CYP gene polymorphism and estrogen status in the elderly

描述(申请人提供)：骨密度因种族和性别不同而不同。黑人和男性往往比白人和女性有更高的骨密度。最近，雌激素代谢逐渐被认为是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的骨骼健康和女性的骨骼健康同样重要，我们认为雌激素代谢在男性的骨丢失和骨维护中也起着关键作用。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，这些变异改变了酶的活性，影响了非活性和活性雌激素代谢物之间的平衡。到目前为止，证明这些变体改变了催化功能的证据非常有限，主要是在体外。这一建议将有助于填补这一知识空白，并确立CYP基因多态对老年人酶活性和骨密度的生物学意义。本研究的主要目的是：1)确定不同民族男女人群中CYP1A1、CYP1B1、CYP1A2和CYP3A4基因多态的发生率；2)确定上述基因多态与雌激素水平和骨密度的功能相关性。这是一项针对50岁或以上的绝经后女性和男性的横断面研究，他们是骨质流失和骨质疏松风险最高的人群。我们打算建立在特定人群中过度代表的CYP基因类型，并通过测量尿中雌激素代谢产物来评估不同变体的功能状态。虽然这不被认为是主要目标，但我们也将测量骨密度并测试假设，即优先将雌激素代谢转移到不活跃途径的变体与较低的骨密度相关，反之亦然。这些数据将被用来制定一个完整的建议，并检验这一长期假设，即CyP450酶基因多态性对老年男性和女性的骨量维持和骨丢失非常重要。另一个长期目标是将评估扩展到年轻人群，以确定CYP基因的多态是否是峰值骨量的重要决定因素。

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.