onset. In silico analysis showed change in transcriptional regulation of selected SNPs. This study reports an important role of CD44 haplotypes with reduced risk of GBC. PMID:24186075

Sharma, Kiran Lata; Yadav, Anu; Gupta, Annapurna; Tulsayan, Sonam; Kumar, Vijay; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

2014-03-01

353

New evidence of a mitochondrial genetic background paradox: Impact of the J haplogroup on the A3243G mutation  

PubMed Central

Background The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients – diagnosed as carriers of the A3243G mutation – by control-region sequencing and RFLP survey of their mtDNAs. Results The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08–0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages. Conclusion Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts. PMID:18462486

Pierron, Denis; Rocher, Christophe; Amati-Bonneau, Patricia; Reynier, Pascal; Martin-Negrier, Marie-Laure; Allouche, Stephane; Batandier, Cecile; de Camaret, Benedicte Mousson; Godinot, Catherine; Rotig, Agnes; Feldmann, Delphine; Bellanne-Chantelot, Christine; Arveiler, Benoit; Pennarun, Erwann; Rossignol, Rodrigue; Crouzet, Marc; Murail, Pascal; Thoraval, Didier; Letellier, Thierry

2008-01-01

354

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

Microsoft Academic Search

BACKGROUND: Vitamin D has been shown to exert manifold immunomodulatory effects. Type 1 diabetes mellitus (T1DM) is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse. We studied the association between T1DM and the initiation codon polymorphism in exon 2 of the vitamin D receptor gene in a Japanese population. We also investigated

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

2001-01-01

355

G(z alpha) deficient mice: enzyme levels in the autonomic nervous system, neuronal survival and effect of genetic background.  

PubMed

Our laboratory has generated a genetically mutant mouse in which the alpha subunit of the heterotrimeric GTP binding protein, G(z) has been made dysfunctional by homologous recombination to determine its in vivo function. These animals show a characteristic failure to thrive phenotype. G(z alpha) is expressed in a variety of nervous system tissues as well as in the adrenal medulla. We therefore examined the autonomic nervous system of the G(z alpha) deficient mouse by measuring the activity of tyrosine hydroxylase and choline acetyltransferase in the superior cervical ganglia, submaxillary gland and the adrenal medulla. Preliminary results using animals of mixed BALB/c and C57BL/6 strains gave inconsistent results. Further experiments demonstrated differences in the activity of tyrosine hydroxylase and choline acetyltransferase between BALB/c and C57BL/6 mouse strains. The analysis of the pure strains showed a reduction in the size and enzyme levels of the adrenal gland and submaxillary glands of the G(z alpha) deficient mouse suggesting a role for adrenal insufficiency and/or nutritional disorders for the failure to thrive phenotype. The survival of sympathetic and sensory neurons was also examined in the G(z alpha) deficient mouse and in the presence of pertussis toxin, sympathetic but not sensory neuronal survival in G(z alpha) deficient mice was significantly attenuated. This suggests that in vivo other pertussis toxin sensitive G proteins may be recruited to compensate for the loss of G(z alpha). PMID:12008073

Powell, Kim L; Matthaei, Klaus I; Heydon, Katharina; Hendry, Ian A

2002-02-01

356

Genetic recombination variation in wild Robertsonian mice: on the role of chromosomal fusions and Prdm9 allelic background.  

PubMed

Despite the existence of formal models to explain how chromosomal rearrangements can be fixed in a population in the presence of gene flow, few empirical data are available regarding the mechanisms by which genome shuffling contributes to speciation, especially in mammals. In order to shed light on this intriguing evolutionary process, here we present a detailed empirical study that shows how Robertsonian (Rb) fusions alter the chromosomal distribution of recombination events during the formation of the germline in a Rb system of the western house mouse (Mus musculus domesticus). Our results indicate that both the total number of meiotic crossovers and the chromosomal distribution of recombination events are reduced in mice with Rb fusions and that this can be related to alterations in epigenetic signatures for heterochromatinization. Furthermore, we detected novel house mouse Prdm9 allelic variants in the Rb system. Remarkably, mean recombination rates were positively correlated with a decrease in the number of ZnF domains in the Prdm9 gene. The suggestion that recombination can be modulated by both chromosomal reorganizations and genetic determinants that control the formation of double-stranded breaks during meiosis opens new avenues for understanding the role of recombination in chromosomal speciation. PMID:24850922

