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) and N-acetyltransferase (NAT1 and NAT2), XRCC1, XPD, vary significantly between ethnic groups. Some differences in cancer incidence among groups may be due to genetic metabolic differences as well as exposure differences. Mission: Our long-term goal is to understanding how genes and environment interact to influence risk of environmentally induced disease. To this end we are engaged in """"""""Environmental Genomics."""""""" This encompasses: 1) identification of candidate environmental response genes, 2) discovery and functional characterization of genetic and phenotypic variation in these genes, and;3) the analysis in population studies of environmental disease susceptibility associated with functional polymorphisms, acquired susceptibility factors and exposures;and the interactions between these factors. Eventually we hope these genomic approaches will help us to develop assays using genotype, gene expression, and other biomarkers of exposure and effect, that will be predictive of future risk. This work has been extended to look at methylation of CpG sites in the human genome. This information will allow us to more carefully determine the bounds of human variability in risk assessment and will be useful in developing prevention strategies to reduce disease incidence. The Genetic Susceptibility Project takes the candidate susceptibility factors from the laboratory genotype/phenotype studies and tests 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) Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n=20), smokers without lung cancer (SNC, n=24), and never smokers (NS, n=8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure. 2) In utero PAH Exposure Alters CpG Methylation Status in Neonates (collaboration with R. Perera, Columbia U.;Pittman et al, Poster). We have previously reported that maternal exposure to ambient polycyclic aromatic hydrocarbons (PAHs) was associated with PAH-DNA adducts in neonatal cord blood and post-natal developmental endpoints. High in utero PAH exposure produced higher PAH-DNA adducts in cord blood than maternal blood suggesting a higher biologically effective dose in the neonates. Although in vitro studies suggest PAH exposure can affect CpG methylation, few human in vivo studies related to methylation have been carried out. Therefore, we have conducted a hypothesis-generating pilot study examining CpG methylation in white blood cell DNA from 12 mother-child pairs from Krakow, Poland, evenly divided between mothers with high and low ambient PAH exposure and an almost even balance of male and female neonates. We measured methylation in triplicate using Illuminas Methylation Cancer Panel I containing 1505 CpG probes, representing 808 genes. We removed from analyses methylation probes near SNPs and those that had poor performance with reference standards. We compared CpG methylation across exposure groups, applying t-tests adjusted for false discovery rate and identified significant differences in methylation associated with maternal PAH exposure. We also selected a subset of 10 CpG sites in 9 biologically-significant genes to test using Pyrosequencing, an alternate technology for measuring methylation. PAH exposure effects were detected among all subjects and within each subgroup (mothers, male and female neonates), but each group showed distinct PAH-related methylation differences. For most CpGs, PAH-associated differences were not consistent between mothers and neonates, suggesting PAH effects may be different in mothers and neonates. Mothers with high PAH exposure had 160 CpG sites in 152 genes (59% hypomethylated) that differed significantly relative to mothers with low exposure. High exposure female neonates had 137 altered CpG sites with 55% hypomethylated;male neonates, 85 sites, 51% hypomethylated. Among high-PAH exposure neonates (both males and females), 27 CpG sites had significantly different methylation levels relative to neonates with low exposure. Interestingly, among neonates, many sites that were hypermethylated in females were hypomethylated in males, and vice versa. Comparing pyrosequencing with Illumina Goldengate results we observed on average a 15% difference between platforms, with the Illumina results showing a higher level of methylation. We performed a cross platform correlation analysis for the 10 assays and found a large range of correlations, some poor. We hypothesize the difference reflects the different technologies employed in the two assays, consistent with a recently published study comparing the two technologies . Among all subjects and across all strata, hypomethylation was most commonly associated with high in utero PAH exposure.

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Lacher, Sarah E; Alazizi, Adnan; Wang, Xuting et al. (2018) A hypermorphic antioxidant response element is associated with increased MS4A6A expression and Alzheimer's disease. Redox Biol 14:686-693
Reynolds, Lindsay M; Lohman, Kurt; Pittman, Gary S et al. (2017) Tobacco exposure-related alterations in DNA methylation and gene expression in human monocytes: the Multi-Ethnic Study of Atherosclerosis (MESA). Epigenetics 12:1092-1100
Su, Dan; Wang, Xuting; Campbell, Michelle R et al. (2017) Correction: Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. PLoS One 12:e0178308
Liu, Yongmei; Reynolds, Lindsay M; Ding, Jingzhong et al. (2017) Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis. Nat Commun 8:393
High, Monica; Cho, Hye-Youn; Marzec, Jacqui et al. (2016) Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants. EBioMedicine 11:73-84
Su, Dan; Wang, Xuting; Campbell, Michelle R et al. (2016) Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. PLoS One 11:e0166486
Stracquadanio, Giovanni; Wang, Xuting; Wallace, Marsha D et al. (2016) The importance of p53 pathway genetics in inherited and somatic cancer genomes. Nat Rev Cancer 16:251-65
Wang, Xuting; Campbell, Michelle R; Lacher, Sarah E et al. (2016) A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders. Cell Rep 15:830-842
Zhao, Ni; Bell, Douglas A; Maity, Arnab et al. (2015) Global analysis of methylation profiles from high resolution CpG data. Genet Epidemiol 39:53-64
Reynolds, Lindsay M; Wan, Ma; Ding, Jingzhong et al. (2015) DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations With Cigarette Smoking and Subclinical Atherosclerosis. Circ Cardiovasc Genet 8:707-16

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