3.8 Article

Pooled DNA Resequencing of 68 Myocardial Infarction Candidate Genes in French Canadians

期刊

CIRCULATION-CARDIOVASCULAR GENETICS
卷 5, 期 5, 页码 547-554

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.112.963165

关键词

myocardial infarction; polymorphism myocardial infarction; population; single nucleotide; polymorphisms; coronary artery disease

资金

  1. Center of Excellence in Personalized Medicine (CEPMED)
  2. Canada Research Chair program
  3. Fonds de recherche du Quebec en Sante (FRQS)
  4. Montreal Heart Institute Foundation
  5. Genome Canada

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Background-Familial history is a strong risk factor for coronary artery disease (CAD), especially for early-onset myocardial infarction (MI). Several genes and chromosomal regions have been implicated in the genetic cause of coronary artery disease/MI, mostly through the discovery of familial mutations implicated in hyper-/hypocholesterolemia by linkage studies and single nucleotide polymorphisms by genome-wide association studies. Except for a few examples (eg, PCSK9), the role of low-frequency genetic variation (minor allele frequency [ MAF]) approximate to 0.1%-5% on MI/coronary artery disease predisposition has not been extensively investigated. Methods and Results-We selected 68 candidate genes and sequenced their exons (394 kb) in 500 early-onset MI cases and 500 matched controls, all of French-Canadian ancestry, using solution-based capture in pools of nonindexed DNA samples. In these regions, we identified 1852 single nucleotide variants (695 novel) and captured 85% of the variants with MAF >= 1% found by the 1000 Genomes Project in Europe-ancestry individuals. Using gene-based association testing, we prioritized for follow-up 29 low-frequency variants in 8 genes and attempted to genotype them for replication in 1594 MI cases and 2988 controls from 2 French-Canadian panels. Our pilot association analysis of low-frequency variants in 68 candidate genes did not identify genes with large effect on MI risk in French Canadians. Conclusions-We have optimized a strategy, applicable to all complex diseases and traits, to discover efficiently and cost-effectively DNA sequence variants in large populations. Resequencing endeavors to find low-frequency variants implicated in common human diseases are likely to require very large sample size. (Circ Cardiovasc Genet. 2012;5:547-554.)

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