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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1942.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Low-Density Lipoprotein Particle Size Loci in Familial Combined Hyperlipidemia

Evidence for Multiple Loci From a Genome Scan

Michael D. Badzioch; Robert P. Igo, Jr; France Gagnon; John D. Brunzell; Ronald M. Krauss; Arno G. Motulsky; Ellen M. Wijsman; Gail P. Jarvik

From the Department of Medicine, Divisions of Medical Genetics (M.D.B., R.P.I., F.G., A.G.M., E.M.W., G.P.J.) and Metabolism, Endocrinology, and Nutrition (J.D.B.), Departments of Genome Science (A.G.M., E.M.W., G.P.J.) and Biostatistics (R.P.I., E.M.W.), University of Washington, Seattle; Department of Epidemiology and Community Medicine (F.G.), University of Ottawa, Ontario, Canada; and Life Sciences Division (R.M.K.), Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley.

Correspondence to Gail Pairitz Jarvik, MD, PhD, Division of Medical Genetics, University of Washington Medical Center, Box 357720, Seattle, WA 98195-7720. E-mail pair{at}u.washington.edu

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.

We used lod score and Markov chain Monte Carlo linkage analysis to perform a genome scan of adjusted LDL size in 4 large families with familial combined hyperlipidemia. We identified significant evidence of linkage to chromosomes 9p, 16q23, and 11q22 and confirmatory evidence for 14q24-31. LDL size is influenced by multiple loci.

Key Words: LDL size • linkage scan • familial combined hyperlipidemia

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