The overall goal of this project is to identify genes that contribute to cardiovascular disease (CVD) by investigating subclinical atherosclerosis within diabetes-affected families in the Diabetes Heart Study (DHS), a population at an increased risk of developing CVD. Identification of the genes that contribute to subclinical atherosclerosis phenotypes such as coronary artery and carotid artery calcified plaque (CorCP and CarCP), abdominal aortic calcified plaque (AACP) and carotid artery intima-media wall thickness (IMT), will further the understanding of the pathogenesis of cardiovascular diseases. We have conducted genome scans for each of these vascular calcification phenotypes using affected sibling pairs from the DHS. We detected a linkage peak for CarCP on chromosome 16p13.13-p13.3 with a LOD score of 3.82 in European American diabetics. Our goal is to use fine mapping followed by positional cloning to identify variants in genes that contribute to CarCP susceptibility in the European American diabetic population. We will further analyze the existing data by including additional covariate adjustments, and exploring pleiotropy and gene by environment interactions. The region of linkage will be refined by genotyping additional single nucleotide polymorphisms (SNPs), and the construction of a dense SNP map within the refined region will aid in the identification of haplotypes associated with the CarCP phenotype. A focused evaluation of candidate genes encompassed by these haplotypes will aid in the identification of specific alleles responsible for CarCP susceptibility. ? ? ?
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