Capilla, Laia; Medarde, Nuria; Alemany-Schmidt, Alexandra; Oliver-Bonet, Maria; Ventura, Jacint; Ruiz-Herrera, Aurora

2014-07-01

357

Oppositional defiant- and conduct disorder-like problems: neurodevelopmental predictors and genetic background in boys and girls, in a nationwide twin study  

PubMed Central

Background. Previous research has supported gender-specific aetiological factors in oppositional defiant disorder (ODD) and conduct disorder (CD). The aims of this study were to identify gender-specific associations between the behavioural problems–ODD/CD-like problems–and the neurodevelopmental disorders–attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD)–and to investigate underlying genetic effects. Methods. 17,220 twins aged 9 or 12 were screened using the Autism–Tics, AD/HD and other Comorbidities inventory. The main covariates of ODD- and CD-like problems were investigated, and the relative importance of unique versus shared hereditary and environmental effects was estimated using twin model fitting. Results. Social interaction problems (one of the ASD subdomains) was the strongest neurodevelopmental covariate of the behavioural problems in both genders, while ADHD-related hyperactivity/impulsiveness in boys and inattention in girls stood out as important covariates of CD-like problems. Genetic effects accounted for 50%–62% of the variance in behavioural problems, except in CD-like problems in girls (26%). Genetic and environmental effects linked to ADHD and ASD also influenced ODD-like problems in both genders and, to a lesser extent, CD-like problems in boys, but not in girls. Conclusions. The gender-specific patterns should be considered in the assessment and treatment, especially of CD. PMID:24795851

Lundstrom, Sebastian; Chang, Zheng; Tajnia, Armin; Jern, Patrick; Lichtenstein, Paul; Nilsson, Thomas; Anckarsater, Henrik

2014-01-01

358

Insights into the genetic susceptibility to type 2 diabetes from genome-wide association studies of glycaemic traits.  

PubMed

Over the past 8 years, the genetics of complex traits have benefited from an unprecedented advancement in the identification of common variant loci for diseases such as type 2 diabetes (T2D). The ability to undertake genome-wide association studies in large population-based samples for quantitative glycaemic traits has permitted us to explore the hypothesis that models arising from studies in non-diabetic individuals may reflect mechanisms involved in the pathogenesis of diabetes. Amongst 88 T2D risk and 72 glycaemic trait loci, only 29 are shared and show disproportionate magnitudes of phenotypic effects. Important mechanistic insights have been gained regarding the physiological role of T2D loci in disease predisposition through the elucidation of their contribution to glycaemic trait variability. Further investigation is warranted to define causal variants within these loci, including functional characterisation of associated variants, to dissect their role in disease mechanisms and to enable clinical translation. PMID:25344220

Marullo, Letizia; El-Sayed Moustafa, Julia S; Prokopenko, Inga

2014-11-01

359

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis  

PubMed Central

Objective To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). Methods Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8,136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the United Kingdom. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan® assays. Results The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29-2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR= 1.51, CI 95% 1.28-1.79). Conclusions Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA. PMID:23946333

Carmona, FD; Solans, R; Miranda-Filloy, JA; Hernandez-Rodriguez, J; Cid, MC; Castaneda, S; Morado, IC; Narvaez, J; Blanco, R; Sopena, B; Garcia-Villanueva, MJ; Monfort, J; Ortego-Centeno, N; Unzurrunzaga, A; Mari-Alfonso, B; Sanchez Martin, J; de Miguel, E; Magro, C; Raya, E; Braun, N; Latus, J; Molberg, O; Lie, BA; Moosig, F; Witte, T; Morgan, AW; Gonzalez-Gay, MA; Martin, J

2014-01-01

360

Differential Susceptibility to Prevention: GABAergic, Dopaminergic, and Multilocus Effects  

