Low-density lipoprotein particle size loci in familial combined hyperlipidemia - Evidence for multiple loci from a genome scan

Objective - Low-density lipoprotein (LDL) size is associated with vascular disease and with familial combined hyperlipidemia (FCHL). Methods and Results - We used logarithm of odds (lod) score and Bayesian Markov chain Monte Carlo (MCMC) linkage analysis methods to perform a 10-cM genome scan of LDL size, measured as peak particle diameter (PPD) and adjusted for age, sex, body mass index, and triglycerides in 4 large families with FCHL (n = 185). We identified significant evidence of linkage to a chromosome 9p locus (multipoint lod(max) = 3.70; MCMC intensity ratio [ IR] = 21) in a single family, and across all 4 families to chromosomes 16q23 (lod(max) = 3.00; IR = 43) near cholesteryl ester transfer protein (CETP) and to 11q22 (lod(max) = 3.71; IR = 120). Chromosome 14q24-31, a region with previous suggestive LDL PPD linkage evidence, yielded an IR of 71 but an lod(max) =1.79 in the combined families. Conclusions - These results of significant evidence of linkage to 3 regions (9p, 16q, and 11q) and confirmatory support of previous reported linkage to 14q in large FCHL pedigrees demonstrate that LDL size is a trait influenced by multiple loci and illustrate the complementary use of lod score and MCMC methods in analysis of a complex trait.