Identification of four gene variants associated with myocardial infarction

Dov Shiftman, Stephen G. Ellis, Charles M. Rowland, Mary J. Malloy, May M. Luke, Olga A. Iakoubova, Clive R. Pullinger, June Cassano, Bradley E. Aouizerat, Raymond G. Fenwick, Richard E. Reitz, Joseph J. Catanese, Diane U. Leong, Christian Zellner, John J. Sninsky, Eric J. Topol, James J. Devlin, John P. Kane

Research output: Contribution to journalArticle

Abstract

Family history is a major risk factor for myocardial infarction (MI). However, known gene variants associated with MI cannot fully explain the genetic component of MI risk. We hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. We studied 11,053 single-nucleotide polymorphisms (SNPs) in 6,891 genes, focusing on SNPs that could influence gene function to increase the likelihood of identifying disease-causing gene variants. To minimize false-positive associations generated by multiple testing, two studies were used to identify a limited number of nominally associated SNPs; a third study tested the hypotheses that these SNPs are associated with MI. In the initial study (of 340 cases and 346 controls), 637 SNPs were associated with MI (P < .05); these were evaluated in a second study (of 445 cases and 606 controls), and 31 of the 637 SNPs were associated with MI (P < .05) and had the same risk allele as in the first study. For each of these 31 SNPs, we tested the hypothesis that it is associated with MI, using a third study (of 560 cases and 891 controls). We found that four of these gene variants were associated with MI (P < .05; false-discovery rate <10%) and had the same risk allele as in the first two studies. These gene variants encode the cytoskeletal protein palladin (KIAA0992 [odds ratio (OR) 1.40]), a tyrosine kinase (ROS1 [OR 1.75]), and two G protein-coupled receptors (TAS2R50 [OR 1.58] and OR13G1 [OR 1.40]); all ORs are for carriers of two versus zero risk alleles. These findings could lead to a better understanding of MI pathophysiology and improved patient risk assessment.

Original languageEnglish (US)
Pages (from-to)596-605
Number of pages10
JournalAmerican Journal of Human Genetics
Volume77
Issue number4
DOIs
StatePublished - Oct 2005

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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