Gene-Environment Interactions and the Risk of Cervical Dysplasia: The Role of DNA Repair Genes and Diesel particulate Matter

摘要

Background: There is growing evidence that air pollution, including diesel particulate matter (DPM), is associated with cervical cancer and dysplasia. One potential mechanism for OPM-induced mutagenesis is related to DNA damage. Therefore, we hypothesized that genetic variation in the DNA repair pathway may modify cervical dysplasia risk. Aim: Determine the role of DNA repair gene-DPM interactions on the risk of cervical dysplasia. Methods: Our study population was drawn from women participating in a multi-center Phase Ⅱ clinical trial between 2000 and 2004, of which 129 had cervical dysplasia (cases) and 177 did not (controls). Census tract-level estimates of DPM concentrations were obtained from the United States Environmental Protection Agency 1999 National-Scale Air Toxics Assessment. Exposure was based on residence at clinic visit and was categorized as low (＜75th percentile) or high (≥75th percentile). Genotyping on 768 single nucleotide polymorphisms (SNPs) in 13 DNA repair genes was performed using the Illumina Golden Gate platform. We utilized a 2-step approach to evaluate gene-environment interactions. In step 1, we examined the association between each SNP (G) and DPM exposure (E). SNPs where p＜0.02 were then included in step 2, a case-control analysis of GxE interactions using logistic regression models. Results: In step 1 of our analysis, we identified seven SNPs that were associated with exposure. In step 2 of our analysis, there was one statistically significant interaction between NBN rs2735388 and DPM exposure (p=0.03). Specifically, women who were NBN rs2735388 AA and had high DPM exposure were more likely to have cervical dysplasia (odds ratio=2.90, 95% confidence interval: 1.17-7.20) compared to women who were TT/TA and had low DPM exposure. Conclusions: In one of the first assessments of gene-air pollution interactions and cervical dysplasia, we found that DPM-associated disease risk was modified by genetic variation in the DNA repair pathway.