© 1999 American Heart Association, Inc.
Original Contributions |
Quantitative Trait Locus Analysis of Plasma Lipoprotein Levels in an Autoimmune Mouse Model
Interactions Between Lipoprotein Metabolism, Autoimmune Disease, and Atherogenesis
From the Departments of Medicine and Microbiology and Molecular Genetics (L.G., M.W.J., A.J.L.), the Molecular Biology Institute, and the Department of Pathology (L.G.), University of California Los Angeles, Los Angeles, California.
Correspondence to Aldons J. Lusis, Division of Cardiology, Department of Medicine, UCLA School of Medicine, 47-123 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail lusislab{at}medicine.medsch.ucla.edu
Abstract—The autoimmune
MRL/lpr mouse strain, a model for systemic lupus
erythematosus, exhibited an unusual plasma
lipoprotein profile, suggesting a possible interaction of autoimmune
disease and lipoprotein metabolism. In an effort to examine
the genetic basis of such interactions, and to study their relationship
to atherogenesis, we performed a quantitative trait locus
analysis using a total of 272 (MRL/lprxBALB/cJ)
second generation (F2) intercross mice. These mice were examined
for levels of total plasma cholesterol, HDL
cholesterol, VLDL and LDL cholesterol,
unesterified cholesterol, autoantibodies, and aortic fatty
streak lesions. Using a genome scan approach, we identified 4
quantitative trait loci controlling plasma lipoprotein levels on
chromosomes (Chrs) 5, 8, 15, and 19. The locus on Chr 15 exhibited lod
scores of 11.1 for total cholesterol and 6.7 for VLDL and
LDL cholesterol in mice fed an atherogenic diet, and it
contains a candidate gene, the sterol regulatory element binding
protein-2. The locus on Chr 5 exhibited lod scores of 3.8 for total
cholesterol and 4.1 for unesterified
cholesterol in mice fed an atherogenic diet, and this locus
has been observed in 2 previous studies. The locus on Chr 8 exhibited a
lod score of 3.1 for unesterified cholesterol in mice fed a
chow diet. This locus contains the lecithin-cholesterol
acyltransferase gene, and decreased activity of the enzyme in the MRL
strain suggests that this gene underlies the quantitative-trait locus.
The locus on Chr 19 exhibited a lod score of 8.4 for HDL
cholesterol and includes the Fas gene, which
is mutated in MRL/lpr mice and is primarily
responsible for the autoimmune phenotype in this cross. That
the Fas gene is responsible for the HDL
quantitative-trait loci is supported by the finding that autoantibody
levels were strongly correlated with HDL cholesterol levels
(
=-0.37, P<0.0001) among the F2 mice. HDL
cholesterol levels were in turn significantly associated
with aortic fatty streak lesions among the F2 mice (=-0.17,
P=0.006). Further, there was a threshold effect of
autoantibody levels on the development of fatty streak lesions
(=0.45, P=0.004 for 42 F2 mice with
anti-dsDNA Ab over 0.5 OD). Our results support the concept that the
high prevalence of coronary artery disease in systemic
lupus erythematosus is due in part to a
reduction of HDL cholesterol levels resulting from the
autoimmune disease.
Key Words: linkage analysis • antibodies, antinuclear • genes • lupus erythematosus, systemic • HDL
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