P3.22 CHROMOSOME 9P21 LOCUS AND CORONARY ARTERY DISEASE – COLLABORATIVE META-ANALYSIS ON ANGIOGRAPHIC BURDEN AND MOLECULAR FUNCTION ANALYSIS

DOI

10.1016/j.artres.2013.10.109How to use a DOI?

Abstract

Objective: Chromosome 9p21 variants showed robust association with coronary heart disease in genome-wide association studies, but questions remain on the mechanism. We investigated the relationship of 9p21 locus with (1) angiographic coronary artery disease (CAD) burden and progression to myocardial infarction (MI); and (2) biological function of vascular smooth muscle cell (VSMC).

Methods and results: We established a collaboration of 21 studies (33,673 patients) with information on both CAD and MI status along with 9p21 genotype. We first confirmed an association between 9p21 and CAD using angiographic ally defined cases and controls (pooled odds ratio (OR)=1.31 (95% CI 1.20–1.43) per copy of risk allele). Among subjects with angiographic CAD, random-effects model identified an association with multi-vessel CAD, compared to those with single-vessel disease (OR=1.10 (95% CI 1.04–1.17)). However, there was no significant association between 9p21 and prevalent MI when both cases and controls had underlying CAD (OR=0.99 (95% CI 0.95–1.03)).Immunohistochemical staining of human atherosclerotic plaque showed co-localization of VSMC with the cell-cycle regulator proteins p16^INK4a, p14^ARF and p15^INK4b, which are encoded by the genes CDKN2A and CDKN2B genomically located nearby the 9p21 locus. The 9p21 risk genotype confers reduced p15^INK4b levels (p=3.7×10⁻²) and higher VSMC content (p=5.6×10⁻⁴) in the plaques. We further examined the influence of 9p21 genotype on primary cultures of VSMC isolated from human umbilical cord. The risk genotype was associated with reduced expression of p16^INK4a, p15^INK4b (p=1.2×10⁻⁵, 1.4×10⁻²), and increased VSMC proliferation (p=1.6×10⁻²).

Conclusions: The 9p21 locus primarily mediates an atherosclerotic phenotype, by influencing CDKN2A/CDKN2B expression and hence VSMC proliferation.

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TY  - JOUR
AU  - K. Chan
AU  - A. Motterle
AU  - R.S. Patel
AU  - X. Pu
AU  - S. Ye
PY  - 2013
DA  - 2013/11/11
TI  - P3.22 CHROMOSOME 9P21 LOCUS AND CORONARY ARTERY DISEASE – COLLABORATIVE META-ANALYSIS ON ANGIOGRAPHIC BURDEN AND MOLECULAR FUNCTION ANALYSIS
JO  - Artery Research
SP  - 132
EP  - 132
VL  - 7
IS  - 3-4
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2013.10.109
DO  - 10.1016/j.artres.2013.10.109
ID  - Chan2013
ER  -