on October 28, 2004
Published online before print October 28, 2004, doi: 10.1161/01.ATV.0000149146.32385.1b
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Submitted on August 31, 2004
Accepted on October 19, 2004
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
Sara Bretschger Seidelmann ;
From the Division of Molecular Medicine (S.B.S., A.R.T., C.L.W.), the Department of Medicine, Institute of Human Nutrition (S.B.S., C.D.L., R.L.L., A.R.T.), and the Division of Molecular Genetics (C.D.L., R.L.L.), Department of Pediatrics, Columbia University, New York; and the Laboratory of Biochemical Genetics and Metabolism (J.L.B.), The Rockefeller University, New York, NY.
* To whom correspondence should be addressed. E-mail: cbw13{at}columbia.edu.
Objective--The purpose of this study was to examine genetic factors responsible for metabolic syndrome and atherosclerosis in a setting of low-density lipoprotein (LDL) receptor deficiency in a cross between C57BL/6J (B6) and PERA/Ei (PERA) inbred mouse strains.
Methods and Results--Comparison of metabolic phenotypes in B6 and PERA strains revealed the PERA genetic background to be dramatically more susceptible to hyperleptinemia, hyperglycemia, hypertriglyceridemia, elevated insulin levels, and body fat increase than the B6 background. To facilitate genetic analysis, metabolic syndrome-related traits and atherosclerotic lesion area were measured in 167 [(PERAxB6.129S7-Ldlrtm1Her)xB6.129S7-Ldlrtm1Her]N2 male and female backcross mice that were homozygous for the Ldlr null allele. Quantitative trait locus analysis was performed using 153 polymorphic microsatellite markers spanning the genome. On chromosome 4, we identified a locus influencing plasma triglyceride, insulin, and leptin concentrations, body weight, and atherosclerosis. Several other genetic loci were identified with separate effects on plasma insulin, body weight, high-density lipoprotein cholesterol, and atherosclerosis.
Conclusions--The PERA strain is highly susceptible to the development of metabolic syndrome after feeding a Western-type diet. This susceptibility is due, in part, to a locus on murine chromosome 4 in which PERA alleles predispose to adiposity, increased insulin, and accelerated atherogenesis in the absence of marked hyperlipidemia.
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