Segregation, linkage and associations studies of small dense LDL particles

"Small dense LDL particles" are associated with elevated triglycerides and decreased HDL cholesterol concentrations. These particles, which are common in the general population with a prevalence of at least 30%, are associated with an several-fold increased risk for cardiovascular complications. There are several lines of evidence that the LDL particle size is genetically controlled. The mode of inheritance, however, as well as the genes responsible remain to be definitely established. First linkage analyses described contrasting results concerning the LDL receptor locus. One study found evidence for linkage of manganese superoxide dismutase locus on chromosome 6 and cholesteryl ester transfer protein (CETP) locus on chromosome 16 and a tentative evidence for linkage with the AI-CIII-AIV locus on chromosome 11. However, confirmation of linkage is mandatory. The proposed project will by to map the chromosomal location(s) of gene(s) controlling the LDL subclass phenotypes. We will investigate a sample of 17 well-characterized families including 506 members already recruited at the Department of Cardiovascular Genetics, Salt Lake City, USA. After determining the mode of inheritance by segregation analysis, we will perform linkage analysis by a candidate gene approach investigating 14 loci which have a priori some relevance for the phenotype. These loci are the LDL receptor and the insulin receptor, the manganese superoxide dismutase locus and the CETP locus, the AI-CIII-AIV complex as well as the apoB locus. Further candidate genes, which never were investigated before, will be genes for the VLDL receptor, the hepatic triglyceride lipase (HTGL), the lipoprotein lipase (LPL), the lecithin:cholesterol acyltransferase (LCAT), the microsomal triglycende transfer protein (MTP), apoE, apoCI and apoCII. If new candidate genes become of potential interest during next time they will be included in the analysis. Different and the newest methods of analysis will be used for these investigations. Once the chromosomal position is determined by linkage, an association between the linked markers and the small, dense LDL phenoytpe will be investigated by association studies.