UGT Polymorphisms and Hormonally-Mediated Biomarkers in Premenopausal Women

描述(由申请人提供)： 女性一生中更多地接触雌激素与某些癌症和激素敏感组织中出现的其他疾病的病因学有关。性激素被代谢成活性较低的化合物，并可通过(I)由UDP-葡萄糖醛酸基转移酶(UGTS)催化的葡萄糖醛酸化作用和(Ii)由磺基转移酶(Sults)催化的硫酸化作用从循环中移除。UGT1a家族的几个成员葡萄糖醛酸酯17？-雌二醇(E2)、雌酮(E1)和儿茶酚雌激素，以及UGT2B家族的成员葡萄糖醛酸儿茶酚雌激素和雄激素。UGT和SULT酶是高度多态的，改变酶功能的多态可以影响内源性和外源性雌激素的清除，从而影响稳态水平。到目前为止，只有一项小型研究评估了这些多态与健康、绝经前女性的激素依赖生物标记物(例如，乳房密度)之间的关系。这项拟议研究的目的是，在我们现有的绝经前妇女横断面研究(NCI R01 CA97366)中，检查UGT和卵巢功能多态与乳房密度、骨密度和类固醇激素谱之间的关系。我们将对女性进行UGT1A1*28、UGT1A3(W11R)、UGT2B4(D458E)、UGT2B7(H268Y)、UGT2B15(D85Y)和SULT1A1(R213H)的基因分型。我们假设，具有与较低的类固醇激素结合活性相关的基因型的女性将具有较高的乳房和骨密度以及较高的循环类固醇激素浓度。作为父母研究的一部分，我们招募了203名年龄在40-45岁之间的健康绝经前妇女，她们在前一年内进行了乳房X光检查。分析乳房X光照片中的乳房密度。在月经周期的卵泡期，取血进行激素测定[血清E1、E1-硫酸盐、E2、脱氢表雄酮(DHEA)、DHEA-硫酸盐、雄烯二酮、睾酮和性激素结合球蛋白(SHBG)]，并获得基因组DNA。此外，还提供尿液用于分析2-和16a-羟基乙酸乙酯。用DEXA测量髋部和脊柱的骨密度，并收集关于一般健康、人口统计学、体力活动、饮食摄入量和生育史的问卷数据。鉴于已有大量相关数据，父母研究为评估这些基因-表型关系提供了一个理想的环境。这是第一次在具有良好特征的健康绝经前妇女群体中研究结合多态与一组激素相关因素之间的关系。由此产生的数据将被用来指导未来更大规模的基于人群的类固醇激素代谢遗传差异研究，并最终可能被用来确定哪些女性更容易受到激素相关疾病的影响。

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.