The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study

Ron Do¹, Changchun Xie²^,³, Xiaohe Zhang², Satu Männistö⁴, Kennet Harald⁴, Shofiqul Islam²^,³, Swneke D. Bailey¹, Sumathy Rangarajan², Matthew J. McQueen², Rafael Diaz⁵, Liu Lisheng⁶, Xingyu Wang⁷, Kaisa Silander⁴^,⁸, Leena Peltonen⁴^,⁸^†, Salim Yusuf², Veikko Salomaa⁴, James C. Engert¹^,⁹^,¹⁰^*, Sonia S. Anand²^,³^*, on behalf of the INTERHEART investigators

1 Department of Human Genetics, McGill University, Montréal, Quebec, Canada, 2 Population Health Research Institute, Hamilton Health Sciences, and McMaster University, Hamilton, Ontario, Canada, 3 Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada, 4 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland, 5 Estudios Cardiologicos Latinoamerica, Rosario, Argentina, 6 Cardiovascular Institute and Fu Wai Hospital, Chinese Hypertension League Institute, Beijing, China, 7 Laboratory of Human Genetics, Beijing Hypertension League Institute, Beijing, China, 8 Human Genomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland, 9 Department of Medicine, McGill University, Montréal, Quebec, Canada, 10 The Research Institute of the McGill University Health Centre, Montréal, Quebec, Canada

Abstract

Background

One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.

Methods and Findings

We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10⁻⁸≤p≤5.21×10⁻⁷). A significant interaction (p = 4.0×10⁻⁴) was observed between rs2383206 and a factor-analysis-derived “prudent” diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10⁻⁷), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10⁻³) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10⁻⁴, and HR = 1.35, p = 4.1×10⁻³, respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10⁻⁹) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).

Conclusions

The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits.

Please see later in the article for the Editors' Summary

Citation: Do R, Xie C, Zhang X, Männistö S, Harald K, et al. (2011) The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study. PLoS Med 9(10): e1001106. doi:10.1371/journal.pmed.1001106

Academic Editor: Cathryn Lewis, Kings College London, United Kingdom

Received: January 11, 2011; Accepted: August 30, 2011; Published: October 11, 2011

Copyright: © 2011 Do et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was funded by the Heart and Stroke Foundation of Ontario (Grant # NA6336). SA holds the Heart and Stroke Foundation of Ontario Michael G. DeGroote endowed Chair in Population Health, and the May Cohen Eli Lilly endowed Chair in Women's Health at McMaster University. VS was supported by the Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, and the Academy of Finland (grant number 129494). SY is supported by an endowed chair from the Heart and Stroke Foundation of Ontario. RDo is a recipient of a Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award from the Canadian Institutes for Health Research. SDB holds a graduate scholarship from the McGill University Health Centre Research Institute and the Department of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: CVD, cardiovascular disease; FFQ, food frequency questionnaire; HR, hazard ratio; LD, linkage disequilibrium; MI, myocardial infarction; OR, odds ratio

* E-mail: jamie.engert@mcgill.ca (JCE); anands@mcmaster.ca (SSA)

FULL-TEXT
PLoS Medicine: The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study