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Center for Environmental GeneticsShuk-mei Ho, Ph.D. Project DescriptionThe unifying research focus of the Center is to study the impact of genetic diversity on individual susceptibility to toxic environmental agents. The CEG has a long history and broad range of accomplishments in environmental genetics, and this research focus has become increasingly important in environmental health science research. The Specific Aims are: Aim 1; Facilitate the identification of susceptibility genes that may interact with environmental agents to induce complex diseases such as type II diabetes, asthma, intracranial strokes, hypertension, and lung cancer. Aim 2; Facilitate studies to analyze the impact of genetic variants of known genes on individual response to specific environmental agents such as airborne particulates, environmental estrogens, metals, and ionizing radiation. Aim 3; Facilitate studies to examine signal transduction pathways induced by response to environmental agents whose exposure is associated with a disease or tissue/cellular damage. Aim 4; Encourage investigators to direct their research toward a focus in environmental genetics. Aim 5; Develop a partnership with the surrounding community to provide education, awareness of environmental health issues, and public policies through the Community Outreach and Education Program (COEP) Core. The Center has four highly successful Research Cores: Ecogenetics, Genetic Toxicology, Respiratory Toxicology, and Signal Transduction. The Human Populations Research Core was initiated to reflect emphasis on human studies related to the Center’s research focus. The goal of the Center is to understand and thus, either prevent or intervene in complex human disease by determining the role of gene- environment interaction in the development of diseases. Project HighlightsComplex DiseasesThere is considerable evidence that genetic factors are involved in prostate cancer susceptibility. Center scientists at the University of Cincinnati have studied the association of 11 single nucleotide polymorphisms (SNPs) in the HEPSIN gene (HPN) with prostate cancer in men of European ancestry. HPN is a likely candidate in prostate cancer susceptibility, as it encodes a transmembrane cell surface serum protease, which is overexpressed in prostate cancer; HPN is also located on 19q11-q13.2, where linkage is found with prostate cancer susceptibility. Center scientists have completed a case-control association study of 590 men with histologically verified prostate cancer and 576 unrelated controls, all of European descent, and found significant allele frequency differences between cases and controls at five SNPs located contiguously within the gene. A major 11-locus haplotype is significantly associated, which provides further support that HPN is a potentially important candidate gene involved in prostate cancer susceptibility. Association of one of the SNPs with Gleason score is also suggestive of a plausible role of HPN in tumor aggressiveness. A unique allelic variant, found in Africans and Mid-Easterners but not Northern Europeans, has apparently evolved in response to the hot arid climates such as the Sahara Desert and Arabia. Pal P, Xi H, Kaushal R, Sun G, Jin CH, Jin L, Suarez BK, Catalona WJ, Deka R. Variants in the HEPSIN gene are associated with prostate cancer in men of European origin. Hum. Genet. 2006 Sep;120(2):187-92. Epub 2006 Jun 17. Role Of Melanocortins As Survival FactorsMelanoma is the most devastating form of skin cancer. The steady increase in the incidence of melanoma, its resistance to chemotherapy, together with its high potential to metastasize, have emphasized the importance of its prevention. It is becoming clear that solar ultraviolet radiation is a main culprit in the etiology of melanoma, the same as in basal and squamous cell carcinomas. It is commonly accepted that skin pigmentation and melanin content are principal determinants of the susceptibility to melanoma and other sun-induced skin cancers. Although this is generally true, however, prediction of melanoma risk based solely on pigmentary phenotype is not always precise and fails to identify high-risk individuals with dark skin color. Center Scientists at the University of Cincinnati have found that other important risk factors need to be considered and better defined, particularly DNA repair capacity. Their studies have revealed the role of melanoma susceptibility genes in regulating DNA repair, and indicated that melanoma patients have a lower DNA repair capacity than the general population. Their findings show that melanocortin rescues human melanocytes from UV-induced apoptosis by enhancing their nucleotide repair capacity and their antioxidant defenses. These beneficial effects of melanocortins promote genomic stability and are absent in cultured human melanocytes expressing loss-of-function melanocortin 1 receptor (MC1R), which exhibited lag in nucleotide excision repair and increased generation of hydrogen peroxide following UV irradiation. These results suggest that the MC1R gene functions as a melanoma susceptibility gene, as loss-of-function alleles compromise the DNA repair capacity and antioxidant defenses of human melanocytes, thus predisposing them to melanoma. Given that the MC1R gene is highly polymorphic, the panel of cultured human melanocytes is being expanded by establishing primary melanocyte cultures from patients from high-risk melanoma families with different MC1R genotypes to elucidate the impact of various MC1R alleles on the function of the receptor and the response of melanocytes to UV. Kadekaro AL, Wakamatsu K, Ito S, Abdel-Malek ZA.
Cutaneous photoprotection and melanoma susceptibility: reaching beyond melanin content to the frontiers of DNA repair. Front Biosci. 2006 Sep 1;11:2157-73. |
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