TWO CANDIDATE GENES LINKED TO LOW BONE DENSITY

Drexel University, Philadelphia PA

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Abstract

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.