Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. Prior studies examining a potential differential relationship of aspirin and NSAIDs with colorectal cancer risk according to genetic factors have been limited to analyses of candidate genes or pathways.
To comprehensively identify common genetic markers that characterize individuals who may obtain differential benefit from aspirin and/or NSAID chemoprevention, we tested gene by environment (G X E) interactions between regular use of aspirin and/or NSAIDs and single nucleotide polymorphisms (SNPs) across the genome in relation to risk of colorectal cancer.
Case-control study using the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) that enrolled cases of colorectal cancer ascertained between 1976 and 2011 and matched controls. Odds ratios (ORs) of colorectal cancer and 95% confidence intervals (95% CIs) were estimated using conventional logistic regression analysis and case-only interaction analysis, after adjusting for age, sex, center, the first three principal components to account for population structure, and known colorectal cancer risk factors. For all genome-wide analyses, a two-sided p-value<5.0×10-8, which yields a genome-wide significance level of 0.05, was considered statistically significant.
10 observational studies (5 case-control and 5 cohort studies) that were initiated between 1976 and 2003 across the U.S., Canada, Australia and Germany.
8,634 colorectal cancer cases and 8,553 controls of European descent.
Genome-wide SNP data generated from genome-wide association scans and imputation to HapMap II, as well as information on regular use of aspirin and/or NSAIDs and other colorectal cancer risk factors collected using in-person interviews and/or structured questionnaires.
Main Outcomes and Measures
Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (OR=0.69; 95% CI=0.64-0.74; P=6.2×10-28) compared to non-regular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the microsomal glutathione S-transferase 1 (MGST1) gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P for interaction=4.6×10-9). Compared to non-regular use, regular use of aspirin and/or NSAIDs was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (OR=0.66; 95% CI=0.61-0.70; P=7.7×10-33), but a higher risk among those with much less common (4%) TA or AA genotypes (OR=1.89; 95% CI=1.27-2.81; P=0.002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the interleukin 16 (IL16) gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P for interaction=8.2×10-9). Compared to non-regular use, regular use of aspirin and/or NSAIDs was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (OR=0.66; 95% CI=0.62-0.71; P=1.9×10-30), but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (OR=0.97; 95% CI=0.78-1.20; P=0.76).
CONCLUSIONS AND RELEVANCE
In this genome-wide investigation of G X E interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and the association of these medications with colorectal cancer risk differed according to genetic variation at two SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.