GENETIC OF BONE GEOMETRY: FRAMINGHAM COHORTS

描述(申请人提供)：本补充申请是我们最近资助的R01(AR050066-01)的扩展，其主要目标是进行基因组筛查，以确定骨几何指标与一组常染色体微卫星标记的多变量连锁。 这项拟议的研究的主要目标是测试候选基因与骨骼几何特性的关联。这项研究将利用弗雷明翰心脏研究参与者现有的手部X光和双X光吸收扫描髋部，这是世界上运行时间最长的队列研究之一。 本补充资料的具体假设为： -遗传因素解释了几何指数的很大一部分变异性，这些几何指数将作为本项目的一部分，在承重股骨和非承重掌骨中得出 -编码骨基质蛋白、性腺类固醇、生长因子和细胞因子的基因的多态将与两个骨骼部位的骨几何指数有关。 在这项拟议的研究中，来自相关和不相关的弗雷明翰参与者的数据将被用来对骨骼几何指数与一些可能在确定骨骼几何形状方面发挥作用的基因进行遗传关联分析。我们的一般方法将是使用无关个体的样本以及来自Framingham的家庭成员样本来测试候选遗传多态和骨几何表型之间的关联和链接/关联。我们为这项工作选择的候选基因将从三个主要信息来源中确定：1)发表的文献，2)体外机械刺激的小鼠股骨的表达谱，以及3)通过使用精炼的骨成像数据和来自同种小鼠品系的微阵列数据与小鼠遗传学家合作。 骨几何形状是衡量骨脆性和骨质疏松性骨折风险的重要指标。阐明骨强度背后的遗传和分子机制最终将导致确定哪些人是骨质疏松性骨折的高危个体，谁可以作为治疗干预的目标。

DESCRIPTION (provided by applicant): This supplemental application is an extension of our recently funded R01 (AR050066-01), of which the primary aim is to perform a genome screen to identify multivariate linkage of bone geometry indices with a set of autosomal microsatellite markers. The primary goal of this proposed study is to test for associations of candidate genes with geometrical properties of bone. This study will take advantage of existing hand x-rays and dual x-ray absorptiometry scans of the hip from participants of the Framingham Heart Study, one of the longest running cohort studies in the world. The specific hypotheses of this supplement are: - Genetic factors explain a significant portion of variability in geometric indices that will be derived as part of this project in both the weight-bearing femur and in non weight-bearing metacarpals - Polymorphisms in genes coding for bone matrix proteins, gonadal steroids, growth factors, and cytokines, will be associated with indices of bone geometry at two skeletal sites. In the proposed study, data from both related and unrelated Framingham participants will be used to perform genetic association analyses of bone geometry indices with a number of genes that are likely to play a role in the determination of bone geometry. Our general approach will be to test an association and linkage/association between candidate genetic polymorphisms and bone geometric phenotypes, using a sample of unrelated individuals, as well as a sample of family members from Framingham. Our selection of candidate genes for this work will be determined from three main sources of information: 1) published literature, 2) expression profiling of mouse femora mechanically stimulated ex vivo, and 3) collaboration with mouse geneticists through the use of refined bone imaging data and microarray data from congenic mouse strains. Bone geometry is an important measure of bone fragility and risk of osteoporotic fractures. Elucidation of genetic and molecular mechanisms underlying bone strength will ultimately lead to the identification of the individuals at highest risk of osteoporotic fractures who can be targeted for therapeutic interventions.