PubMed Central

Background Randomized prevention trials provide a unique opportunity to test hypotheses about the interaction of genetic predispositions with contextual processes to create variations in phenotypes over time. Methods Using two longitudinal, randomized prevention trials, molecular genetic and alcohol use outcome data were gathered from more than 900 youths to determine whether prevention program participation would, across 2 years, moderate genetic risk for increased alcohol use conferred by the dopaminergic and GABAergic systems. Results We found that (a) variance in dopaminergic (DRD2, DRD4, ANKK1) and GABAergic (GABRG1, GABRA2) genes forecast increases in alcohol use across 2 years, and (b) youths at genetic risk who were assigned to the control condition displayed greater increases in alcohol use across 2 years than did youths at genetic risk who were assigned to the prevention condition or youths without genetic risk who were assigned to either condition. Conclusions This study is unique in combining data from two large prevention trials to test hypotheses regarding genetic main effects and gene × prevention interactions. Focusing on gene systems purported to confer risk for alcohol use and abuse, the study demonstrated that participation in efficacious prevention programs can moderate genetic risk. The results also support the differential susceptibility hypothesis that some youths, for genetic reasons, are more susceptible than others to both positive and negative contextual influences. PMID:23294086

Brody, Gene H.; Chen, Yi-fu; Beach, Steven R. H.

2013-01-01

361

Genome Survey Sequencing and Genetic Background Characterization of Gracilariopsis lemaneiformis (Rhodophyta) Based on Next-Generation Sequencing  

PubMed Central

Gracilariopsis lemaneiformis has a high economic value and is one of the most important aquaculture species in China. Despite it is economic importance, it has remained largely unstudied at the genomic level. In this study, we conducted a genome survey of Gp. lemaneiformis using next-generation sequencing (NGS) technologies. In total, 18.70 Gb of high-quality sequence data with an estimated genome size of 97 Mb were obtained by HiSeq 2000 sequencing for Gp. lemaneiformis. These reads were assembled into 160,390 contigs with a N50 length of 3.64 kb, which were further assembled into 125,685 scaffolds with a total length of 81.17 Mb. Genome analysis predicted 3490 genes and a GC% content of 48%. The identified genes have an average transcript length of 1,429 bp, an average coding sequence size of 1,369 bp, 1.36 exons per gene, exon length of 1,008 bp, and intron length of 191 bp. From the initial assembled scaffold, transposable elements constituted 54.64% (44.35 Mb) of the genome, and 7737 simple sequence repeats (SSRs) were identified. Among these SSRs, the trinucleotide repeat type was the most abundant (up to 73.20% of total SSRs), followed by the di- (17.41%), tetra- (5.49%), hexa- (2.90%), and penta- (1.00%) nucleotide repeat type. These characteristics suggest that Gp. lemaneiformis is a model organism for genetic study. This is the first report of genome-wide characterization within this taxon. PMID:23875008

Sui, Zhenghong; Fu, Feng; Wang, Jinguo; Chang, Lianpeng; Guo, Weihua; Li, Binbin

2013-01-01

362

The mineralization phenotype in Abcc6?/? mice is affected by Ggcx gene deficiency and genetic background - A model for pseudoxanthoma elasticum  

