Genetic Susceptibility To Carcinogens

National Institute Of Environmental Health Sciences

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Abstract

Background. Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to environmentally induced disease. The group has developed genotyping assays for the at-risk variants of enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Population studies indicate that for these candidate susceptibility genes, the frequency of the at-risk genotypes for glutathione transferase M1 (GSTM1), theta 1 (GSTT1), Pi (GSTP1), N-acetyltransferase (NAT1 and NAT2), XRCC1, XPD, P53 pathway, and NRF2 pathway vary significantly between ethnic groups. Some differences in cancer incidence among groups may be due to genetic differences as well as exposure differences. Mission: Our long-term goal is to understanding how genes, the epigenome and the environment interact to influence risk of environmentally induced disease. To this end we are engaged in Environmental Epigenomics. This encompasses: 1) identification of candidate environmental response genes, 2) discovery and functional characterization of genetic, epigenetic and phenotypic variation in these genes, and; 3) the analysis in population studies of environmental disease susceptibility associated with functional polymorphisms, acquired susceptibility factors such as epigenetic changes and environmental exposures; and the interactions between these factors. Eventually we hope these genomic approaches may identify biomarkers of exposure and effect, that will be predictive of future risk, and potentially useful in precision medicine. A current primary focus is to look at methylation levels of CpG sites in the human genome in relationship to exposures. Methylation profiles in blood and other tissues have promise as exposure biomarkers, markers of early pathology or perhaps biomarkers of disease. This information will allow us to more carefully determine the bounds of human variability to guide risk assessment and may be useful in developing prevention strategies to reduce disease incidence. In the Genetic Susceptibility Project we take the candidate susceptibility factors from the laboratory genotype/phenotype studies and test them in population studies. We are collaborating with numerous NIH, and university-based epidemiology groups to design and carryout appropriate tests of these factors in population-based epidemiology studies. Progress/accomplishments: 1) Anniston, Alabama was home to a major polychlorinated biphenyl (PCB) production facility from 1929 until 1971. The Anniston Community Health Survey I and II (ACHS-I 20052007, ACHS-II 20132014) were conducted to explore the effects of PCB exposures. In this report we examined associations between PCB exposure and DNA methylation in whole blood using EPIC arrays (ACHS-I, n = 518; ACHS-II, n = 299). For both cohorts, 35 PCBs were measured in serum. We modelled methylation versus PCB wet-weight concentrations for: the sum of 35 PCBs, mono-ortho substituted PCBs, di-ortho substituted PCBs, tri/tetra-ortho substituted PCBs, oestrogenic PCBs, and antiestrogenic PCBs. Using robust multivariable linear regression, we adjusted for age, race, sex, smoking, total lipids, and six blood cell-type percentages. We carried out a two-stage analysis; discovery in ACHS-I followed by replication in ACHS-II. In ACHS-I, we identified 28 associations (17 unique CpGs) at p 6.70E-08 and 369 associations (286 unique CpGs) at FDR p 5.00E-02. A large proportion of the genes have been observed to interact with PCBs or dioxins in model studies. Among the 28 genome-wide significant CpG/PCB associations, 14 displayed replicated directional effects in ACHS-II; however, only one in ACHS-II was statistically significant at p 1.70E-04. While we identified many novel CpGs significantly associated with PCB exposures in ACHS-I, the differential methylation was modest and the effect was attenuated seven years later in ACHS-II, suggesting a lack of persistence of the associations between PCB exposures and altered DNA methylation in blood cells. 2)he Anniston Community Health Survey (ACHS-I) was initially conducted from 2005 to 2007 to assess polychlorinated biphenyl (PCB) exposures in Anniston, Alabama residents. In 2014, a follow-up study (ACHS-II) was conducted to measure the same PCBs as in ACHS-I and additional compounds e.g., polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like non-ortho (cPCBs) substituted PCBs. In this epigenome-wide association study (EWAS), we examined the associations between PCDD, PCDF, and PCB ex-posures and DNA methylation. Whole blood DNA methylation was measured using Illumina EPIC arrays (n=292). We modeled lipid-adjusted toxic equivalencies (TEQs) for: Dioxins (sum of 28 PCDDs, PCDFs, cPCBs, and mPCBs), PCDDs,PCDFs,cPCBs,and mPCBs using robust multivariable linear regression adjusting forage,race,sex,smoking, bisulte conversion batch, and estimated percentages of six blood cell types. Among all exposures we identied 10 genome-wide (Bonferroni p6.74E08) and 116 FDR (p5.00E02) signicant associations representing 10 and 113 unique CpGs, respectively. Of the 10 genome-wide associations, seven (70%) occurred in the PCDDs and four (40%) of these associations had an absolute differential methylation 1.00%, based on the methylation difference be-tween the highest and lowest exposure quartiles. Most of the associations (six, 60%) represented hypomethylation changes. Of the 10 unique CpGs, eight (80%) were in genes shown to be associated with dioxins and/or PCBs based on data from the 2019 Comparative Toxicogenomics Database. In this study, we have identied a set of CpGs in blood DNA that may be particularly susceptible to dioxin, furan, and dioxin-like PCB exposures.