Low-Density Lipoprotein Particle Size Loci in Familial Combined Hyperlipidemia

Abstract

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.