UGT Polymorphisms and Hormonally-Mediated Biomarkers in Premenopausal Women

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DESCRIPTION (provided by applicant): Greater exposure to estrogen throughout a woman's lifetime is implicated in the etiology of certain cancers and other conditions arising in hormone-sensitive tissues. Sex hormones are metabolized to less active compounds and can be removed from circulation via (i) glucuronidation, catalyzed by UDP- glucuronosyltransferases (UGTs) and (ii) sulfation, catalyzed by sulfotransferases (SULTs). Several members of the UGT1A family glucuronidate 17¿-estradiol (E2), estrone (E1) and catechol estrogens and members of the UGT2B family glucuronidate catechol estrogens and androgens. The UGT and SULT enzymes are highly polymorphic, and polymorphisms altering enzyme function can affect clearance of endogenous and exogenous estrogens, thereby influencing steady-state levels. To date, only one small study has evaluated the relationship between these polymorphisms and a hormone-dependent biomarker (e.g., breast density) in healthy, premenopausal women. The aim of the proposed study is to examine, in our existing cross-sectional study of premenopausal women (NCI R01 CA97366), relationships between functional polymorphisms in the UGTs and SULTs and breast density, bone density, and steroid hormone profile. We will genotype women for the following functional polymorphisms: UGT1A1*28, UGT1A3(W11R), UGT2B4(D458E), UGT2B7(H268Y), UGT2B15(D85Y) and SULT1A1(R213H). We hypothesize that women with genotypes associated with lower steroid hormone conjugating activity will have higher breast and bone densities and higher circulating steroid hormone concentrations. As part of the parent study, we recruited 203 healthy, premenopausal women, ages 40-45 years, who had a screening mammogram taken within the previous year. Mammograms were analyzed for breast density. During the follicular phase of the menstrual cycle, a blood sample was drawn for hormone measures [serum E1, E1-sulfate, E2, dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, testosterone, and sex-hormone binding globulin (SHBG)] and to obtain genomic DNA. In addition, urine was provided for analysis of 2- and 16a-hydroxyE1. Hip and spine bone densities were measured by DEXA, and questionnaire data on general health, demographics, physical activity, dietary intake, and reproductive history also were collected. The parent study provides an ideal setting in which to evaluate these genotype-phenotype relationships, given the large amount of relevant data already available. This is the first study to examine relationships between conjugating polymorphisms and a panel of hormone-related factors in a well-characterized population of healthy, premenopausal women. Resulting data will be used to guide future, larger, population-based studies of genetic differences in steroid hormone metabolism and may ultimately be used to identify women who are more susceptible to hormone-related conditions.