SummaryMany common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.
Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation. Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome. Design, Setting, and Patients Prospective, observational, single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007. On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry, VerifyNow P2Y12 and Plateletworks assays, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/adenosine diphosphate [ADP] cartridge and Innovance PFA P2Y). Cut-off values for high on-treatment platelet reactivity were established by receiver operating characteristic curve analysis.Main Outcome Measurement The primary end point was defined as a composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke. The primary safety end point included TIMI (Thrombolysis In Myocardial Infarction) criteria major and minor bleeding.Results At 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry (11.
Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.
Highlights d The Uganda Genome Resource comprises genetic and phenotypic data on 6,400 individuals d Ugandans show geographically correlated genetic substructure and complex admixture d The Uganda sequence panel substantially improves imputation in African populations d The Uganda Genome Resource enables novel discovery of loci associated with traits
Objective To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel.Design Systematic review and meta-analysis with a structured search algorithm and prespecified eligibility criteria for retrieval of relevant studies; dominant genetic model assumptions and quantitative methods for calculating summary effect estimates from study level odds ratios; systematic assessment of bias within and between studies; and grading of the cumulative evidence by consensus criteria.
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