DNA base excision repair genetic risk scores, oxidative balance, and incident, sporadic colorectal adenoma

Abstract

Associations of individual base excision repair (BER) genotypes with colorectal adenoma risk are unclear, but likely modest. However, genetic risk scores (GRS) that aggregate information from multiple genetic variants might be useful for assessing genetic predisposition to colorectal adenoma. We analyzed data pooled from three colonoscopy-based case-control studies of incident, sporadic colorectal adenoma (n = 488 cases, 604 controls) that collected blood for genotyping and extensive dietary and other data. We randomly split our population sample into training samples (half of the participants) and validation samples (the remaining participants) 10 times. Associations of 65 individual single nucleotide polymorphisms (SNPs) in 15 BER genes were assessed in the training samples and used to combine information from multiple risk variants into a BER GRS among the validation samples using unweighted and weighted methods. We also combined 15 extrinsic exposures with known pro- or antioxidant properties into an oxidative balance score (OBS). Associations of the BER GRS with colorectal adenoma, overall and jointly with the OBS, were assessed using multivariable logistic regression. The odds ratio for those in the highest relative to the lowest tertile of the weighted BER GRS was 2.07 (95% confidence interval, 1.26-3.40; p_trend = 0.01). Relative to those with both a low GRS and a high (more antioxidant) OBS, the estimated direct association for those with both a high BER GRS and a low OBS was stronger than for those in other GRS/OBS categories. Our findings suggest that BER genotypes collectively may be associated with incident sporadic colorectal adenomas.

Keywords: DNA base excision repair; colorectal adenoma; genetic risk score; oxidative balance; single nucleotide polymorphisms.