Single nucleotide polymorphisms associated with abnormal coronary microvascular function.

Abstract

BACKGROUND: Single nucleotide polymorphisms (SNPs) are the most common source of

genetic variation. Although microvascular pathology is associated with

cardiovascular events, genetic phenotypes causing microvascular disease remain

largely unknown. This study identifies sex-specific SNPs associated with coronary

microvascular dysfunction. METHODS AND RESULTS: Six hundred and forty-three

patients without significant obstructive coronary heart disease were enrolled,

referred for cardiac catheterization, and underwent invasive coronary

microcirculatory assessment. Patient data were collected from 1529 autosomal SNPs

and seven X chromosome SNPs, which were selected to represent the variability

from 76 candidate genes with published associations with coronary vasoreactivity,

angiogenesis, inflammation, vascular calcification, atherosclerosis risk factors,

female hormones, blood coagulation, or coronary heart disease. Coronary flow

reserve (CFR) was assessed by an intracoronary injection of adenosine. Patients

were categorized according to a CFR above or below 2.5 and were stratified by

sex.After adjusting for age, sex, and BMI, this study shows that SNPs within

VEGFA and CDKN2B-AS1 are associated with abnormal CFR (P<0.005). SNPs within

MYH15, VEGFA, and NT5E are associated with abnormal CFR in men. No SNPs were

associated with abnormal CFR in women. CONCLUSION: Genetic variations within

defined regions of VEGFA and CDKN2B-AS1 genes are associated with coronary

microvascular dysfunction. Furthermore, sex-specific allelic variants within

MYH15, VEGFA, and NT5E are associated with an increased risk of coronary

microvascular dysfunction in men.