Quantitative trait loci analysis for the differences in susceptibility to atherosclerosis and diabetes between inbred mouse strains C57BL/6J and C57BLKS/J.

Mice from the inbred strain C57BLKS/J (BKS) exhibit increased susceptibility to both diabetes and atherosclerosis compared to C57BL/6J (B6) mice. To determine whether the differences in diabetes and atherosclerosis are related, we carried out a cross between B6-db/db and BKS. We selected 99 female F2-db/db progeny, tested the progeny for plasma lipids, plasma glucose, and fatty-streak lesions, and used quantitative trait loci (QTL) analysis to identify the chromosomal regions associated with these phenotypes. No major QTL were found for total cholesterol, VLDL-cholesterol, or triglycerides. Two suggestive QTL were found for HDL-cholesterol (LOD scores of 2. 7 and 2.8), and two suggestive loci were found for plasma glucose (LOD scores of 2.3 and 2.0). Lesion size was not correlated with plasma lipid levels or glucose. Lesion size was determined by a locus at D12Mit49 with a LOD score of 2.5 and a significant likelihood ratio statistic. The gene for apolipoprotein apoB lies within the region, but apoB levels were similar in strains B6 and BKS. The QTL on Chr 12 was confirmed by constructing a congenic strain with BKS alleles in the QTL region on a B6 genetic background. We conclude that susceptibilities to diabetes and atherosclerosis are not conferred by the same genes in these strains and that a major gene on Chr 12, which we name Ath6, determines the difference in atherosclerosis susceptibility.

[1]  D. Beier,et al.  Characterization of the murine gene encoding Aop2 (antioxidant protein 2) and identification of two highly related genes. , 1998, Genomics.

[2]  A. Woods,et al.  Syndecans: synergistic activators of cell adhesion. , 1998, Trends in cell biology.

[3]  Y. Mizui,et al.  Genetic mapping of mouse tumor necrosis factor-α converting enzyme (Tace) to chromosome 12 , 1998 .

[4]  D. Levine,et al.  Automated measurement of mouse apolipoprotein B: convenient screening tool for mouse models of atherosclerosis. , 1997, Clinical chemistry.

[5]  A. Lusis,et al.  Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism. , 1997, The Journal of clinical investigation.

[6]  Nicole Nelson,et al.  A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells , 1997, Nature.

[7]  Robert V Farese,et al.  Genetic regulation of cholesterol homeostasis: chromosomal organization of candidate genes. , 1996, Journal of lipid research.

[8]  D. L. Wilson,et al.  Increased atherosclerosis in streptozotocin-induced diabetic mice. , 1996, The Journal of clinical investigation.

[9]  A. Lusis,et al.  Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach. , 1995, The Journal of clinical investigation.

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

[11]  B. Taylor,et al.  PCR-amplification of simple sequence repeat variants from pooled DNA samples for rapidly mapping new mutations of the mouse. , 1994, Genomics.

[12]  J. Naggert,et al.  Atherosclerosis in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. , 1994, Metabolism: clinical and experimental.

[13]  E S Lander,et al.  Systematic detection of errors in genetic linkage data. , 1992, Genomics.

[14]  Douglas L. Coleman.  The influence of genetic background on the expression of mutations at the diabetes (db) locus in the mouse. VI: Hepatic malic enzyme activity is associated with diabetes severity. , 1992, Metabolism: clinical and experimental.

[15]  T. Mohandas,et al.  Chromosome mapping of the murine syndecan gene. , 1991, Genomics.

[16]  B. Mccarthy,et al.  Comparative analysis of sequences at the 5' end of the human and mouse apolipoprotein B genes. , 1991, DNA and cell biology.

[17]  B. Mccarthy,et al.  Analysis of two different tandem repetitive elements within the human apolipoprotein B gene. , 1991, Journal of lipid research.

[18]  R. Williams,et al.  Quantitative assessment of atherosclerotic lesions in mice. , 1987, Atherosclerosis.

[19]  M. Daly,et al.  MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. , 1987, Genomics.

[20]  B. Paigen,et al.  Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H. , 1987, Atherosclerosis.

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

[22]  D. Coleman,et al.  Symposium IV: Diabetic syndrome in animals. Influence of genetic background on the expression of mutations at the diabetes locus in the mouse. II. Studies on background modifiers. , 1975, Israel journal of medical sciences.

[23]  P. McNamara,et al.  Morbidity and Mortality in Diabetics In the Framingham Population: Sixteen Year Follow-up Study , 1974, Diabetes.