Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Abstract

Genome-wide association studies (GWAS) have identified over a dozen loci associated with colorectal cancer (CRC) risk. Here we examined potential effect-modification between single nucleotide polymorphisms (SNPs) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23); rs6983267 at 8q24 (MYC); rs10795668 at 10p14 (FLJ3802842); rs3802842 at11q23 (LOC120376); rs4444235 at 14q22.2 (BMP4); rs4779584 at15q13 (GREM1); rs9929218 at16q22.1 (CDH1); rs4939827 at18q21 (SMAD7); rs10411210 at19q13.1 (RHPN2); and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/non-steroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal p-interaction =1.3×10–4; adjusted p-value 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS appears to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption.

Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations

“…This type of population effect could be reflecting different population history 30 and possibly gene-environment interactions. 31 Galicia is a large, but quite isolated region in North-western Spain, surrounded by important geographic barriers and characterized by specific cultural characteristics including language, which could have contributed to the emergence of genetic diversity. In fact, founder effects have been commonly observed in Galicia.…”

Meta-analysis of the ADH1B and ALDH2 Polymorphisms and the Risk of Colorectal Cancer in East Asians

“…Many studies have shown that polymorphisms in a significant number of genes affect the risk of colorectal can- (24). In particular, ALDH2 and ADH1B polymorphisms have been extensively investigated recently.…”

The Role of Soluble, Insoluble Fibers and Their Bioactive Compounds in Cancer: A Mini Review

“…Cancer due to epigenetics is described by aberrations in the following four mechanisms; range of post-translational modifications to modify histones (protein around which genetic material coils), DNA methylation, chromatin remodeling and non-coding RNAs [6] [8]. The lack of precise biomarkers [6] [7], need for advanced imaging technique [10] [11], statistical techniques limitations, and hypothesized loci on DNA with limited work on them [12]- [14]; are some factors that currently prevent exploration of root to cancer, and therefore to analyze risk and prevent the disease. A significant element, under the umbrella of gene-environment interaction/epigenetics, is diet [5]; therefore, the National Institutes of Health (NIH) recommends a high fiber, low fat diet, with abundant intake of fruits and vegetables for cancer prevention [15].…”

“…For instance, a study carried out in 2011 indicate minimal gene-environment interaction, as there is not convincing association between fruits, vegetables consumption and risk of Colorectal Cancer (CRC), and only marginally significant relationship with red meat and calcium [17]. Whereas, another study carried out in 2012 indicated effectiveness of vegetable only [12]. Later, another study in 2014 with efforts employed to improve statistical analysis, reflected gene-environment interaction for meat at genome-wide significance threshold in increasing cancer, and for fiber, fruits and vegetables in decreasing cancer [13] [18].…”