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。由于最近的报告表明，雌激素对男性骨骼健康的重要性与女性相同，我们认为雌激素代谢在男性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是造成骨密度性别和种族差异的原因。此外，我们假设，这种变异性在雌激素代谢是由于β基因多态性的关键酶，代谢雌激素的变异，改变了酶的活性，影响之间的平衡非活性和活性的雌激素代谢产物。到目前为止，有非常有限的证据，主要是在体外，这些变体已经改变了催化功能。这一建议将有助于填补这一知识空白，并建立在老年人的酶活性和骨密度的β-淀粉样蛋白基因多态性的生物学意义。本研究的主要目的是：1）确定CYP 1A 1、CYP 1B 1、CYP 1A 2和CYP 3A 4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和骨密度的功能相关性。这是一项对50岁或以上绝经后女性和男性的横断面研究，这些人群是骨丢失和骨质疏松症风险最高的人群。我们打算确定在特定人群中过度表达的雌激素基因型，并通过测量尿雌激素代谢产物来评估不同变体的功能状态。虽然这不是主要目标，但我们还将测量骨矿物质密度，并检验以下假设：优先将雌激素代谢转移到非活性途径的变体与骨密度降低相关，反之亦然。这些数据将被用来开发一个完整的建议和测试的长期假设，即α 450酶基因多态性是重要的骨量维持和骨质流失的老年男性和女性。另一个长期目标是将评估扩展到年轻人群，以确定β基因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.