The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease: a population based cohort study

Abstract

Background: Chromosome 9p21 variants are associated with cardiovascular disease (CVD) but not with any of its known risk markers. However, recent studies have suggested that the risk associated with 9p21 variation is modified by a prudent dietary pattern and smoking. We tested if the increased risk of CVD by the 9p21 single nucleotide polymorphism rs4977574 is modified by intakes of vegetables, fruits, alcohol, or wine, and if rs4977574 interacts with environmental factors on known CVD risk markers.

Methods: Multivariable Cox regression analyses were performed in 23,949 individuals from the population-based prospective Malmö Diet and Cancer Study (MDCS), of whom 3,164 developed CVD during 15 years of follow-up. The rs4977574 variant (major allele: A; minor allele: G) was genotyped using TaqMan® Assay Design probes. Dietary data were collected at baseline using a modified diet history method. Cross-sectional analyses were performed in 4,828 MDCS participants with fasting blood levels of circulating risk factors measured at baseline.

Results: Each rs4977574 G allele was associated with a 16% increased incidence of CVD (95% confidence interval (CI), 1.10-1.22). Higher vegetable intake (hazard ratio (HR), 0.95 [CI: 0.91-0.996]), wine intake (HR, 0.91 [CI: 0.86-0.96]), and total alcohol consumption (HR, 0.92 [CI: 0.86-0.98]) were associated with lower CVD incidence. The increased CVD incidence by the G allele was restricted to individuals with medium or high vegetable intake (Pinteraction = 0.043), and to non- and low consumers of wine (Pinteraction = 0.029). Although rs4977574 did not associate with any known risk markers, stratification by vegetable intake and smoking suggested an interaction with rs4977574 on glycated hemoglobin and high-density lipoprotein cholesterol (Pinteraction = 0.015 and 0.049, respectively).

Conclusions: Our results indicate that rs4977574 interacts with vegetable and wine intake to affect the incidence of CVD, and suggest that an interaction may exist between environmental risk factors and rs4977574 on known risk markers of CVD.

Keywords: Cardiovascular disease; Chromosome 9p21; Diet; Gene; Gene–diet interactions.

Figure 1

Mean HbA _1C levels in tertiles of vegetable intake by rs4977574 genotype in MDC-CC. The G allele was only associated with elevated HbA_1C levels among individuals in the lowest tertile of vegetable intake (β = 0.48 mmol/mol, SE = 0.18 per G allele, P = 0.009). Higher vegetable intake was only associated with lower HbA_1C among individuals with AG (β = −0.28 mmol/mol, SE = 0.12 per risk tertile, P = 0.019) and GG genotypes (β = −0.43 mmol/mol, SE = 0.20 per risk tertile, P = 0.032).

Figure 2

Mean HDLC levels in smoking status categories by rs4977574 genotype in MDC-CC. The G allele was only associated with lower levels of HDLC among never-smokers (β = −0.02 mmol/L, SE = 0.008 per G allele, P = 0.045). Higher risk categories of smoking were associated with lower HDLC for all genotypes. The magnitude of this association was largest among individuals with AA genotype (β = −0.05 mmol/L, SE = 0.01 per higher risk category, P = 1 × 10⁻⁷) compared with AG (β = −0.03 mmol/L, SE = 0.009 per higher risk category, P = 0.0004) and GG (β = −0.02 mmol/L, SE = 0.01 per higher risk category, P = 0.024) genotypes.