Genetics of Bone and Vascular Calcium in Type 2 Diabetes

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DESCRIPTION (provided by applicant): The broad long-term objectives are to improve health and reduce deaths in people from osteoporosis, CVD and type 2 diabetes. The specific aims are focused on the genetic and environmental factors that contribute to vascular calcification (VC) and bone mineralization (BM) in type 2 diabetic families. The health relatedness is that cardiovascular disease (CVD) is the number one cause of death in the U.S. and the risk of CVD is significantly increased in individuals with type 2 diabetes. Osteoporosis is present in 10 million citizens with another 18 million estimated to have low bone mass. This is an ancillary proposal to the "Genetic Epidemiology of Subclinical CVD in Type 2 Diabetes" (HL67348) also know as the "Diabetes Heart Study" or DHS. DHS uses a family study design and quantitative measurement of CVD phenotypes to locate and identify genes contributing to subclinical atherosclerosis in sibling pairs concordant for type 2 diabetes. The impact of lifestyle and environment on gene expression for subclinical disease as measured by BM and VC will be determined. In this proposal, measures of bone mineralization and aortic VC will be added to our existing array of CVD phenotypes, which include vascular calcium (VC) of the coronary and carotid arteries. We will use the additional quantitative measures of BM (QCT, DXA, QUS & Biomarkers) to understand the genetic relation between BM, VC, CVD, osteoporosis and type 2 diabetes. The Specific Aims are: 1) Measure and describe BM & VC in a high-risk population for CVD, families with sibling pairs concordant for type 2 diabetes and unaffected family members. 2) Measure the strength of association between vascular calcium and bone mineralization - further characterize the association by presence or absence of type 2 diabetes, ethnicity, and gender. 3) Estimate the familial aggregation and heritability of BM & VC in the Diabetes Heart Study families.4) Investigate if candidate gene polymorphisms, previously identified for BM & VC, are associated with the primary phenotypes measured in DHS. 5) Identify specific chromosomal regions containing quantitative trait loci (QTLs), which influence BM &VC, using the genome-wide screen. 6) Perform fine mapping, conduct association and haplotype analyses, and identify novel candidate genes for chromosomal regions with strong evidence for linkage to the primary phenotypes, BM, VC and CVD. An established and active multidisciplinary team of investigators using advanced methods of phenotype quantification, molecular genetics, and genetic epidemiology will conduct this research.