Antioxidant enzyme and DNA base repair genetic risk scores' associations with systemic oxidative stress biomarker in pooled cross-sectional studies

Oxidative stress is hypothesized to contribute to the pathogenesis of several chronic diseases. Numerous dietary and lifestyle factors are associated with oxidative stress; however, little is known about associations of genetic factors, individually or jointly with dietary and lifestyle factors, with oxidative stress in humans. We genotyped 22 haplotype-tagging single nucleotide polymorphisms (SNPs) in 3 antioxidant enzyme (AE) genes and 79 SNPs in 14 DNA base excision repair (BER) genes to develop oxidative stress-specific AE and BER genetic risk scores (GRS) in two pooled cross-sectional studies ( = 245) of 30-74-year-old, White, cancer- and inflammatory bowel disease-free adults. Of the genotypes, based on their associations with a systemic oxidative stress biomarker, plasma F -isoprostanes (FiP) concentrations, we selected 4 SNPs for an AE GRS, and 12 SNPs of 5 genes ( , , , , and ) for a BER GRS. We also calculated a previously-reported, validated, questionnaire-based, oxidative stress biomarker-weighted oxidative balance score (OBS) comprising 17 anti- and pro-oxidant dietary and lifestyle exposures, with higher scores representing a higher predominance of antioxidant exposures. We used general linear regression to assess adjusted mean FiP concentrations across GRS and OBS tertiles, separately and jointly. The adjusted mean FiP concentrations among those in the highest relative to the lowest oxidative stress-specific AE and BER GRS tertiles were, proportionately, 11.8% ( = 0.12) and 21.2% ( = 0.002) higher, respectively. In the joint AE/BER GRS analysis, the highest estimated mean FiP concentration was among those with jointly high AE/BER GRS. Mean FiP concentrations across OBS tertiles were similar across AE and BER GRS strata. Our pilot study findings suggest that DNA BER, and possibly AE, genotypes collectively may be associated with systemic oxidative stress in humans, and support further research in larger, general populations.