Abstract 2731: A Novel Genetic Marker for Coronary Spasm and Stenosis in Women from a Genome-Wide SNP Analysis
Objective: Coronary spasm is important in the pathogenesis of variant angina and also ischemic heart diseases. The prevalence of coronary spasm is much higher in Japanese than in Caucasians, and in patients where there is a family history of coronary spasm: this suggests that genetic factors may be involved in its pathogenesis. We performed an investigation of the genetic factor(s) associated with coronary spasm and stenosis utilizing a genome-wide case control study.
Methods and Results: We recruited 411 consecutive Japanese women (201 with coronary spasm; 210 controls) who all underwent an acetylcholine (ACh) provocation test. No subjects had any significant organic stenosis in their coronary arteries after an intracoronary injection of isosorbide dinitrate. For SNP analysis, 116,204 single nucleotide polymorphisms (SNPs) were genotyped for 100 women (50 with coronary spasm; 50 controls) utilizing the Affymetrix GeneChip 100K Set. Case-control studies were performed with the other 311 women (151 with coronary spasm; 160 controls) using the 10 lowest permutation P-value SNPs from the initial SNP analysis. We discovered SNP rs10498345, located on chromosome 14q21.1, is a genetic marker for coronary spasm in Japanese women (Odds ratio[OR]= 0.43, P=9.48×10-7). The minor allele frequencies for SNP rs10498345 between the subjects with coronary spasm and controls are 0.154 and 0.298, respectively. Haplotype analysis showed that haplotype H2, the only haplotype containing the protective A allele at SNP rs10498345, was most strongly associated with coronary spasm (P=1×10-4). SNP rs10498345 was strongly associated with a vasoconstrictor response to ACh utilizing quantitative coronary angiography. We next examined the genotype of frequencies in SNP rs10498345 among the 100 consecutive Japanese women with significant coronary stenosis. This analysis showed that SNP rs10498345 was also significantly associated with coronary stenosis (OR=0.500, P=1.11×10-3). Nearby SNP rs10498345, we discovered a novel 4.7kb RNA transcript lacking poly(A) in the endothelial cells and arterial smooth muscle cells.
Conclusion: SNP rs10498345 is significantly associated with coronary spasm and stenosis in Japanese women utilizing genome-wide SNP analysis.