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2008 Core Annual Report.doc
2008 Core Annual Report.doc
2008 Core Annual Report.doc
2008 Core Annual Report.doc
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  • 1. 2. A. 4. PROGRESS REPORT: Genes and Environment Research Core (Co-Directors: Rebbeck and Whitehead). The Genes and the Environment Research Core is focused on the role of genetics in determining responses to environmental exposures. A specific interest is the differential interactions between different genotypes (and genotype profiles) and exposures (i.e. carcinogens, tobacco smoke, air-pollutants, xenobiotics, exogenous hormones, sunlight and diet) that elicit, or modify the risk of, adverse health effects. Ultimately, genetic profiles will be used to identify those at particular/excess risk from environmental exposures, and to determine their level of risk, likely disease course, and capacity to respond to preventive and therapeutic remedies. The Research Core has positioned itself to be responsive to the NIH-wide initiative on Gene-Environment Interactions and the NIH-roadmap on the Epigenome and Epigenetics. Currently, the research emphasis continues to be placed on: (1) elucidating the interactions between the genetic determinants that may govern lung cancer susceptibility (e.g. those impacting smoking behavior and addiction, the metabolic activation of carcinogens, ensuing oxidative stress, DNA-damage and repair, and cell cycle) with environmental exposures (e.g. polycyclic aromatic hydrocarbons (PAH)); (2) elucidating the interaction of genetic determinants of melanoma and circadian rhythm with environmental exposures, e.g. UV sunlight and daylight, respectively; (3) elucidating the interactions between genetic determinants of reproductive malignancies, e.g. prostate, breast and testicular cancer, with exposure to endocrine disruptors; and (4) elucidating the interactions between the genetic determinants of birth-defects (e.g. spina bifida and autism) with environmental and nutritional exposures. Investigators in this Core have published 25 papers, and have been awarded two new RO1 grants related to environmental health science in the last year. A T32 Training Grant in Genes and Environmental Health was also submitted. Dr. Jinbo Chen, Assistant Professor of Biostatistics was appointed to this Research Core as a new member. Her research interests are in the development of statistical methods for molecular epidemiological studies. 2. A. 4. 1. Ongoing Collaborative Research Between Core Members. Gene Environment Interactions in Lung Cancer. These studies fall into two categories: (a) genetic predisposition to lung cancer and (b) genetic determinants of nicotine addiction and both are dependent on being able to measure biomarkers of carcinogen exposure and response. (a) Genetic Predisposition to Lung Cancer. Drs. Whitehead (P.I.), Penning (Co-P.I.), Albelda, Baldwin, Blair, Lerman, Rebbeck, Troxel, Vachani (University of Pennsylvania), Lazarus and Muscat (Penn State Medical College), and Thomas and Joseph (Lincoln University) are in the second year of funding by the PA Department of Health to establish a Center for Gene-Environment Interactions in Lung cancer. This grant was funded by the Tobacco-Settlement fund that was ear-marked for gene-environment interaction studies; the award is for 4.2M in Total Costs over 4 years, with the expectation that sustainability of the Program will be achieved. The hypothesis under test is that there are genetic differences in responses to lung carcinogens that are (a) tobacco-specific [e.g. nicotine-derived nitrosamino-ketone; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone], and (b) found in tobacco smoke and the environment (e.g. polycyclic aromatic hydrocarbons, PAH), and that such individual differences result in predisposition to lung cancer. This predicts that (i) lung cancer susceptibility is governed by complex gene-environment interactions with SNPs in particular genes contributing to the “mutator” phenotype that causes mutations in proto-oncogenes or tumor suppressor genes to transform lung cells; and (ii) polluted environments in which PAH (and other carcinogens) are at relatively high levels will act via a subset of susceptibility genes to raise lung cancer incidence in smokers and non-smokers alike. In Philadelphia County the yearly lung cancer rates for men and women are respectively 115.7 and 70.0 per 100,000, whereas in Dauphin County the corresponding rates are much lower at 83.9 and 47.6 per 100,000. In the former region, air pollution as well as health disparities typical of large urban settings likely contribute to the 50% higher burden of lung cancer. Smokers with lung cancer (1200), control disease-free smokers (1200), and non-smokers with lung cancer (200), will be recruited through the University of Pennsylvania and Penn State
