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: 6571315
• 负责人: REINA C VILLAREAL
• 金额: --
• 依托单位: BARNES-JEWISH HOSPITAL
• 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 2003-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6571315
• 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）：种族和性别之间的骨密度各不相同。黑人和男性往往比白人和女性具有更高的骨密度。最近，雌激素代谢已逐渐成为绝经后妇女骨密度的重要决定因素。因为最近的报道表明，雌激素对男性和女性的骨骼健康同样重要，所以我们认为雌激素代谢在男性的骨丢失和骨骼维持中也起着至关重要的作用。我们建议雌激素代谢的差异可能解释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CYP基因多态性引起的，这些酶对雌激素进行代谢，从而导致变化，从而改变了酶活性，从而改变了影响无效和活性雌激素代谢物之间平衡的酶活性。迄今为止，有非常有限的证明，主要是体外，这些变体已经改变了催化功能。该建议将在知识上填补这一空白，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基因多态性的普遍性在不同种族的男性和男性中2）以确定上述基因在雌激素状态和骨密度上的多态性功能相关性。这是对50岁或以上的绝经后女性和男性的横断面研究，这些人口遭受骨质流失和骨质疏松症的风险最高。我们打算建立在特定人群中代表过多的CYP基因型，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。尽管它不是一个主要目标，但我们还将测量骨矿物质密度并检验以下假设，即优先将雌激素代谢转移到非活性途径的变体与较低的骨密度和较低的骨骼密度相关。这些数据将用于制定一个完整的建议，并检验了CYP 450酶基因多态性的长期假设对于老年男性和女性的骨骼质量维持和骨质流失很重要。另一个长期目标是将评估扩展到年轻人群，以确定CYP基因的多态性是否是峰值骨骼质量的重要决定因素。