Artery Research

Volume 7, Issue 3-4, September 2013, Pages 132 - 132

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

Authors
K. Chan1, A. Motterle1, R.S. Patel1, 2, X. Pu1, S. Ye1
1William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom
2Department of Medicine, Emory University School of Medicine, Atlanta, United States of America
Available Online 11 November 2013.
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 p16INK4a, p14ARF and p15INK4b, which are encoded by the genes CDKN2A and CDKN2B genomically located nearby the 9p21 locus. The 9p21 risk genotype confers reduced p15INK4b 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 p16INK4a, p15INK4b (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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Journal
Artery Research
Volume-Issue
7 - 3-4
Pages
132 - 132
Publication Date
2013/11/11
ISSN (Online)
1876-4401
ISSN (Print)
1872-9312
DOI
10.1016/j.artres.2013.10.109How to use a DOI?
Open Access
This is an open access article distributed under the CC BY-NC license.

Cite this article

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  -