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.
Highlights
Colorectal cancer is the third most common neoplasm and the third leading cause of cancer death in both men and women across most ethnic-racial groups [1]
Attention has largely focused on candidate single nucleotide polymorphisms (SNPs) in genes directly involved in the metabolism of selected nutrients; for example, metabolism of B-vitamins [11], key nutrients found in fruits and vegetables; or the metabolism of carcinogenic by-products resulting from cooking or processing of meat [12]
Within the 10p14 region rs4143094 showed the most significant interaction with processed meat (ORinteraction for each copy of T-allele and increasing quartile of processed meat = 1.17, p = 8.73E-09, Table 1 and Figure 2), with no evidence of heterogeneity. This SNP, as well as correlated SNPs surrounding the rs4143094 SNP, indicate a strong signal peak in the 10p14 region near the GATA binding protein 3 (GATA3) gene; as expected SNPs less correlated with rs4143094 show less significant interactions (Figure 3)
Summary
Colorectal cancer is the third most common neoplasm and the third leading cause of cancer death in both men and women across most ethnic-racial groups [1]. Attention has largely focused on candidate SNPs in genes directly involved in the metabolism of selected nutrients; for example, metabolism of B-vitamins [11], key nutrients found in fruits and vegetables; or the metabolism of carcinogenic by-products resulting from cooking or processing of meat [12]. From these candidate gene/pathway-approaches, few genetic variants have been consistently identified and further investigation is warranted
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