The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study

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.

Figure 1. Prudent diet modifies the effect of the Chromosome 9p21 variant rs2383206 on acute myocardial infarction in the INTERHEART study.

Prudent diet is derived from a factor analysis and is made up of several individual food items, including fruits and raw vegetables. The test of homogeneity was performed using the Breslow-Day test. ORs and 95% confidence intervals are shown in blue. ORs presented are per allele, i.e., the OR equals the increase in risk for each copy of the risk allele. Box sizes are proportional to the precision of the estimate (1/standard error²). Tertiles for prudent diet (1, 2, and 3, with 1 being the lowest prudent diet score group) were calculated for each ethnicity separately.

Figure 2. Prudent diet modifies the effect of the Chromosome 9p21 variant rs4977574 on cardiovascular disease in the FINRISK study.

Prudent diet is derived from a composite score of fruit, vegetable, and berry intake (see Methods). The test of homogeneity was performed using the Breslow-Day test. HRs and 95% confidence intervals are shown in blue. HRs presented are per allele. Box sizes are proportional to the precision of the estimate (1/standard error²).

Figure 3. Risk of acute myocardial infarction associated with prudent diet and the Chromosome 9p21 variant rs2383206 in the INTERHEART study.

The reference class is the group bearing two protective alleles for rs2383206 (genotype AA) and having a high prudent dietary pattern score. ORs and 95% confidence intervals are shown in blue. Box sizes are proportional to the precision of the estimate (1/standard error²).

Figure 4. Risk of cardiovascular disease associated with prudent diet and the Chromosome 9p21 variant rs4977574 in the FINRISK study.

The reference class is the group bearing two protective alleles for rs4977574 (genotype AA) and having a prudent diet (see Methods). HRs and 95% confidence intervals are shown in blue. Box sizes are proportional to the precision of the estimate (1/standard error²).