TWO CANDIDATE GENES LINKED TO LOW BONE DENSITY

描述(改编自申请人的描述)：参数和 七个家系全基因组筛查的非参数连锁分析 已经表明染色体区域1p36包含易感基因 用于低骨密度(BMD)。其中有两个候选基因 Interval是赖氨酸羟基酶基因plod，以及赖氨酸羟基酶基因TNFR2 肿瘤坏死因子-α受体2。参数分析基于 单基因遗传模式，一个家庭，来自德系犹太血统， 表明与这一染色体区间有关联。生化和 对该家族中一个成员的赖氨酰羟基酶进行了分子分析 与I型胶原赖氨酸过度羟化一致 高于正常稳态赖氨酸羟基酶的mRNA水平。 七个独立兄弟姐妹对的非参数分析 这些家庭支持将这一染色体区域与低骨密度特征联系起来。 这项研究将通过以下方式缩小与连锁一致的染色体间隔 邻近和内部的额外多态标记的分析 候选基因。赖氨酰的生化和分子特性 羟基酶将在更多的家庭成员中进行研究 受影响的家族，以及赖氨酸中可能的突变或变异 将对羟基酶基因进行鉴定。 为了在更大的人群中测试这些基因座与BMD的相关性， 将对更多的德系犹太人同胞对进行连锁测试 两个候选基因，以及基于家庭的关联性研究将是 已执行。这项研究将确定两个基因对人类健康的重要性 骨密度的遗传，并将提供易感性的基础 在人群中进行测试。

DESCRIPTION (Adapted from the applicant's description): Parametric and non-parametric linkage analysis of a genome-wide screen of seven families has suggested that the chromosomal region 1p36 contains susceptibility loci for low bone mineral density (BMD). Two candidate genes located within this interval are PLOD, the gene for lysyl hydroxylase, and TNFR2, the gene for tumor necrosis factor-alpha receptor 2. Parametric analysis was based on a model of monogenic inheritance, and one family, of Ashkenazi Jewish origin, had suggested linkage to this chromosomal interval. Biochemical and molecular analyses of lysyl hydroxylase in one member of this family were consistent with an over-hydroxylation of type I collagen lysines due to higher than normal steady state lysyl hydroxylase mRNA levels. Non-parametric analysis of all the independent sib pairs within the seven families supported linkage of this chromosomal region to the low BMD trait. This study will narrow the chromosomal interval consistent with linkage by analysis of additional polymorphic markers both near and within the candidate genes. The biochemical and molecular characteristics of lysyl hydroxylase will be studied in additional family members from the one affected family, and the putative mutation or variant in the lysyl hydroxylase gene will be characterized. To test the relevance of these loci to BMD in a larger population, additional sib pairs of Ashkenazi Jewish origin will be tested for linkage to the two candidate genes, and family-based association studies will be performed. This study will define the importance to two genes to the inheritance of bone density, and will provide the basis for susceptibility testing in the population.