CYP gene polymorphism and estrogen status in the elderly

CYP基因多态性与老年人雌激素状况

• 批准号: 6730763
• 负责人: REINA C VILLAREAL
• 金额: $ 7.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730763
• 关键词: African American; blood chemistry; body composition; bone density; caucasian American; clinical research; cytochrome P450; enzyme activity; estrogens; female; gender difference; genetic polymorphism; genetic susceptibility; genotype; hormone regulation /control mechanism; human old age (65+); human subject; immunologic assay /test; male; osteoporosis; pathologic bone resorption; postmenopause; racial /ethnic difference; steroid hormone metabolism; urinalysis

DESCRIPTION (provided by applicant): Bone density varies between races and by gender. Blacks and men tend to have higher bone densities than whites and women. Lately, estrogen metabolism has slowly gained recognition as an important determinant of bone density in postmenopausal women. Because recent reports suggest that estrogen is likewise important to skeletal health in men as it is in women, we believe that estrogen metabolism also plays a critical role in bone loss and bone maintenance in men. We propose that differences in estrogen metabolism may account for gender and racial differences in bone density. Furthermore, we hypothesize that this variability in estrogen metabolism is due to CYP gene polymorphisms of the key enzymes that metabolize estrogen resulting in variants that have altered enzyme activity affecting the balance between inactive and active estrogen metabolites. To date there is very limited proof, mostly in-vitro, that these variants have altered catalytic function. This proposal would serve to fill in this gap in knowledge and establish the biological significance of CYP gene polymorphism on enzyme activity and bone density in the elderly. The primary aims of this proposal are 1) to determine the prevalence of gene polymorphism of CYP1A1, CYP1B1, CYP1A2 and CYP3A4 among women and men of different ethnic groups 2) to determine the functional correlates of polymorphisms of the above-mentioned genes on estrogen status and bone density. This is a cross-sectional study of postmenopausal women and men 50 years of age or over, the population who are at highest risk for bone loss and osteoporosis. We intend to establish the CYP genotypes that are over-represented in a particular population and evaluate the functional status of the different variants by measuring urinary estrogen metabolites. Although it is not considered a primary goal, we will also measure bone mineral density and test the hypothsesis that variants that preferentially shifts estrogen metabolism to the inactive pathway is associated with a lower bone density and vice -versa. These data will be used to develop a full proposal and test the long-term hypothesis that CYP 450 enzyme gene polymorphism is important for bone mass maintenance and bone loss in elderly men and women. Another long-term goal is to extend evaluation to the younger population, to determine if polymorphisms of the CYP genes are important determinant of peak bone mass.

描述（由申请人提供）：骨密度因种族和性别而异。黑人和男性的骨密度往往高于白人和女性。最近，雌激素代谢逐渐被人们认识为绝经后妇女骨密度的重要决定因素。由于最近的报告表明雌激素对男性骨骼健康与女性骨骼健康同样重要，因此我们相信雌激素代谢在男性骨质流失和骨骼维持中也发挥着关键作用。我们认为雌激素代谢的差异可能解释了骨密度的性别和种族差异。此外，我们假设雌激素代谢的这种变异性是由于代谢雌激素的关键酶的 CYP 基因多态性导致的变异体改变了酶活性，影响了非活性和活性雌激素代谢物之间的平衡。迄今为止，只有非常有限的证据（主要是体外证据）表明这些变体改变了催化功能。该提案将有助于填补这一知识空白，并确定 CYP 基因多态性对老年人酶活性和骨密度的生物学意义。该提案的主要目的是 1) 确定 CYP1A1、CYP1B1、CYP1A2 和 CYP3A4 基因多态性在不同种族的女性和男性中的患病率 2) 确定上述基因多态性与雌激素状态的功能相关性和骨密度。这是一项针对 50 岁或以上绝经后女性和男性的横断面研究，这些人群是骨质流失和骨质疏松症风险最高的人群。我们打算建立在特定人群中代表性较高的 CYP 基因型，并通过测量尿雌激素代谢物来评估不同变体的功能状态。尽管这不被认为是主要目标，但我们还将测量骨矿物质密度并测试以下假设：优先将雌激素代谢转移到不活跃途径的变异与较低的骨密度相关，反之亦然。这些数据将用于制定完整的提案并测试长期假设，即 CYP450 酶基因多态性对于老年男性和女性的骨量维持和骨质流失很重要。另一个长期目标是将评估范围扩大到年轻人群，以确定 CYP 基因的多态性是否是峰值骨量的重要决定因素。