TWO CANDIDATE GENES LINKED TO LOW BONE DENSITY

描述（根据申请人的描述改编）：参数和 7个家系全基因组筛选的非参数连锁分析 提示染色体1p36区域含有易感位点 用于低骨矿物质密度（BMD）。 两个候选基因位于这个 间隔是PLOD，赖氨酰羟化酶的基因，和TNFR2， 肿瘤坏死因子α受体2。 参数分析基于 单基因遗传的模式，一个家庭，德系犹太血统， 暗示了与这段染色体间隔的联系 生化和 对赖氨酰羟化酶家族的一个成员进行了分子分析， 与I型胶原蛋白赖氨酸的过度羟基化一致， 高于正常稳态赖氨酰羟化酶mRNA水平。 非参数分析的所有独立的同胞对内的七个 家族支持该染色体区域与低BMD性状的连锁。 这项研究将缩小与连锁一致的染色体间隔， 分析附近和内部的额外的多态性标记 候选基因 赖氨酰的生化和分子特性 羟化酶将在其他家庭成员的研究，从一个 受影响的家庭，和推定的突变或变异的赖氨酰 将表征羟化酶基因。 为了在更大的人群中测试这些位点与BMD的相关性， 另外一对德系犹太血统的同胞将进行连锁试验 两个候选基因，和家庭为基础的关联研究将是 执行。 本研究将确定两个基因对 骨密度的遗传，并将提供易感性的基础 在人群中测试。

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.