  • 2. Schools of Medicine, located respectively in Philadelphia and Dauphin Counties (Vachani, Albelda and Lazarus, Muscat). Biomarkers for NNK and PAH will be measured to estimate exposures to carcinogens derived from tobacco smoke and environmental pollution (Penning and Blair). Variants of more than 50 genes involved in the metabolic activation and subsequent detoxification of NNK and PAH, as well as DNA adduct repair genes, will be genotyped to test for associations with lung cancer (Whitehead, Vachani and Albelda). Biomarkers of folate status and functional polymorphisms in folate-metabolizing enzymes will also be evaluated as potential direct or indirect modifiers of disease risk (Whitehead). Risk estimates for genetic and phenotypic variables will be calculated for the following categories of subjects with lung cancer: residents of geographic locations with high or low levels of air pollution, regardless of race; African Americans in locations with high levels of air pollution; Caucasians in locations with high or low levels of air pollution; smokers and non-smokers in each of the above categories. Demographic and clinical data and blood and urine samples are being collected at a single study visit. This data set includes de-identified disease history, tobacco use history, alcohol use history, occupational history and vitamin use. Separate questionnaires are being administered to controls by study staff and student interns from Lincoln University to assess socio-economic background, access to health care, and attitudes towards smoking cessation, genetic and blood tests. This program has the potential to identify genetic and/or phenotypic risk factors for lung cancer applicable to the general population, those living in areas with high levels of environmental pollution, and minorities. It is likely that the data generated in the course of this program will be invaluable for effectively addressing issues of health disparities and "environmental justice" and may thereby facilitate significant improvements in the health of Pennsylvanians. This four-year grant enables patient recruitment for the first three years and the final year will be used for genotyping, phenotyping, and data analysis. Since the initiation of funding the following progress has been made: [a] IRB approvals, consent forms and HIPPA compliance at the three participating institutions has been achieved; [b] all questionnaires have been designed and tested; [c] Standard Operating Procedures have been put in place for blood draws and urine collection at the University of Pennsylvania and Hershey Medical College; [d] a relational data-base in ORACLE has been built with separate fields for the data to be collected; [e] approximately 200 patients and 200 controls have been recruited; [f] a pilot folate genotype- phenotype study of cases has been partly completed; and [g] assays for measuring biomarkers of tobacco exposure and response have been developed and validated. (b) Genetic Predisposition to Nicotine Addiction. Key publications in the past year include identification of novel genetic variants that predispose individuals to smoking relapse using pathway-based genetic analysis (Conti et al., Human Mol Gen, 2008; Heitjan et al., Am. J. Med Gen, 2007) and genome-wide association analysis (Uhl et al., Archives of General Psychiatry, 2008); use of a phenotypic marker of CYP2A6 activity (which regulates nicotine metabolism) to predict response to pharmacotherapy for smoking cessation (Patterson et al., Clinical Pharmacology and Therapeutics, 2008), and examination of the cost-effectiveness of pharmacogenetic testing for smoking cessation (Heitjan et al., Pharmacogenomics J, 2008). Importantly, fast metabolizers of nicotine were found to have higher ratios of 3’-hydroxycotinine : cotinine which can be related to the CYP2A6 genotype leading to higher rates of smoking. Unfortunately, CYP2A6 is the same enzyme involved in the metabolic activation of NNK and may subject these individuals to a higher risk of lung cancer than could be expected from just a higher rate of smoking alone. (c) Detection of Biomarkers of Cigarrete Smoke Exposure and Response (U01-ESO16004-02). This