© 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
This article has been cited by other articles:
 |
|
 |
|
  A. J. Wilhelm, M. Zabalawi, J. M. Grayson, A. E. Weant, A. S. Major, J. Owen, M. Bharadwaj, R. Walzem, L. Chan, K. Oka, et al. Apolipoprotein A-I and Its Role in Lymphocyte Cholesterol Homeostasis and Autoimmunity Arterioscler. Thromb. Vasc. Biol., June 1, 2009; 29(6): 843 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. U. Eriksson and R. R. Singh Cutting Edge: Migration of Langerhans Dendritic Cells Is Impaired in Autoimmune Dermatitis J. Immunol., December 1, 2008; 181(11): 7468 - 7472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Burgess-Herbert, A. Cox, S.-W. Tsaih, and B. Paigen Practical Applications of the Bioinformatics Toolbox for Narrowing Quantitative Trait Loci Genetics, December 1, 2008; 180(4): 2227 - 2235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. M. Stylianou, S. R. Langley, K. Walsh, Y. Chen, C. Revenu, and B. Paigen Differences in DBA/1J and DBA/2J reveal lipid QTL genes J. Lipid Res., November 1, 2008; 49(11): 2402 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. A. Moen, A. P. Tholens, P. J. Voshol, W. de Haan, L. M. Havekes, P. Gargalovic, A. J. Lusis, K. W. van Dyk, R. R. Frants, M. H. Hofker, et al. The Hyplip2 locus causes hypertriglyceridemia by decreased clearance of triglycerides J. Lipid Res., October 1, 2007; 48(10): 2182 - 2192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Wergedal, C. L. Ackert-Bicknell, W. G. Beamer, S. Mohan, D. J. Baylink, and A. K. Srivastava Mapping genetic loci that regulate lipid levels in a NZB/B1NJxRF/J intercross and a combined intercross involving NZB/B1NJ, RF/J, MRL/MpJ, and SJL/J mouse strains J. Lipid Res., August 1, 2007; 48(8): 1724 - 1734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wittenburg, M. A. Lyons, R. Li, U. Kurtz, X. Wang, J. Mossner, G. A. Churchill, M. C. Carey, and B. Paigen QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains, J. Lipid Res., August 1, 2006; 47(8): 1780 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Stanic, C. M. Stein, A. C. Morgan, S. Fazio, M. F. Linton, E. K. Wakeland, N. J. Olsen, and A. S. Major Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus PNAS, May 2, 2006; 103(18): 7018 - 7023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Su, Y. Li, J. C. James, M. McDuffie, A. H. Matsumoto, G. A. Helm, J. L. Weber, A. J. Lusis, and W. Shi Quantitative Trait Locus Analysis of Atherosclerosis in an Intercross Between C57BL/6 and C3H Mice Carrying the Mutant Apolipoprotein E Gene Genetics, March 1, 2006; 172(3): 1799 - 1807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Srivastava, S. Mohan, G. L. Masinde, H. Yu, and D. J. Baylink Identification of quantitative trait loci that regulate obesity and serum lipid levels in MRL/MpJ x SJL/J inbred mice J. Lipid Res., January 1, 2006; 47(1): 123 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Asahina, M. Sato, and K. Imaizumi Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats J. Lipid Res., October 1, 2005; 46(10): 2289 - 2294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Q. Nhan, W. C. Liles, and S. M. Schwartz Role of Caspases in Death and Survival of the Plaque Macrophage Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 895 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, P. Gargalovic, J. Wong, J. L. Gu, X. Wu, H. Qi, P. Wen, L. Xi, B. Tan, R. Gogliotti, et al. Hyplip2, a New Gene for Combined Hyperlipidemia and Increased Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1928 - 1934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, R. Korstanje, D. Higgins, and B. Paigen Haplotype Analysis in Multiple Crosses to Identify a QTL Gene Genome Res., September 1, 2004; 14(9): 1767 - 1772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Korstanje, R. Li, T. Howard, P. Kelmenson, J. Marshall, B. Paigen, and G. Churchill Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population J. Lipid Res., May 1, 2004; 45(5): 881 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Welch, S. Bretschger, P.-Z. Wen, M. Mehrabian, N. Latib, J. Fruchart-Najib, J. C. Fruchart, C. Myrick, and A. J. Lusis Novel QTLs for HDL levels identified in mice by controlling for Apoa2 allelic effects: confirmation of a chromosome 6 locus in a congenic strain Physiol Genomics, March 12, 2004; 17(1): 48 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L.M. Herrera, T. Didishvili, L. V. Lopez, R. H. Myers, and N. Ruiz-Opazo Genome-Wide Scan Identifies Novel QTLs for Cholesterol and LDL Levels in F2[Dahl RxS]-Intercross Rats Circ. Res., March 5, 2004; 94(4): 446 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C.M. Bonne, M. G. den Bieman, G. F. Gillissen, A. Lankhorst, C. J. Kenyon, B. F.M. van Zutphen, and H. A. van Lith Quantitative Trait Loci Influencing Blood and Liver Cholesterol Concentration in Rats Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2072 - 2079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang and B. Paigen Quantitative Trait Loci and Candidate Genes Regulating HDL Cholesterol: A Murine Chromosome Map Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): 1390 - 1401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. Pitman, R. Korstanje, G. A. Churchill, E. Nicodeme, J. J. Albers, M. C. Cheung, M. A. Staton, S. S. Sampson, S. Harris, and B. Paigen Quantitative trait locus mapping of genes that regulate HDL cholesterol in SM/J and NZB/B1NJ inbred mice Physiol Genomics, May 10, 2002; 9(2): 93 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mehrabian, L. W. Castellani, P.-Z. Wen, J. Wong, T. Rithaporn, S. Y. Hama, G. P. Hough, D. Johnson, J. J. Albers, G. A. Mottino, et al. Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei C57BL/6J) J. Lipid Res., December 1, 2000; 41(12): 1936 - 1946. [Abstract] [Full Text]
|
|
|
|
|
|
N. Kato, T. Tamada, T. Nabika, K. Ueno, T. Gotoda, C. Matsumoto, T. Mashimo, M. Sawamura, K. Ikeda, Y. Nara, et al. Identification of Quantitative Trait Loci for Serum Cholesterol Levels in Stroke-Prone Spontaneously Hypertensive Rats Arterioscler. Thromb. Vasc. Biol., January 1, 2000; 20(1): 223 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Singaraja, V. Bocher, E. R. James, S. M. Clee, L.-H. Zhang, B. R. Leavitt, B. Tan, A. Brooks-Wilson, A. Kwok, N. Bissada, et al. Human ABCA1 BAC Transgenic Mice Show Increased High Density Lipoprotein Cholesterol and ApoAI-dependent Efflux Stimulated by an Internal Promoter Containing Liver X Receptor Response Elements in Intron 1 J. Biol. Chem., August 31, 2001; 276(36): 33969 - 33979. [Abstract] [Full Text] [PDF]
|
|