Genetic variation in insulin pathway genes and distal colorectal adenoma risk

Background Insulin, glucose, and other insulin-related proteins that mediate insulin signaling are associated with colorectal neoplasia risk, but associations with common genetic variation in insulin axis genes are less clear. In this study, we used a comprehensive tag single-nucleotide polymorphisms (SNPs) approach to define genetic variation in six insulin axis genes ( IGF1 , IGF2 , IGFBP1 , IGFBP3 , IRS1 , and IRS2 ) and three genes associated with estrogen signaling ( ESR1 , ESR2 , and PGR ). Methods We assessed associations between SNPs and distal colorectal adenoma (CRA) risk in a case–control study of 1,351 subjects. Cases were individuals with one or more adenomas diagnosed during sigmoidoscopy, and controls were individuals with no adenomas at the sigmoidoscopy exam. We used unconditional logistic regression assuming an additive model to assess SNP-specific risks adjusting for multiple comparisons with P act . Results Distal adenoma risk was significantly increased for one SNP in IGF2 [per minor allele OR = 1.41; 95 % confidence interval (CI) = 1.16, 1.67; P act = 0.005] and decreased for an ESR2 SNP (per minor allele OR = 0.78; 95 % CI = 0.66, 0.91; P act = 0.041). There was no statistically significant heterogeneity of these associations by race, sex, BMI, physical activity, or, in women, hormone replacement therapy use. Risk estimates did not differ in the colon versus rectum or for smaller (<1 cm) versus larger ( > 1 cm) adenomas. Conclusions These data suggest that selected genetic variability in IGF2 and ESR2 may be modifiers of CRA risk.