Gene-Environment initiative was initiated in the oxidative stress core with the knowledge that cigarette smoke exposure is often associated with an increase in oxidative stress. Investigators (Blair, Penning, Mesaros) involved in this project are developing stable isotope dilution methodologies to measure a panel of biomarkers of: oxidative stress (8-oxo-dGuo, heptano-etheno-dGuo; F(2α)-isoprostanes): nicotine exposure (nicotine, cotinine, trans-3’-hydroxy-cotinine and their glucuronides) and NNK (NNAL-glucuronide); benzo[a]pyrene (B[a]P) exposure (3-hydroxy-B[a]P); and folate status (folic acid, tetrahydrofolate (THF) 5-methyl-THF and 5,10-methenyl-THF). Assays for established analytes were developed in the Molecular Profiling Core (Mesaros). These panels of biomarkers are being used in a sub-set of smokers and non-smokers to see if they can discriminate between the two population sets (Vachani and Troxel). Differences in 8-oxo-dGuo were somewhat disappointing, however, differences in the isoprostanes and the heptano-etheno-dGuo adduct, a unique lipid peroxidation DNA adduct, were robust indicators of smoking exposure. These biomarkers have sufficient specificity and selectivity that they will be tested in a validation set. Biomarker analysis of tobacco and environmental PAH are being developed.
  • 3. Gene-Environment Interactions in Melanoma. Drs. Rebbeck and Kanetsky have been involved in multi-center consortia to understand melanoma susceptibility. Drs. Rebbeck and Kanetsky have worked with the Gene-Environment Melanoma Study Group to study abnormal nevus phenotype and its associated increased risk of melanoma (Int. J. Cancer (2008) 124: 420-8) They report a pooled analysis conducted using individual nevus data from 15 case-control studies (5,421 melanoma cases and 6,966 controls). The aims were to quantify the risk better and to determine whether relative risk varies by latitude. Bayesian unconditional logistic random coefficients models were employed to study the risk associated with nevus characteristics. Participants with whole body nevus counts in the highest of 4 population-based categories had a greatly increased risk of melanoma compared with those in the lowest category (pooled odds ratio (pOR) 6.9; 95% confidence interval (CI): 4.4, 11.2) for those aged <50 years and pOR 5.1 (95% CI: 3.6, 7.5) for those aged >/=50). The pOR for presence compared with absence of any clinically atypical nevi was 4.0 (95% CI: 2.8, 5.8). The pORs for 1-2 and >/=3 large nevi on the body compared with none were 2.9 (95% CI: 1.9, 4.3) and 7.1 (95% CI: 4.7, 11.6), respectively. The relative heterogeneities among studies were small for most measures of nevus phenotype, except for the analysis of nevus counts on the arms, which may have been due to methodological differences among studies. The pooled analysis also suggested that an abnormal nevus phenotype is associated most with melanomas on intermittently sun-exposed sites. The presence of increased numbers of nevi, large nevi and clinically atypical nevi on the body are robust risk factors for melanoma showing little variation in relative risk among studies performed at different latitudes. Genetic Predisposition to Testicular Cancer. Drs. Nathanson and Kanetsky were funded by the NCI to study “Inherited Genetic Variation and Predisposition to Testicular Cancer (R01-CA114478; Total Costs 3.9M). Testicular germ cell tumors (TGCT) are the most common cancer in men ages 20-40. Interestingly, TGCT suspectibility is almost entirely limited to the white population. In that population disease incidence has more than doubled over the past forty years, without clear etiology. These data suggest that both genetic effects and environmental exposures are likely to play an important role in determining TGCT susceptibility. In particular, exposure to endocrine disrupting chemicals during the pre-natal period has been postulated to play a role in TGCT susceptibility. TGCT is known to develop from primordial germ cells (PGCs). As an initial component of the study, a genome wide association study (GWAS) in the TGCT population has been completed and analysis is underway. Preliminary results have readily identified genetic variants which have a substantial risk for TGCT. Investigators will further study the contribution of genetic variants to TGCT risk using a population-based case-control study in the Philadelphia metropolitian area. Recruitment of 550 TGCT cases and 1100 age and race matched controls without a history of TGCT will be