Genetic Studies Of Osteogenesis Imperfecta Type Ⅰ And Two Candidate Genes Of Osteoporosis

Genetic diseases mainly consisting of monogenic disorders and complex disorders constitute the major risk for people's health, and are becoming the focus in biomedical research. Osteogenesis imperfecta (01) is a typical monogenic disorder related to bone tissue. Seven different types have been described, in which OI type I (OI I) is the most common form of OI. Numerous studies have suggested that ethnic, genetic and molecular heterogeneity exist within OI I. The disease in Caucasian OI I patients is mostly caused by COLlAl mutations, while in African black OI I cases is mainly related to COL1A2 defects. But till present, no comprehensive molecular genetic studies have been performed in Chinese OI I patients. Osteoporosis is a widely and seriously influenced complex disorder related to bone tissue. Low bone mineral density (BMD) is recognized as a major risk factor of osteoporosis. Hitherto, a number of studies have been conducted on relationship of many candidate genes of osteoporosis with BMD, yielded conflicting results. The purpose of this study is: 1) to investigate if mutations of the type I collagen loci COLlAl and COL1A2 are responsible for OI I in Chinese pedigrees/patients; 2) to study if two important candidate genes of osteoporosis, i.e., ostecalcin (BGP) gene and insulin-like growth factor-I (IGF-1) gene, are quantitative trait loci (QTLs) of BMD variation in Chinese population. This study recruited 8 OI I pedigrees (including a very large OI I kindred comprising 132 members, in which 43 are patients) and 402 nuclear families of health subjects (consisting of 1,263 subjects, and each familycontains at least one female offspring aged 20-45) in Chinese Han population. 1) By performing linkage analysis in the large OII kindred to the COLlAl and COL1A2 genes. Negative LOD score of-8.50 at 9 = 0.001 was observed for the COL1A2 gene, while positive LOD score of 2.31 at 0 = 0.001 was found for the COLlAl gene. However, followed mutation screening the COLlAl gene in the proband of this large OI I kindred via denaturing high performance liquid chromatography (DHPLC) and direct sequencing didn't reveal any pathologic mutations in the COL1Al gene. Moreover, the extended mutation analysis of the COL1Al gene in probands of the seven other OI I pedigrees identified no pathologic mutation either. 2) By employing quantitative transmission disequilibrium test (QTDT), association and linkage of a Hindlll polymorphism in the BGP gene and a CA repeat polymorphism in the IGF-1 gene with BMD variation were simultaneously tested, no significant results were found. This study suggests that 1) mutations in the type I collagen loci COLlAl and COL1A2 may not be responsible for OI I in Chinese pedigrees/patients, and the actual genetic basis of OI I in Chinese pedigrees/patients remains to be elucidated; 2) No evidence is supported that the BGP gene and the IGF-1 gene as QTLs underlying BMD variation in Chinese pre-menopausal women.