Atherosclerosis quantitative trait loci are sex- and lineage-dependent in an intercross of C57BL/6 and FVB/N low-density lipoprotein receptor-/- mice.

Atherosclerosis is a complex disease that is affected by environmental as well as genetic factors. The aim of the present study was to identify loci of atherosclerosis susceptibility in a cross of atherosclerosis-susceptible C57BL/6 and atherosclerosis-resistant FVB/N mice on the low-density lipoprotein (LDL) receptor (LDLR)-deficient background (LDLR(-/-)) and to test whether these loci are affected by lineage. A total of 459 F(2)s were generated in two ways: In cross "mB6xfFVB," male B6.LDLR(-/-) mice were crossed to female FVB.LDLR(-/-) mice to generate 107 female and 112 male F(2)s. In cross "mFVBxfB6," male FVB.LDLR(-/-) mice were crossed to female B6.LDLR(-/-) mice to generate 120 female and 120 male F(2)s. Animals were phenotyped for cross-sectional atherosclerotic lesion area at the aortic root, and a genome scan was carried out with 192 microsatellite markers. Quantitative trait locus mapping revealed significant loci of atherosclerosis susceptibility on chromosomes 3, 10, and 12. On chromosome 10 maximal logarithm of odds (LOD) scores of 13.1 (D10Mit16, 16 cM) and 5.7 (D10Mit168, 9 cM) were found in female and male mice, respectively. On chromosome 3, a maximal LOD score of 5.1 (D3Mit45, 79 cM) was detected only in females. On proximal chromosome 12 significant LOD scores were lineage-dependent, with maximal LOD scores of 3.9 (D12Mit82, 3 cM) and 4.8 (D12Mit189, 24 cM) present only in female mice of cross mB6xfFVB and male mice of cross mFVBxfB6, respectively. We conclude that, in this intercross, loci of atherosclerosis susceptibility are in part sex- and lineage-dependent. Awareness of these complexities may have major consequences for the identification of atherosclerosis susceptibility genes by quantitative trait locus mapping.

[1]  D. Teupser,et al.  Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Teupser,et al.  Low atherosclerotic response of a strain of rabbits to diet-induced hypercholesterolemia. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[3]  A. Tall,et al.  Quantitative Trait Locus Mapping of Genetic Modifiers of Metabolic Syndrome and Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice: Identification of a Locus for Metabolic Syndrome and Increased Atherosclerosis on Chromosome 4 , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[4]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[5]  Jason L Johnson,et al.  Characteristics of Intact and Ruptured Atherosclerotic Plaques in Brachiocephalic Arteries of Apolipoprotein E Knockout Mice , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[6]  P. Pajukanta,et al.  Genetics of atherosclerosis. , 2004, Annual review of genomics and human genetics.

[7]  G. Churchill,et al.  Lineage is an Epigenetic Modifier of QTL Influencing Behavioral Coping with Stress , 2005, Behavior genetics.

[8]  R. Hammer,et al.  Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. , 1993, The Journal of clinical investigation.

[9]  A. Roberts,et al.  Genetic factors in the development of atheroma and on serum total cholesterol levels in inbred mice and their hybrids. , 1977, Progress in biochemical pharmacology.

[10]  W. Reik,et al.  Epigenetic reprogramming in mammals. , 2005, Human molecular genetics.

[11]  A. Tall,et al.  Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6 using the Ldlr knockout mouse model , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Wolf,et al.  Genetic and Environmental Contributions to Atherosclerosis Phenotypes in Men and Women: Heritability of Carotid Intima-Media Thickness in the Framingham Heart Study , 2003, Stroke.

[13]  N. Maeda,et al.  Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. , 1992, Science.

[14]  K. Manly,et al.  Map Manager QTX, cross-platform software for genetic mapping , 2001, Mammalian Genome.

[15]  A. Ghazalpour,et al.  Using Mice to Dissect Genetic Factors in Atherosclerosis , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[16]  G. Churchill,et al.  Sex- and lineage-specific inheritance of depression-like behavior in the rat , 2004, Mammalian Genome.

[17]  A. Lusis,et al.  Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[18]  B. Paigen,et al.  Fine mapping of Ath6, a quantitative trait locus for atherosclerosis in mice , 2001, Mammalian Genome.

[19]  A. Lusis,et al.  Genetic Locus in Mice That Blocks Development of Atherosclerosis Despite Extreme Hyperlipidemia , 2001, Circulation research.

[20]  D. Teupser,et al.  Induction of Atherosclerosis by Low-Fat, Semisynthetic Diets in LDL Receptor–Deficient C57BL/6J and FVB/NJ Mice: Comparison of Lesions of the Aortic Root, Brachiocephalic Artery, and Whole Aorta (En Face Measurement) , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[21]  J. Carpten,et al.  Modulation of non-templated nucleotide addition by Taq DNA polymerase: primer modifications that facilitate genotyping. , 1996, BioTechniques.

[22]  Gary A. Churchill,et al.  Quantitative Trait Loci Analysis for Plasma HDL-Cholesterol Concentrations and Atherosclerosis Susceptibility Between Inbred Mouse Strains C57BL/6J and 129S1/SvImJ , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[23]  E. Schadt,et al.  Genetic loci for diet-induced atherosclerotic lesions and plasma lipids in mice , 2003, Mammalian Genome.

[24]  E. Skamene,et al.  ATH-3, a new gene for atherosclerosis in the mouse. , 1989, Clinical and investigative medicine. Medecine clinique et experimentale.

[25]  Jae Hyun Kim,et al.  Quantitative trait loci analysis for the differences in susceptibility to atherosclerosis and diabetes between inbred mouse strains C57BL/6J and C57BLKS/J. , 1999, Journal of lipid research.

[26]  B. Paigen,et al.  Variation in susceptibility to atherosclerosis among inbred strains of mice. , 1985, Atherosclerosis.

[27]  A. Yashin,et al.  Heritability of death from coronary heart disease: a 36‐year follow‐up of 20 966 Swedish twins , 2002, Journal of internal medicine.

[28]  B. Paigen.  Genetics of responsiveness to high-fat and high-cholesterol diets in the mouse. , 1995, The American journal of clinical nutrition.

[29]  G. Fonarow,et al.  Genetic Basis of Atherosclerosis: Part I: New Genes and Pathways , 2004, Circulation.

[30]  J. Breslow.  Genetic markers for coronary heart disease , 2001, Clinical cardiology.

[31]  G. Duyk,et al.  A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse. , 2002, Genetics.

[32]  P. Yancey,et al.  Cholesterol efflux is defective in macrophages from atherosclerosis-susceptible White Carneau pigeons relative to resistant show racer pigeons. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[33]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[34]  S. Heath,et al.  Genetic background determines the extent of atherosclerosis in ApoE-deficient mice. , 1999, Arteriosclerosis, thrombosis, and vascular biology.