Identification of STXBP2 as a novel susceptibility locus for myocardial infarction in Japanese individuals by an exome-wide association study

Abstract

We performed exome-wide association studies to identify genetic variants—in particular, low-frequency variants with a large effect size—that confer susceptibility to coronary artery disease or myocardial infarction in Japanese. The exome-wide association studies were performed with 12,698 individuals (3488 subjects with coronary artery disease including 2438 with myocardial infarction, 9210 controls) and with the use of the Illumina HumanExome-12 DNA Analysis or Infinium Exome-24 BeadChip. The relation of allele frequencies for 41,339 single nucleotide polymorphisms that passed quality control to coronary artery disease or myocardial infarction was examined with Fisher's exact test. The exome-wide association study for coronary artery disease revealed that 126 single nucleotide polymorphisms were significantly ( P <1.21 × 10 ⁻⁶) associated with this condition. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus, and dyslipidemia showed that six of these polymorphisms were related ( P < 0.01) to coronary artery disease, but none was significantly ( P < 9.92 × 10 ⁻⁵) associated with this condition. The exome-wide association study for myocardial infarction revealed that 114 single nucleotide polymorphisms were significantly ( P <1.21 × 10 ⁻⁶) associated with this condition. Multivariable logistic regression analysis with adjustment for covariates revealed that nine of these polymorphisms were related ( P < 0.01) to myocardial infarction. Among these nine polymorphisms, rs188212047 [G/T (L212F)] of STXBP2 was significantly (dominant model; P = 4.84 × 10 ⁻⁸; odds ratio, 2.94) associated with myocardial infarction. STXBP2 may thus be a novel susceptibility locus for myocardial infarction in Japanese.