Identification of four gene variants associated with myocardial infarction.
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.
Shiffman
Dov
D
Celera Diagnostics, Alameda, CA, USA. dov.shiffman@celeradiagnostics.com
Ellis
Stephen G
SG
Rowland
Charles M
CM
Malloy
Mary J
MJ
Luke
May M
MM
Iakoubova
Olga A
OA
Pullinger
Clive R
CR
Cassano
June
J
Aouizerat
Bradley E
BE
Fenwick
Raymond G
RG
Reitz
Richard E
RE
Catanese
Joseph J
JJ
Leong
Diane U
DU
Zellner
Christian
C
Sninsky
John J
JJ
Topol
Eric J
EJ
Devlin
James J
JJ
Kane
John P
JP
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*