PubMed Central

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by ectopic mineralization of connective tissues, and shows considerable intra- and inter-familial phenotypic variability. PXE is caused by mutations in the ABCC6 gene, and targeted ablation of Abcc6 in mouse recapitulates PXE. In this study, we examined the hypothesis that the GGCX gene encoding ?-glutamyl carboxylase may interfere with the mineralization process in Abcc6?/? mice. Thus, Abcc6?/? and Ggcx+/? mice were generated on 129S1;C57 and 129S1;129X1;C57 genetic backgrounds, respectively, and backcrossed with C57BL/6J for 5 generations. Thus, these strains differ by the 129X1 contribution to the background of the mice. We then generated Abcc6?/?;Ggcx+/+ and Abcc6?/?;Ggcx+/? mice by crossing Abcc6?/? and Ggcx+/? mice. The degree of mineralization of connective capsule of vibrissae, a biomarker of the mineralization process in PXE, was evaluated by computerized morphometric analysis and quantified colorimetrically by calcium and phosphate levels in tissues. The mineralization of the vibrissae in Abcc6?/? mice takes place at ~5-6 weeks of age and is significantly enhanced at 3 months of age in comparison to wild-type mice (>10-fold, p<0.001). However, the onset of mineralization in Abcc6?/?;Ggcx+/+ mice was delayed until between 3-4 months of age, suggesting that the genetic background plays a role in modifying the mineralization process. The mineralization in the Abcc6?/?;Ggcx+/? mice was accelerated in comparison with age-matched Abcc6?/?;Ggcx+/+ mice, with ~3-fold difference at 3, 4 and 9 months of age (p<0.01). The mineralization process was also accelerated in these mice by a special custom-designed diet with mineral modifications. These findings suggest a role for both the GGCX gene and the genetic background as well as dietary factors in modulating the phenotypic severity of PXE caused by loss-of-function mutations in ABCC6. PMID:19784827

Li, Qiaoli; Uitto, Jouni

2010-01-01

363

Integrated genomics of susceptibility to alkylator-induced leukemia in mice  

Microsoft Academic Search

BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) is a secondary, generally incurable, malignancy attributable to chemotherapy exposure. Although there is a genetic component to t-AML susceptibility in mice, the relevant loci and the mechanism(s) by which they contribute to t-AML are largely unknown. An improved understanding of susceptibility factors and the biological processes in which they act may lead to the

Patrick Cahan; Timothy A. Graubert

2010-01-01

364

Rare association of Hodgkin lymphoma, Graves' disease and myasthenia gravis complicated by post-radiation neurofibrosarcoma: coincidence or genetic susceptibility?  

PubMed

With Hodgkin lymphoma (HL), other (autoimmune) diseases may occasionally occur or associate, whereas as a late treatment-complication, second tumour may develop. In our patient HL was diagnosed in 1996 and consequently received COPP/ABV and mantle irradiation. Due to the residual mediastinal tumour CRu was declared but later on no progression/relapse could be proved by PET. In 2000 Graves's disease, in 2001 myasthenia gravis was diagnosed, which showed resistance for immunosuppressant drugs, thus plasmapheresis, intravenous immunoglobulin treatments were applied. In 2005, the residual mediastinal tumour started progressive growth, which leads to thoracotomy in which the tumour was removed, it was malignant peripheral nerve sheath tumour. The disease showed progression despite the chemotherapy applied and the patient died in 2007 due to respiratory failure. Not even the postmortem histopathologic examination revealed the relapse of HL. Association of Hodgkin lymphoma, and two antibody-mediated autoimmune diseases, Graves' disease and myasthenia gravis, is rare and has not yet been reported in the literature. The etiologic role of genetic predisposition and immune regulatory disorder must definitely be thought of, as the possibility of mere coincidence is extremely small. Malignant peripheral nerve sheath tumour is a rare complication of irradiation, which underlines the importance of the risk or/and response adapted therapy of HL. PMID:19381762

Simon, Zsófia; Ress, Zsuzsa; Toldi, József; Trauninger, Anita; Miltényi, Zsófia; Illés, Arpád

2009-05-01

365

Mitochondrial Genetic Background Modifies the Relationship between Traffic-Related Air Pollution Exposure and Systemic Biomarkers of Inflammation  

PubMed Central

Background Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin. Objective We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations). Methods Inflammation biomarkers were measured weekly in each subject (?12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-? (TNF-?), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NOx), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (<0.25 µm, 0.25–2.5 µm, and 2.5–10 µm in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed-effects models. Results IL-6 and TNF-? were associated with traffic-related air pollutants (BC, CO, NOx and PAH), and with mass and oxidative potential of quasi-ultrafine particles <0.25 µm. These associations were stronger for haplogroup H than haplogroup U. Conclusions Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects. PMID:23717615

Wittkopp, Sharine; Staimer, Norbert; Tjoa, Thomas; Gillen, Daniel; Daher, Nancy; Shafer, Martin; Schauer, James J.; Sioutas, Constantinos; Delfino, Ralph J.

