Copy Number Polymorphism and Pharmacogenomics Associated with Osteonecrosis of the Femoral Head

Osteonecrosis of the femoral head affects young active patients and is a debilitating disease if left untreated. Although its pathogenesis is still an enigma, various risk factors such as venous outflow occlusion, steroid overuse, alcohol abuse, systemic lupus erythematosus, vasculitis, radiation therapy, arterial thrombosis or embolism, Gaucher’s disease, caisson disease, and myeloproliferative disorders are suggested to be associated with it. In our previous study, we have noticed a variety of genetic polymorphisms in C677T methylenetetrahydrofolate reductase and other candidate genes associated with thrombophila or hypofibrinolysis such as 4G/5G polymorphism of the plasminogen activator inhibitor-1, prothrombin 20210 A, and apolipoprotein A1 polymorphisms in patients with osteonecrosis of the femoral head. Single nucleotide polymorphisms and copy number variations are common types of sequence variation and might involve in common, polygenic diseases in addition to the genetic polymorphism in a single gene. With identification of copy number polymorphisms in the human genome, it is believed that a better understanding of the role of genomic variations and structure will understand both the normal and disease state. More interestingly, these polymorphisms may contribute to a variety of different pharmacologic responses of individuals to the same medication such as the ABCB1 C3435T and G2677T/A polymorphism associated with the steroid-induced osteonecrosis of the femoral head. Recently, several other studies have reported a relationship between copy number variations and human diseases including autism, bipolar disorder, immunity, inflammation, rheumatoid arthritis, and schizophrenia. In this proposal, based on the previous National Science Council grant (NMRPG350131), clinical subjects of osteonecrosis of the femoral head and control subjects with detailed clinical information and laboratory data will be further analyzed using comparative genomic hybridization method for copy number variation polymorphism. We will segregate the patients into different groups and implement microarrays to confirm reciprocally with the restriction polymorphism in a 4-year period. In the first year, thrombophilia/hypofibrinolysis associated with copy number variation will be studied. In the second year, we will study methyletetrahydrofolate reductase polymorphism/hyperhomocysteinemia and lipid metabolism, lipoprotein A, apolipoprotein A1/B polymorphism associated with copy number variation. In the third year, the copy number variation profiling in antiphospholipid antibody syndrome and endothelial nitric oxide synthease gene polymorphism will specifically be analyzed. Cases with history of bisphosphonate therapy for at least 6 months will be used for pharmacogenetic studies. In the fourth year, we hope to discover potential annotated copy number variations and associated candidate genes in subjects with osteonecrosis of the femoral head. Reciprocal verification and confirmation of phenotypic, genotypic, and copy number variation polymorphisms in stratified patient groups will be carried. It is hoped the genetic polymorphism study on osteonecrosis of the femoral head will shed light on the understanding of its pathomechanism, common pathogenetic pathways for disease development or progression, individual responses to pharmacologic agent (bisphosphonate) underlying by genetic backgrounds, and its differences between different ethical groups.

Project ID:PC10001-0072
External Project ID:NSC98-2314-B182A-094-MY3