CYP gene polymorphism and estrogen status in the elderly

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，雌激素代谢逐渐被认为是绝经后妇女骨密度的重要决定因素。因为最近的报告表明，雌激素对男性的骨骼健康和女性一样重要，我们相信雌激素代谢在男性骨质流失和骨骼维持中也起着关键作用。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可变性是由于代谢雌激素的关键酶的CYP基因多态性导致变异，改变了酶活性，影响了活性和非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，证明这些变体改变了催化功能。本研究将填补这方面的知识空白，确立CYP基因多态性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)确定不同民族男女中CYP1A1、CYP1B1、CYP1A2和CYP3A4基因多态性的患病率；2)确定上述基因多态性与雌激素水平和骨密度的功能相关性。这是一项针对绝经后的女性和50岁以上的男性的横断面研究，他们是骨质流失和骨质疏松症的高危人群。我们打算建立在特定人群中过度代表的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。虽然这不是主要目标，但我们也将测量骨密度，并测试这样的假设，即优先将雌激素代谢转移到非活性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一个完整的建议，并测试cyp450酶基因多态性对老年男性和女性骨量维持和骨质流失很重要的长期假设。另一个长期目标是将评估扩展到年轻人群，以确定CYP基因的多态性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.