A novel genetic marker for coronary spasm in women from a genome-wide single nucleotide polymorphism analysis.
OBJECTIVE
Coronary spasm plays an important role in the pathogenesis of variant angina and also ischemic heart diseases in general, and it is more likely to occur in angiographically normal coronary arteries than in stenotic coronary arteries. We previously found a -786T/C polymorphism in the 5'-flanking region of the endothelial nitric oxide synthase (eNOS) gene and reported that this polymorphism is associated with coronary spasm. We report on an investigation of the genetic factor(s) associated with coronary spasm utilizing a genome-wide case-control study.


RESULTS
We recruited 411 consecutive Japanese women (201 with coronary spasm; 210 controls) who were all underwent an acetylcholine provocation test. For single nucleotide polymorphism analysis (SNP), 116,204 SNPs were genotyped for 100 women (50 with coronary spasm; 50 controls) utilizing the Affymetrix GeneChip 100 K Set. Case-control studies were performed with 311 women (151 with coronary spasm; 160 controls) using the 10 lowest permutation P value SNPs from the initial SNP analysis. Finally, we discovered SNP rs10498345, a genetic marker for coronary spasm in Japanese women (Odds ratio=0.43, P=9.48x10(-7)). Haplotype analysis showed that haplotype H2, the only haplotype containing the protective A allele at SNP rs10498345, was most strongly associated with coronary spasm (permutation P value <1x10(-4)). SNP rs10498345 was strongly associated with the vasoconstrictor response to acetylcholine. Northern blot analysis revealed a novel 4.7 kb RNA transcript, which lacked poly (A), nearby SNP rs10498345.


CONCLUSIONS
SNP rs10498345 was strongly associated with coronary spasm in Japanese women utilizing genome-wide SNP analysis.
Suzuki
Satoru
S
Division of Cardiology, Department of Internal Medicine, The Jikei University, Tokyo, Japan.
Yoshimura
Michihiro
M
Nakayama
Masafumi
M
Abe
Koji
K
Yamamuro
Megumi
M
Nagayoshi
Yasuhiro
Y
Kojima
Sunao
S
Kaikita
Koichi
K
Sugiyama
Seigo
S
Yasue
Hirofumi
H
Ogawa
Hisao
H
D016022:Case-Control Studies; D002874:Chromosome Mapping; D003324:Coronary Artery Disease / Q000235:genetics*; D003329:Coronary Vasospasm / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D005819:Genetic Markers