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 gender specific SNPs associated with coronary microvascular dysfunction. Methods and Results Six-hundred and forty-three patients without significant obstructive coronary heart disease (CHD) were enrolled, referred for cardiac catheterization, and underwent invasive coronary microcirculatory assessment. Patient data was collected from 1529 autosomal SNPs and 7 X chromosome SNPs which were selected to represent the variability from 76 candidate genes having published associations with coronary vasoreactivity, angiogenesis, inflammation, vascular calcification, atherosclerosis risk factors, female hormones, blood coagulation, or CHD. Coronary flow reserve (CFR) was assessed by 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 demonstrates 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. Conclusions Genetic variation 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.

Sex‐Specific Genetic Variants are Associated With Coronary Endothelial Dysfunction

“…As previously described,15, 23DNA was extracted from blood using the Mayo Clinic Biospecimens Accessioning and Processing facility. Pico Green analysis was run on all samples to assess quality.…”

“…As described previously, 15 cardiac catheterization and coronary microvascular function testing was performed on 643 patients enrolled between January 1993 and December 2010. The decision to pursue cardiac catheterization and invasive coronary physiology testing was made by the referring cardiologist.…”

“…Eating, drinking, or tobacco use was discontinued for at least 12 hours prior to the procedure. [15][16][17][18][19][20][21][22] Diagnostic coronary angiography was performed with a 6F or 7F guiding catheter using a standard femoral percutaneous approach. Nonionic contrast material was used.…”

Male-specific association of the APC rs383830 T allele with the risk of coronary heart disease

“…The rs974819 polymorphism of PDGFD has been shown to be associated with an increased risk of CHD in Han Chinese, with a sex-dependent genetic effect (Zhou et al, 2012). Furthermore, an association has been identified between sex-specific allelic variants within MYH15, VEGFA, and NT5E and an increased risk of coronary microvascular dysfunction in men but not in women ( Yoshino et al, 2014). A strong association between rs702553 and stroke has also only been found in young men but not in women (Liao et al, 2010).…”

Microvascular dysfunction

“…In this issue of Coronary Artery Disease , Yoshino et al provide additional mechanistic insight into the pathogenesis of microvascular dysfunction by identifying an underlying genetic basis for the disease [7]. The investigators genotyped 643 patients with microvascular dysfunction and examined 1,536 single nucleotide polymorphisms (SNPs) occurring in 76 biologically relevant genes.…”