LAUSR

Colorectal cancer (CRC) risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment (G×E) interactions can provide biological insights into the effects of obesity on CRC risk. Here, we assessed potential genome-wide G×E interactions between body mass index (BMI) and common single nucleotide polymorphisms (SNPs) for CRC risk using data from 36,415 CRC cases and 48,451 controls from three international CRC consortia (CCFR, CORECT, and GECCO). The G×E tests included the conventional logistic regression using multiplicative terms (one-degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G×E interactions under specific conditions. BMI was associated with higher CRC risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher CRC risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with CRC risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and CRC.