The overall goal is to understand the genetic basis of, and identify quantitative trait loci for, risk factorsforcardiovascular disease including LDL density, HDL level, and apoB level, as well as PLTP activity, in familieswith familial combined hyperlipidemia (FCHL). FCHL is the most common lipid disorder leading to prematurevascular disease. Small dense LDL, depressed HDL level, and elevated apoB level are importantatherogenic components of the phenotype of FCHL. PLTP activity is an important covariate. Use of fourlarge FCHL families will increase sample homogeneity and joint consideration of covariates, includingplasma lipoprotein transfer protein activity, will improve power to detect linkage for these loci. Theseinvestigations consider large families with FCHL and evidence of Mendelian segregation of each trait, forwhom a 10 cM genomic scan has already been completed, allowing efficient mapping studies of theseatherogenic FCHL-related phenotypes. Three loci with significant evidence of linkage were identified foradjusted LDL size (peak particle diameter), using both Iod score and newer Markov chain Monte Carlo(MCMC) methods in analyses of both each family separately and the families combined. Usng thesemethods for complex traits is expected to result in detection of significant linkage evidence for HDL andapoB level. These will be followed by fine mapping and efforts to identify the underlying genes, beginningwith LDL size/density traits. Mapping followed by identification of previously undetected genes for these traitswill advance both the basic biology of lipid disorders and the potential to diagnose, prevent, and treatvascular disease.
Showing the most recent 10 out of 485 publications
