There is growing evidence of a link between osteoporosis and atherosclerosis. Recent studies document that bone mineral density (BMD) is inversely correlated with severity of aortic and coronary artery calcification, markers of atherosclerosis. Several common pathways have been proposed to link these two disorders. The overall objective of this project is to evaluate the relationship between BMD and coronary artery and aortic calcification, measured by Electron Beam CT, in 700 members of a large Amish pedigrees already participating in the Amish Family Osteoporosis Study (AFOS). By focusing on families, we can tease out the respective contributions of genetic and non-genetic factors to this clustering of traits. The AFOS was initiated in 1997 to identify genes influencing susceptibility to osteoporosis in families ascertained for fracture risk. Through NIH funding available to the AFOS parent study, we will genotype 391 highly polymorphic short tandem repeat (STR) markers spaced at approximately 10 cM intervals and perform a genome-wide scan to detect quantitative trait loci (QTLs) associated with variation in BMD and related traits. The Old Order Amish are ideal for the funded and proposed studies since they are a closed founder population who are relatively genetically homogeneous, have very large family sizes, and well-documented genealogies. The study proposed here will use the available measures of BMD, related traits, and genotypes in the AFOS along with the newly collected measures of vascular calcification. This study, a natural extension of the AFOS, brings together a strong interdisciplinary team of researchers with a substantial track record in both cardiovascular disease and osteoporosis and expertise in epidemiology, statistical genetics, and molecular genetics. The specific goals proposed are to determine if BMD is correlated with coronary artery and aortic calcification CAC and, if so, to determine the contribution of common genes or shared environments to this association in families. We will next assess genetic heritability and non-genetic contributions to variability in vascular calcification determinants of CAC in these families. We will assess the individual and joint contributions of lipid oxidation to BMD and vascular calcification CAC. Using the extensive genotyping that will be available, we will perform a genome wide scan of coronary artery and aortic calcification CAC. These results will complement the similar analyses obtained on the bone-related phenotypes. Finally, we will determine if chromosomal regions linked to variation in BMD are also linked to variation in vascular calcification or to another possible joint determinant such as CAC (or to lipid oxidation). These studies will provide insights into joint determinants osteoporosis and atherosclerosis. Such insights could lead to elucidation of specific genetic pathways that can be exploited in the future for early identification of high-risk individuals, as well as development of new preventive and therapeutic approaches.
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