available for final analyses. All cases are being enumerated through the New Jersey and Pennsylvania state cancer registries. Both cases and controls complete a questionnaire addressing known, presumed, and hypothesized risk factors for TGCT and provide a blood or saliva sample. Haplotypes and functional SNPs will be typed in the genes of interest. Analyses will be conducted for specific variants and common haplotypes, alone and in conjunction with each other and exposure data after appropriate adjustment for potential confounders. The findings from this study will contribute to our understanding of determinants of TGCT susceptibility and environmental factors. Genetic Predisposition to Birth and Developmental Defects. Two gene-environment interaction studies involving patient cohorts aimed at identifying genetic risk factors for neural tube defects (Whitehead) and autism (Pinto-Martin) are being conducted. (a) Low Folate/ High Homocysteine Phenotype and Birth Defects. A low folate, high homocysteine (i.e. hyperhomocysteinemic) phenotype has been associated with several human pathologies, including spina bifida and other neural tube defects. This phenotype can be caused by nutritional factors or by functional variants of enzymes and other gene products that are involved in folate metabolism, absorption, transport or catabolism. Lifestyle factors are also implicated, in particular smoking. In a non-genetic study (Whitehead) it was shown that smoking has a significant folate lowering and homocysteine raising effect in young women; this work was extended to establish whether the DHFR “c.86+60_78” insertion/deletion polymorphism has a significant effect on both folate and homocysteine concentrations. The homozygous del/del genotype conferred a favorable phenotype characterized by high folate and low homocysteine to young women of childbearing age; however, smoking abolished this apparent advantage. Though untested, this observation has led to the hypothesis that folate-related birth defects may be potentiated by smoking in women who would otherwise be at relatively low
  • 4. risk of having an adverse pregnancy outcome. Further work has been facilitated by the development of robust LC-MRM/MS methods (Blair and Whitehead) to precisely quantify serum homocysteine (Biomed Chromatogr. (2007) 21: 117-112) and both serum and red blood cell folate derivatives (Rapid Commun. Mass Spectrom. (2008) 22: 2403-2412). Comprehensive folate/homocysteine phenotyping in healthy pre- menopausal women has revealed associations between both tetrahydrofolate concentration and MTHFR genotype and elevated levels of the potent pro-inflammatory chemokine MCP-1 (Birth Defects Res. (Part A) Clin. Mol. Teratol. (2008) 736-41). To our knowledge this is the first demonstration of a link between genetically mandated aspects of folate phenotype and elevated levels of markers of sub-clinical inflammation. The connection has been confirmed in a genotype-phenotype study of rheumatoid arthritis patients treated with the anti-folate drug methotrexate, and is being prepared for publication. (b) Gene and Environment Interactions in Autism. The Center for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) is directed by Dr. Pinto-Martin. A significant advance in understanding the etiology of autism spectrum disorders (ASD) has been the recognition of the strong genetic influence on ASD occurrence, although no specific genes have been identified. The cause of ASD is multi- factorial and multiple gene-environment interactions (it is believed that at least 15 loci could contribute to etiology) may be responsible. It is hypothesized that the causal events leading to the disorder arise prenatally, although there is some data to suggest possible postnatal insults as contributing factors. The ongoing Study to Explore Early Development will address these gaps in knowledge. The study cohorts will provide DNA needed for genetic analyses as well as biomarkers of exposures and, potentially, disease. Blood specimens from parents are valuable not only as a source of parental DNA, but to allow the exploration of correlations of biomarkers within and across families. Case children include children with ASD; a comparison group of children who have developmental problems excluding ASD will be called the neuro-developmentally impaired comparison group (NIC). Both case and NIC groups will be drawn from children in the relevant Philadelphia, Montgomery and Chester county birth cohorts who are evaluated or receive services for developmental problems. A second comparison group of children (subcohort) will be drawn randomly from the same birth cohorts. Comparisons between cases and the subcohort will identify risk factors for ASD relative to children from the general population, which are developing normally. Comparisons between cases and the NIC may distinguish risk factors for ASD independent of factors shared with other developmental problems. 