© 1999 American Heart Association, Inc.
Original Contributions |
A Genome Search Identifies Major Quantitative Trait Loci on Human Chromosomes 3 and 4 That Influence Cholesterol Concentrations in Small LDL Particles
From the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Tex.
Correspondence to David L. Rainwater, PhD, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail david{at}darwin.sfbr.org
Abstract—Small, dense LDL
particles are associated with increased risk of
cardiovascular disease. To identify the genes that
influence LDL size variation, we performed a genome-wide screen for
cholesterol concentrations in 4 LDL size fractions. Samples
from 470 members of randomly ascertained families were typed for 331
microsatellite markers spaced at 
15 cM intervals. Plasma LDLs were
resolved by using nondenaturing gradient gel electrophoresis into 4
fraction sizes (LDL-1, 26.4 to 29.0 nm; LDL-2, 25.5 to 26.4 nm; LDL-3,
24.2 to 25.5 nm; and LDL-4, 21.0 to 24.2 nm) and
cholesterol concentrations were estimated by staining with
Sudan Black B. Linkage analyses used variance component methods
that exploited all of the genotypic and phenotypic information in the
large extended pedigrees. In multipoint linkage analyses with
quantitative trait loci for the 4 fraction sizes, only LDL-3, a
fraction containing small LDL particles, gave peak multipoint
log10 odds in favor of linkage (LOD) scores that exceeded
3.0, a nominal criterion for evidence of significant linkage. The
highest LOD scores for LDL-3 were found on chromosomes 3 (LOD=4.1), 4
(LOD=4.1), and 6 (LOD=2.9). In oligogenic analyses, the 2-locus
LOD score (for chromosomes 3 and 4) increased significantly
(P=0.0012) to 6.1, but including the third locus on
chromosome 6 did not significantly improve the LOD score
(P=0.064). Thus, we have localized 2 major quantitative
trait loci that influence variation in cholesterol
concentrations of small LDL particles. The 2 quantitative trait loci on
chromosomes 3 and 4 are located in regions that contain the genes for
apoD and the large subunit of the microsomal triglyceride
transfer protein, respectively.
Key Words: LDL size fractions • genome-wide screen • linkage analysis • Mexican Americans
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