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Cohort Profile: East London Genes & Health (ELGH), a community based population genomics and health study of British-Bangladeshi and British-Pakistani people
CYP2C19 Genotype Prevalence and Association With Recurrent Myocardial Infarction in British–South Asians Treated With Clopidogrel
BACKGROUND: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Prior studies of genetic polymorphisms in CYP2C19 and their relationship with clinical efficacy have not included South Asian populations. OBJECTIVES: The objective of this study was to assess prevalence of common CYP2C19 genotype polymorphisms in a British-South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel. METHODS: The Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants were studied. CYP2C19 diplotypes were assessed using array data. Multivariable logistic regression was used to test for association between genetically inferred CYP2C19 metabolizer status and recurrent myocardial infarction, controlling for known cardiovascular disease risk factors, percutaneous coronary intervention, age, sex, and population stratification. RESULTS: Genes & Health cohort participants (NÂ =Â 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss-of-function CYP2C19 allele. The prevalence of poor metabolizers carrying 2Â CYP2C19 loss-of-function alleles is 13%, which is higher than that in previously studied European (2.4%) and Central/South Asian populations (8.2%). Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; PÂ =Â 0.019). CONCLUSIONS: A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry
Inference of disease associations with unmeasured genetic variants by combining results from genome-wide association studies with linkage disequilibrium patterns in a reference data set
Results from whole-genome association studies of many common diseases are now available. Increasingly, these are being incorporated into meta-analyses to increase the power to detect weak associations with measured single-nucleotide polymorphisms (SNPs). Imputation of genotypes at unmeasured loci has been widely applied using patterns of linkage disequilibrium (LD) observed in the HapMap panels, but there is a need for alternative methods that can utilize the pooled effect estimates from meta-analyses and explore possible associations with SNPs and haplotypes that are not included in HapMap
A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms.
Background: The HLA genes, located in the MHC region on chromosome 6p21.3, play an important role in many
autoimmune disorders, such as celiac disease (CD), type 1 diabetes (T1D), rheumatoid arthritis, multiple sclerosis, psoriasis
and others. Known HLA variants that confer risk to CD, for example, include DQA1*05/DQB1*02 (DQ2.5) and DQA1*03/
DQB1*0302 (DQ8). To diagnose the majority of CD patients and to study disease susceptibility and progression, typing these
strongly associated HLA risk factors is of utmost importance. However, current genotyping methods for HLA risk factors
involve many reactions, and are complicated and expensive. We sought a simple experimental approach using tagging
SNPs that predict the CD-associated HLA risk factors.
Methodology: Our tagging approach exploits linkage disequilibrium between single nucleotide polymorphism (SNPs) and
the CD-associated HLA risk factors DQ2.5 and DQ8 that indicate direct risk, and DQA1*0201/DQB1*0202 (DQ2.2) and
DQA1*0505/DQB1*0301 (DQ7) that attribute to the risk of DQ2.5 to CD. To evaluate the predictive power of this approach,
we performed an empirical comparison of the predicted DQ types, based on these six tag SNPs, with those executed with
current validated laboratory typing methods of the HLA-DQA1 and -DQB1 genes in three large cohorts. The results were
validated in three European celiac populations.
Conclusion: Using this method, only six SNPs were needed to predict the risk types carried by .95% of CD patients. We
determined that for this tagging approach the sensitivity was .0.991, specificity .0.996 and the predictive value .0.948.
Our results show that this tag SNP method is very accurate an
Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA
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