2013-01-01

366

Toll-like receptor 2 and 9 genetic polymorphisms and the susceptibility to B cell Non-Hodgkin Lymphoma in Egypt.  

PubMed

Non-Hodgkin lymphomas (NHL) entail considerable heterogeneity regarding their morphology, clinical course, etiological factors, or response to therapy. Increased incidence of NHL in immunocompromised individuals and after autoimmune diseases suggests that infections and immune dysregulation could play a role in the susceptibility to NHL. Accordingly, genetic variation in Toll-like receptor (TLR) genes might be considered as molecular risk factors for NHL. The aim of the current study was to investigate the possible association between genetic polymorphism of the TLRs genes and B cell NHL (B-NHL) risk in Egypt. The present study included 100 B-NHL patients and 100 healthy controls. Genotyping of TLR2-1350 T/C and TLR9-1237 T/C were done by polymerase chain reaction restricted fragment length polymorphism (PCR-RFLP) technique. The frequency of TLR2-1350 T/C polymorphic genotypes in B-NHL patients was 18 % for the heteromutant genotype (TC) and 1 % for the homomutant (CC). There was no statistical difference in the distribution of TLR2-1350 T/C genotypes between B-NHL patients and controls. As for TLR9-1237 T/C, the frequency of the heteromutant genotype (TC) was 58 % and the homomutant genotype (CC) was 1 % in B-NHL patients. Calculated risk estimation revealed that TLR9-1237 (TC) heterotype conferred almost fourfold increased risk of B-NHL (odds ratio (OR)?=?3.93, 95 % confidence interval (CI)?=?2.16-7.14), and the risk was higher in patients with indolent subtypes (OR?=?6.64, 95 %CI?=?2.31-9.08). In conclusion, the study revealed that TLR9-1237 T/C polymorphism can be considered as molecular risk factor for B-NHL among Egyptians. PMID:24912772

Rahman, Hala Aly Abdel; Khorshied, Mervat Mamdooh; Khorshid, Ola M Reda; Mahgoub, Shirihan Mahmoud

2014-11-01

367

C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population  

PubMed Central

Aim: The inflammatory marker C-reactive protein (CRP) has been strongly correlated with the risk of cardiovascular disease. Some single-nucleotide polymorphisms (SNPs) have been reported to be associated with serum CRP levels. In this study, we assessed the genetic association between SNPs within the CRP gene and ischemic and hemorrhagic stroke in the Han Chinese population. Methods: This study comprises 564 ischemic stroke patients, 220 hemorrhagic stroke patients and 564 controls from the ethnic Han Chinese population in Wuhan. Four CRP SNPs, ?757A>G (rs3093059), ?717A>G (rs2794521), ?286C>T>A (rs3091244) and +2147C>T (rs1205), were genotyped from patients using TaqMan assays. Results: The A allele frequency for the ?717A>G polymorphism was significant higher in controls than in ischemic stroke patients (P=0.037), after adjustment for traditional risk factors (odds ratio 0.28; 95% CI 0.12–0.65; P=0.003), suggesting a protective effect for this allele against ischemic stroke. Haplotype analysis showed that the H3 (G-C-C) haplotype conferred a significantly increased risk of ischemic stroke (odds ratio 1.052, 95% CI 1.001–1.106: P=0.047). Neither CRP genotypes nor haplotypes showed an association with hemorrhagic stroke. However, the frequency for haplotype H5 (A-T-C) was significantly higher in ischemic stroke than hemorrhagic stroke patients (P=0.0003). Conclusion: These data suggest that the CRP gene ?717A allele confers a protective effect against ischemic stroke. Furthermore, the H3 haplotype (G-C-C) is an independent risk marker for ischemic stroke, whereas the H5 haplotype (A-T-C) can be used as a prognostic marker of hemorrhagic stroke. PMID:19262552

Wang, Qi; Ding, Hu; Tang, Jia-rong; Zhang, Lan; Xu, Yu-jun; Yan, Jiang-tao; Wang, Wei; Hui, Ru-tai; Wang, Cong-yi; Wang, Dao-wen

2009-01-01

368