GENETIC OF BONE STRUCTURAL GEOMETRY: FRAMINGHAM COHORTS

描述：(由申请人提供)骨几何形状是衡量骨骼脆性和骨质疏松性骨折风险的有效指标。这项研究的主要目的是识别和评估决定骨骼几何特性的基因。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。来自Framingham研究的描述良好的家系以及现有的基因组扫描，包括均匀分布在整个基因组中的微卫星，将使我们能够对骨骼几何形状的遗传变异来源进行研究。 阐明骨骼结构和强度背后的遗传和分子机制将最终导致确定哪些人具有最高的骨质疏松性骨折风险，谁可以作为治疗干预的目标。 这项研究的具体假设是： -遗传因素解释了几何指数的很大一部分可变性，这些几何指数将作为本项目的一部分，在减轻体重的股骨和不减轻重量的掌骨中得出。 -股骨和掌骨的骨几何指数将与染色体基因显著相关。 -将找到股骨和掌骨指数的共同遗传来源，对股骨的骨密度和脚后跟的定量超声波也有多效性影响，这些已经作为Framingham骨质疏松研究的一部分进行了调查。 最初的连锁结果将通过对基因组区域的额外标记进行基因分型来精炼，这些标记的LOD分数提示与股骨和掌骨几何指数的连锁。我们的目标是通过检查这些区域内的多态标记来微调数量性状基因座的定位。连锁分析还将与位于峰下的候选基因的基于家族的关联测试相结合，并与单核苷酸多态进行额外的定位。

DESCRIPTION: (provided by applicant) Bone geometry is a valid measure of bone fragility and risk of osteoporotic fractures. The primary aim of this study is to identify and evaluate genes determining 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. Well-described pedigrees from the Framingham Study along with an existing genome scan, including microsatellites uniformly distributed throughout the genome, will allow us to perform a study of the genetic sources of variation in bone geometry. Elucidation of genetic and molecular mechanisms underlying bone structure and strength will ultimately lead to the identification of the individuals at highest risk of osteoporotic fractures who can be targeted for therapeutic interventions. The specific hypotheses of this study 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-beating femur and in non weight-beating metacarpals. - Significant linkage with chromosomal loci will be found for indices of bone geometry at femur and metacarpals. - Common genetic sources will be found for femoral and metacarpal indices, with pleiotropic effect also on bone mineral density of femur and quantitative ultrasound of heel that are already investigated as part of the Framingham Osteoporosis Study. Initial linkage results will be refined by genotyping additional markers in genomic regions with LOD scores suggestive of linkage with femoral and metacarpal geometric indices. Our goal is to fine-tune localization of quantitative trait loci by examining polymorphic markers within these regions. Linkage analysis will also be combined with family based tests of association with candidate genes that lie under the peak, with additional mapping with single nucleotide polyrnorphisms.