Identification of Osteoporosis Susceptibility Gene in Calcium Signaling Pathway -Second and Third Years

Osteoporosis is among the most common and costly diseases and is increasing in prevalence owing to the ageing of our global population. Clinically defined largely through bone mineral density, osteoporosis and osteoporotic fractures have reasonably high heritabilities, prompting much effort to identify the genetic determinants of this disease. Recently, several groups conducted genome-wide association studies and identified many loci associated with susceptibility to osteoporosis mainly in Caucasian; however, the genetic contribution to osteoporosis is not entirely known. To uncover additional susceptibility gene(s) for osteoporosis, we will perform a genetic association study in a Taiwanese population. The polymorphisms of ITPKC signaling pathway will be genotyped completely. ITPKC is an upstream gene of Orai1 which can initiate the process of calcium signaling as well as inflammation. Thus, we propose to study the relationship between genetic polymorphisms of ITPKC-mediated calcium signaling and osteoporosis. Two specific aims will be tested: (1) To determine the association between the polymorphisms of ITPKC signaling pathways and the risk of osteoporosis, (2) To test the interaction between the genes’ polymorphisms and the development/pathogenesis of osteoporosis. In this study, we will recruit 1000 cases and 1000 controls (without osteoporosis) in the Taipei Medical University Hospital and Wan-Feng Hospital. ITPKC signaling pathways include major genes. They are ITPKC, P2X, P2Y, STIM, ORAI, TRPC, SYK, and interleukins. The tagging Single nucleotide polymorphisms (tSNPs) of each gene will be selected from the three major genomics database: NCBI, UCSC, and Ensembl. We will primarily select tagging SNPs, non-synonymous SNPs, SNPs located in conserved regions and the common SNP (frequency ≥ 10%). Genotyping will be done at the department of pharmacy, Taipei Medical University (TMU) by using the TaqMan SNP genotyping technique, RFLP or Invader assay. All these methods can be performed at the ABI 7500 and 7900 platforms. Statistical Analyses include Hardy Weinberg equilibrium test and linkage disequilibrium calculation. Genetic polymorphisms in collagen type 1, Vitamin D receptor, Estrogen receptor and tumor necrosis factor will be tested for validation. We expect to obtain the relationships between SNPs and osteoporosis. The results may be applied to preventive medicine and intervention to reduce the risk of osteoporosis in a Taiwanese population.