GENETICS OF SEX EFFECTS ON BONE DENSITY AND TURNOVER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。骨质疏松症和相关的骨骼脆弱性是最重要的公共卫生问题，影响1010万人，其中77%是妇女。我们迫切需要了解产生这种复杂表型和性别差异的生物学机制。低骨量是骨质疏松易感性最可靠的指标，是基因和环境复杂相互作用的结果。面骨矿物质密度（aBMD）提供了当前骨量的测量，而骨转换的血清测量反映了个体在任何时间发生的骨形成和吸收的程度。aBMD和骨转换生化指标，单独或联合使用，是骨折风险的有效预测指标。研究一致表明，这些表型有很强的遗传影响。识别导致这些影响的基因所在的染色体区域，并了解相关的基因型-环境（GxE）相互作用，对于确定可能从早期干预中获益最多的骨折高危个体的方案至关重要。本研究的总体目的是检测和表征基因型与性别、年龄和生殖史之间的相互作用对纯种狒狒骨密度和骨转换的影响。数据包括骨密度测量、骨转换血清标志物、临床和生殖史、331个高度多态性微卫星标记位点的基因型和狒狒全基因组连锁图谱。本研究的具体目的是：1)检测和表征性别、年龄和女性生殖史变量对区域骨密度表型变异和血清骨转换测量的影响；2)量化性别基因型、年龄基因型和生殖史基因型变量相互作用对aBMD正常定量变异和骨转换血清测量的影响；3)(a)评估先前定位于这些狒狒的骨相关定量性状位点（qtl）对检测到的GxE相互作用的影响；(b)进行全基因组连锁筛选，定位检测到GxE效应的新qtl。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Osteoporosis and associated skeletal fragility are paramount public health concerns, affecting 10.1 million individuals, 77% of whom are women. The need to understand the biological mechanisms producing this complex phenotype and this sex difference is immediate. Low bone mass, the most reliable indicator of osteoporosis susceptibility, results from complex interactions between genes and environment. Areal bone mineral density (aBMD) provides a measure of current skeletal mass, while serum measures of bone turnover reflect the degree of bone formation and resorption occurring in an individual at any one time. aBMD and biochemical markers of bone turnover, used alone and together, are effective predictors of fracture risk. Studies consistently show strong genetic effects on these phenotypes. Identifying chromosomal regions harboring genes responsible for these effects, and understanding relevant genotype-by-environment (GxE) interactions are essential for the development of protocols to identify individuals at greatest risk for fracture who might benefit most from early intervention. The overall aim of this research is to detect and characterize effects of interactions between genotype and ¿sex, -age, and ¿reproductive history on BMD and bone turnover in pedigreed of baboons. Data include measures of BMD, serum markers of bone turnover, clinical and reproductive histories, genotypes at 331 highly polymorphic microsatellite marker loci, and a baboon whole genome linkage map. The specific aims of this research are to: 1) detect and characterize the effects of sex, age, and female reproductive history variables on the phenotypic variance in area BMD and serum measures of bone turnover; 2) Quantify the effects of genotype-by-sex, genotype-by-age, and genotype-by-reproductive history variable interactions on normal quantitative variation n aBMD and serum measures of bone turnover, and 3) (a) assess the effects of bone-related quantitative trait loci (QTLs), previously localized in these baboons, on detected GxE interactions and (b) conduct whole genome linkage screens to localize new QTLs responsible for detected GxE effects.