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, 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 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. A current primary focus is to look at methylation levels 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) Chronic cigarette smoking exposes airway epithelial cells to thousands of carcinogens, oxidants and DNA damaging agents and creates a field of molecular injury in the airway. Gene expression studies of bronchial epithelial cells from current and former smokers have identified transcription-based biomarkers that may prove useful in early diagnosis of lung cancer. The p53 gene is commonly mutated in lung cancer and transcription of the p53 pathway is often disregulated. This study examines the relationship between airway gene expression variation and genetic variation in this key molecular pathway associated with smoking exposure and lung cancer. Using several bioinformatics strategies, we identified candidate p53 pathway genes and candidate single nucleotide polymorphisms that might contribute to individual differences in gene expression and/or cancer status. We selected 446 SNPs in the p53 pathway , including 157 haplotype tagging SNPs in 19 genes with transcription mediated by p53 binding sites, 6 SNPs located in known p53 binding sites (or response elements, RE), 281 SNPs located in putative p53 binding sites. These polymorphisms were genotyped in nonsmokers, healthy smokers and smokers with lung cancer (n=52) who had whole-genome airway gene-expression studies performed. Analyzing associations between genotype and gene expression, we found significant associations for cis-acting SNPs (between putative regulatory SNPs and the expression of nearby genes) and also for a trans-acting effect for the p53 coding SNP (Pro72Arg) with the expression of p53 target genes. In addition, considering that SNP genotypes that affect gene expression might have a different distribution relative to cancer status, we tested for frequency differences among groups. A SNP in the 3 UTR of CD59 was associated with lower CD59 mRNA levels and with cancer diagnosis. Among p53 RE SNPs associated with gene expression, we selected 26 SNPs for functional evaluation of their impact on p53-DNA binding using a microsphere-based binding assay. A number of these p53 RE SNPs showed allele-specific affinity for p53, especially two (near PMAIP1 and PLAUR), that reduced binding (50 to 80%). This study has identified some potentially functional SNPs in the p53 pathway that may modulate the airway gene expression response to smoking and influence risk for developing tobacco-related lung cancer (submitted). 2) As part of a team led by Dr. Stephanie London, EB, NIEHS, we have examined CpG methylation in cord blood in relation to maternal smoking. Epigenetic modifications due to in utero exposures may play a critical role in early programming for childhood and adult illness. Maternal smoking is a risk factor for adverse health outcomes in children but the underlying mechanisms are unclear. We examined maternal plasma cotinine (an objective biomarker of smoking) measured during pregnancy in relation to DNA methylation at 473,844 CpG sites (CpGs) in 1,062 newborn cord bloods from the Norwegian Mother and Child Cohort Study (MoBa) using the Infinium HumanMethylation450 BeadChip. We found differential DNA methylation at epigenome-wide statistical significance (p-value<1.06x10-7) for 26 CpGs mapped to 10 genes. We replicated findings for CpGs in AHRR, CYP1A1, and GFI1 at Bonferroni-corrected statistical significance in 36 cord blood DNA samples (18 from newborns of smoking mothers) in a study from the U.S. AHRR and CYP1A1 play a key role in the aryl hydrocarbon signaling pathway, which mediates the detoxification of the components of tobacco smoke. GFI1 is involved in diverse developmental processes but has not previously been implicated in responses to tobacco smoke. Our hypothesis-free epigenome-wide screen demonstrates altered methylation patterns at birth in children of mothers who smoke during pregnancy. These results provide support for the role of epigenetic mechanisms in modulating the effects of in utero exposures. We are extending this project to identify the cell types in cord blood that are the targets for tobacco smoke induced methylation changes. 3) To examine if similar tobacco induced changes occur in adults, we carried out a preliminary study in 62 adults and determine that many of the methylation changes are shared with neonates. These results, which have been confirmed by other groups, led us to apply for and receive funding from FDA/ICTR to pursue additional studies. We are currently separating blood cells types from smokers and nonsmokers to determine the target cells for smoking induced methylation changes.

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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 :
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 :
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
Wang, Xuting; Pittman, Gary S; Bandele, Omari J et al. (2014) Linking polymorphic p53 response elements with gene expression in airway epithelial cells of smokers and cancer risk. Hum Genet 133:1467-76
Ciencewicki, Jonathan M; Wang, Xuting; Marzec, Jacqui et al. (2014) A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection. FASEB J 28:1947-56
Azzam, Gregory; Wang, Xuting; Bell, Douglas et al. (2013) CSF1 is a novel p53 target gene whose protein product functions in a feed-forward manner to suppress apoptosis and enhance p53-mediated growth arrest. PLoS One 8:e74297
Campbell, Michelle R; Karaca, Mehmet; Adamski, Kelly N et al. (2013) Novel hematopoietic target genes in the NRF2-mediated transcriptional pathway. Oxid Med Cell Longev 2013:120305
Joubert, Bonnie R; HÃ¥berg, Siri E; Nilsen, Roy M et al. (2012) 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect 120:1425-31

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