2. A. 4. 2. Training Grant Application. Investigators in this Core submitted an Institutional T32 Training Grant to NIEHS entitled “Combined Training Program in Genes and Environmental Health” which obtained a priority score of 2.02 and was not funded. The training program proposed a dual mentorship model whereby each trainee would be mentored by a geneticist and an environmental health scientist. Unique aspects of the training program were that (i) a “Summer Research Institute” was proposed in bench genomics, and (ii) individuals with a genetics background could work on environmental health/exposure biology problems, whereas individuals with the latter background could work on genetic problems. The research base for the genetics portions of the training program consisted of several multi-investigator grants: (a) PA-DOH Center for Gene-Environmental Interactions in Lung Cancer (Whitehead and collaborators); (b) 2P50CA093372-03 Gene Discovery in Melanoma Etiology (Rebbeck); (c) Inherited Genetic Variation and Predisposition to Testicular Germ Cell Tumors (Nathanson); (d) Center for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) (Pinto-Martin); while the research base for the environmental health/exposure biology portion of the training program also consists of: several multi-investigator grants: (a) 2P50CA084718-07 Transdisciplinary Tobacco Use Research Center (TTURC) (Lerman); 5U01HD050088-02 Network for Premature Birth Research Analytical Core (Parry, Blair, Baldwin); Biomarkers of Exposure and Response to Cigarette Smoke (Blair); and the planned Center for Ozone, Airway Biology and Translational Studies in Asthma (Panettieri). The application will be modified to address the Summary Statement and submitted to NHGRI. 2. A. 4. 3. Research Outreach. Genome-wide association studies to detect disease susceptibility genes require the sharing of data in consortia for validation and replication. Dr. Whitehead and Penning collaborate with Drs. Lazarus and Muscat (Penn State Medical College) as part of the PA-DOH Center for Gene-Environment Interactions in Lung Cancer. In February 2008 they attended a conference at M.D. Anderson Cancer Center under the auspices of the International Lung Cancer Consortium Organization (ILCCO). A subsequent application to join ILCCO was approved. Dr. Kanetsky and Rebbeck are members of the Genes and Environment and Melanoma Study
  • 5. Group. This is an international consortium to identify melanoma susceptibility genes with involvement of research institutions in the US, Canada, Italy and Australia. The CEET was host to the Annual Environmental Health Sciences Core Center Meeting and the thematic symposium was in “Omics Approaches in Environmental Health Sciences”. Speakers included both senior and junior investigators from the CEET and other Environmental Health Science Core Centers. Topics covered included: genomics (Dr. Shyam Biswal: “Nrf2 Directed Environmental Stress Response in Lung Diseases and Inflammation” and Dr. Avrum Spira: “Airway Gene Expression as a Biomarker of Host Response to Tobacco Smoke”); genotyping (Dr. Alexander S. Whitehead: “Folate Genotypes and Phenotypes as Indicators of Nutritionally and Environmentally Driven Disease” and Dr. Kate Nathanson: “Testicular Germ Cell Tumors- Towards an Understanding of Genetic and Environmental Risk factors); proteomics (Dr. Dan Libeler: “Protein Damage by Reactive Intermediates: Targets and Stress Signaling” and Dr. Gene Ciccimaro: “Absolute Quantification of Cellular Kinase Activation”); biomarkers (Dr. Ian Blair: “Exposure and Biological Response Biomarkers of Cigarette Smoke” and Dr. Matthew Perzanowksi: “Biomarkers of Airway Inflammation in Exhaled Breath”; systems biology (Dr. Leona Samson: “Genomic Predictors of Exposure and of Responses to Environmental Agents” and Dr. Todd Lamitina: “Revealing Environmental Response Networks With Comparitive Genomic Approaches in C. elegans”) and bioinformatics (Dr. Carolyn Mattingly: “The Comparative Toxicogenomics Data Base”). The schedule for the event is listed in the Appendix Items. 2. A. 4. 