Genetics of Bone Density in Mexican Americans

描述（由申请人提供）：骨质疏松症是美国老年人发病的主要原因。圣安东尼奥家庭骨质疏松症研究（SAFES）于1997年启动，目的是确定墨西哥裔美国大家庭骨密度（BMD）的决定因素。共有来自34个家庭的897名受试者参加了本研究的基线阶段。通过同时参与一项更大的研究——圣安东尼奥家庭心脏研究（SAFHS），这些受试者获得了广泛的基因型信息，该研究旨在确定这些家庭中动脉粥样硬化的遗传决定因素。到目前为止，我们已经从SAFES中获得了几个令人兴奋的结果。其中最重要的是检测到非常有力的证据表明前臂骨密度与4p染色体上的一个区域有连锁关系（多点引导得分= 4.3）。我们还观察到骨密度升高与糖尿病的关系，骨密度降低与颈动脉壁增厚的关系，颈动脉壁增厚是40岁及以上女性动脉粥样硬化的亚临床指标。后一种观察结果支持越来越多的证据表明骨质疏松症和心血管疾病具有共同的病因决定因素。我们建议在第二个5年资助期内重新测量骨密度，以评估骨密度的5年变化，并开始对4p染色体上影响骨密度的推测数量性状位点进行精细定位。目前正在与正在进行的SAFHS受试者重新检查一起进行重复DXA扫描。我们将评估5年骨密度变化的可持续性，并确定骨质流失的预测因素。我们将利用位置候选基因方法来追求主要的精细定位目标。我们将对连锁区域的20个基因的编码和调控区域进行测序，以确定序列变异，然后对SAFES参与者全样本中的所有常见变异进行基因型分析，以进行关联和单倍型分析。

DESCRIPTION (provided by applicant): Osteoporosis is a major cause of morbidity among older Americans. The San Antonio Family Osteoporosis Study (SAFES) initiated in 1997 with the aim of identifying the determinants of bone mineral density (BMD) in large Mexican American families. A total of 897 subjects from 34 families were enrolled in the baseline phase of this study. Extensive genotypic information was made available on these subjects through their concurrent participation in a larger study, the San Antonio Family Heart Study (SAFHS), designed to identify the genetic determinants of atherosclerosis in these families. To date, we have obtained several exciting results from the SAFES. Foremost among these was the detection of very strong evidence for linkage of fore arm BMD to a region on chromosome 4p (multipoint led score = 4.3). We also observed associations of increased BMD with diabetes and of decreased BMD with carotid wall thickening, a subclinical measure of atherosclerosis in women aged 40 yr and older. This latter observation supports a growing body of evidence suggesting that osteoporosis and CVD share common etiologic determinants. We propose in the second 5-year funding period to re-measure BMD to assess 5-yr change in BMD and to begin fine mapp ng of the putative quantitative trait locus affecting BMD on chromosome 4p. Repeat DXA scans are currently being obtained in conjunction with the ongoing re-examination of SAFHS subjects. We will estimate hedtability of 5-yr changes in BMD and determine predictors of bone loss. We will utilize a positional candidate gene approach to pursue the major fine mapping aim. We will sequence coding and regulatory regions of 20 genes in the region of linkage to identify sequence variation and will then genotype all common variants in the full sample of SAFES participants for association and haplotype analysis.