ABSTRACT
Background: 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. Methods: 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 (n = 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 F2-isoprostanes (FiP) concentrations, we selected 4 GSTP1 SNPs for an AE GRS, and 12 SNPs of 5 genes (XRCC1, TDG, PNKP, MUTYH, and FEN1) 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. Results: 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% (p = 0.12) and 21.2% (p = 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. Conclusion: 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.
ABSTRACT
Background: Inflammation is implicated in the etiology of various aging-related diseases. Numerous dietary and lifestyle factors contribute to chronic systemic inflammation; genetic variation may too. However, despite biological plausibility, little is known about associations of antioxidant enzyme (AE) and DNA base excision repair (BER) genotypes with human systemic inflammation. Methods: We genotyped 22 single nucleotide polymorphisms (SNPs) in 3 AE genes, and 79 SNPs in 14 BER genes to develop inflammation-specific AE and BER genetic risk scores (GRS) in two pooled cross-sectional studies (n = 333) of 30-74-year-old White adults without inflammatory bowel disease, familial adenomatous polyposis, or a history of cancer or colorectal adenoma. Of the genotypes, based on their associations with a biomarker of systemic inflammation, circulating high sensitivity C-reactive protein (hsCRP) concentrations, we selected 2 SNPs of 2 genes (CAT and MnSoD) for an AE GRS, and 7 SNPs of 5 genes (MUTYH, SMUG1, TDG, UNG, and XRCC1) for a BER GRS. A higher GRS indicates a higher balance of variant alleles directly associated with hsCRP relative to variant alleles inversely associated with hsCRP. We also calculated previously-reported, validated, questionnaire-based dietary (DIS) and lifestyle (LIS) inflammation scores. We used multivariable general linear regression to compare mean hsCRP concentrations across AE and BER GRS categories, individually and jointly with the DIS and LIS. Results: The mean hsCRP concentrations among those in the highest relative to the lowest AE and BER GRS categories were, proportionately, 13.9% (p = 0.30) and 57.4% (p = 0.009) higher. Neither GRS clearly appeared to modify the associations of the DIS or LIS with hsCRP. Conclusion: Our findings suggest that genotypes of DNA BER genes collectively may be associated with systemic inflammation in humans.