Genetic risk factors modulate the association between physical activity and colorectal cancer

Physical activity is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–physical activity interaction analysis. Using logistic regression (1-d.f), two-step screening and testing method (EDGE), and joint tests (3-d.f), we analyzed interactions between common genetic variants across the genome and physical activity in relation to CRC risk. Self-reported physical activity levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk; 39,992 participants) and as study- and sex-specific quartiles of activity (42,602 participants). Physical activity was inversely associated with CRC risk overall (OR [active vs. inactive] = 0.85; 95% CI = 0.81–0.90). The two-step EDGE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and physical activity for CRC risk ( p -interaction = 2.6 × 10 −8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95% CI = 0.75–0.85), but no significant physical activity–CRC associations among CT or TT carriers. When physical activity was modeled as quartiles, the 1-d.f. test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between physical activity and CRC ( p -interaction = 3.5 × 10 −8 ). Stratification at this locus showed that an increase in physical activity (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95% CI = 0.72–0.82). In summary, we identified two genetic variants that modified the association between physical activity and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be involved in the protective association between physical activity and colorectal carcinogenesis.