title: Identification of four gene variants associated with myocardial infarction.
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.
authors.affiliation: Celera Diagnostics, Alameda, CA, USA. dov.shiffman@celeradiagnostics.com
authors.forename: Dov
authors.initials: D
authors.lastname: Shiffman
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ellis
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rowland
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Malloy
authors.forename: May M
authors.initials: MM
authors.lastname: Luke
authors.forename: Olga A
authors.initials: OA
authors.lastname: Iakoubova
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: June
authors.initials: J
authors.lastname: Cassano
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Fenwick
authors.forename: Richard E
authors.initials: RE
authors.lastname: Reitz
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Catanese
authors.forename: Diane U
authors.initials: DU
authors.lastname: Leong
authors.forename: Christian
authors.initials: C
authors.lastname: Zellner
authors.forename: John J
authors.initials: JJ
authors.lastname: Sninsky
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
authors.forename: James J
authors.initials: JJ
authors.lastname: Devlin
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*