Genome-wide diet-gene interaction analyses for risk of colorectal cancer

Abstract

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.

Figure 1. Associations between red and processed meat, vegetable, fruit and fiber intake and colorectal cancer risk.

Odds ratios (ORs) per quartile of increasing intake, lowest quartile = reference group, N = total number of subjects, case = number of cases.

Figure 2. Forest plot for meta-analysis of interaction analysis for rs4143094 and processed meat.

Odds ratios (ORs) and 95% confidence intervals (95% CI) are presented for each additional copy of the count (or tested) allele (T) and for each increasing quartile of processed meat intake in the multiplicative interaction model. The box sizes are proportional in size to the inverse of the variance for each study, and the lines visually depict the confidence interval. Results from the fixed-effects meta-analysis are shown as diamonds. The width of the diamond represents the confidence interval.

Figure 3. Regional association results for the interaction between processed meat and rs4143094 with surrounding SNPs.

The top half of the figure has physical position along the x-axis, and the −log10 of the meta-analysis p-value of the interaction term on the y-axis. Each dot on the plot represents the p-value of the interaction for one SNPxD in relation to colorectal cancer conducted across all studies. The most significant SNP in the region (index SNP) is marked as a purple diamond. The color scheme represents the pairwise correlation (r²) for the SNPs across the region with the index SNP. Correlation was calculated using the HapMap CEU data. The bottom half of the figure shows the position of the genes across the region. These regional association plots are also known as LocusZoom plots.