Single nucleotide polymorphisrn ?617 C/A in the Nrf2 gene promoter modifies gene expression-air pollution relationships in subjects with coronary artery disease

摘要

Background: We previously found positive associations between traffic-related air pollution exposures and gene expression in Nrf2-mediated antioxidant response genes and other genes. We hypothesize that genetic variation in NRF2 will alter relationships between pollutant exposure and expression of Nrf2-mediated genes. Aims: We aimed to determine if the -617C＞A SNP in the Nrf2 promoter, a polymorphism shown to decrease binding and promoter activity, modifies our prior pollutant-gene expression relations. Methods: We measured whole blood gene expression levels weekly (12 weeks) in 40 subjects with coronary heart disease living in retirement communities in the Los Angeles area. We measured outdoor air pollutants: size-fractionated PM (including quasi-ultrafine PM＜0.25μm), elemental and organic carbon (EC, OC), black carbon (BC), polycyclic aromatic hydrocarbons in PM (PAH), and gases (NOx, 03). We estimated primary and secondary OC (OCpri, SOC) from total OC. We genotyped the -617 position of NRF2 by sequencing. We used mixed effects regression models to test effect modification with pollutant~*genotype interaction terms. We tested informative genes from our prior analysis: NRF2, HMOX1, SOD2, NQO1, GCLC, GCLM, CAT, GSTP1, CYP1B1, IL1B and SELP. Results: We identified 8 carriers of the risk allele (8AC, OAA) and 32 non-carriers (CC). We found pollutant-genotype interactions for NRF2, SOD2, CYP1B1, NQO1, IL1B and SELP. In 617A carriers, NRF2 expression was lower in association with several pollutants. For SOD2, carriers had higher expression with exposure to traffic pollutants including: qUFP, PAH, EC, BC, OCpri, and NOx; as well as OC and SOC. Among carriers, we found increased IL1B and SELP, and decreased CYP1B1 with exposure. Conclusion: Overall, we found complex relationships with possible support for both a direct (CYP1B1) and an indirect role (SOD2, IL1B and SELP) of Nrf2 in mediating the gene expression changes associated with air pollution exposure.