4. Community Outreach. As part of the Lung Cancer Susceptibility Gene Initiative Dr. Whitehead has established a collaboration with Dr. Judith Thomas, Dean of the School of Social Sciences and Dr. Joseph, Professor of Sociology at Lincoln University which is a premier institution for educating underrepresented minorities in Pennsylvania. Three types of subjects are enrolled in this genotyping study (i) African Americans from a relatively polluted region (Philadelphia); (ii) Caucasians from a relatively polluted region (Philadelphia), and (iii) Caucasians from a relatively unpolluted area (Hershey). As there are serious issues of health disparities and environmental justice between these groups it is important to understand how potentially carcinogenic environmental pollution is viewed by people in these three groups (both smoking related and non-smoking related). Disparities may also exist in how genetic risk information is perceived by these groups. Data on this topic may help the development of more effective genetic screening strategies in the future. Lincoln University minority undergraduates are directly involved in administering the questionnaires and conduct summer internships in the CEET (and at Penn State Medical College). They participate in data analysis under the direction of Drs. Joseph and Thomas. Dr. McCauley has an educational grant from NIEHS: R25-ES012089 (09/30/07-07/31/12) Genes and Environment: New Education to Involve Communities. This project promotes public understanding of the social, ethical and legal implications of research on genetic susceptibility to environmental toxicants. In recognition of the potential impact of genetic science developments in the 21st century, Dr. McCauley proposes a broad partnership of schools, unions and workers, scientists, and minority communities to develop a forum to share views on socio-ethical issues related to gene-environmental research and to educate all parties on these views. The four communities represented in this project are environmental scientists, labor advocacy groups, environmental justice community organizers and youth educators. Each of these four partners brings a unique and valuable view to the development of outreach and educational programs around issues of gene-environmental susceptibility. The project will assess community readiness to focus on this issue, develop community-driven educational and outreach programs and develop mechanisms for ongoing dialogue as the science develops and community issues emerge. The broader view of this project is that these activities will provide an arena for these four communities to come together and share each group's perspectives of the issues of importance in areas of gene-environmental susceptibility. The stages of the design of this project start with work within each community partner and build to activities in which the communities work together to share the perspectives of the others on the issues of interest. 2. A. 4. 5. Young Investigators. The Research Core has identified two young investigators for mentorship by the CDC, these include Dr. Todd Lamitina (Assistant Professor of Physiology) and Dr. Katherine Nathanson (Assistant Professor of Medicine). Both presented their work at the Annual Environmental Health Sciences Core Centers Mtg. hosted by the CEET in October, 2008.
  • 6. 2. A. 4. 6. Plans for Next Year. Collaborative Research. Dr. Whitehead has initiated discussions with Drs. Schultz, Bartolomei and Baldwin to position the core to respond to RFAs on epigenetics and the epigenome. These discussions also involve an appraisal of the assays for high-through put methylation imprinting of genes, and the consideration that epigenetic changes can also be affected by the chlorination status of cytosine. To this end the core is also in discussion with Dr. Larry Sowers at Loma Linda University to determine how to incorporate detection of other nucleobase modifications. Dr. Whitehead has also entered into discussions to determine whether folate phenotype/genotype may predispose individuals to pre-term birth and preeclampsia and thereby establish a gene-nutrition interaction. New Grant Initiatives. The PA-DOH grant “Center for Gene-Environmental Interactions in Lung Cancer” will be sustained by planning and submitting a P01 on this topic to the NCI. Investigators in the CEET who are either participating on this grant or who have NIEHS and NCI grants that speak to this topic have begun monthly meetings to prepare for this application. A target submission date could be the fall of 2009.