Quantitative Trait Locus Mapping of Genetic Modifiers of Metabolic Syndrome and Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Abstract

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 [(PERAϫB6.129S7-Ldlr tm1Her )ϫB6.129S7-Ldlr tm1Her ]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. Key Words: quantitative trait loci Ⅲ metabolic syndrome Ⅲ atherosclerosis T he metabolic syndrome, also known as syndrome X, was reintroduced by Reaven in the late 1980s to describe the clustering of cardiovascular risk factors, including insulin resistance, impaired glucose tolerance, high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations, obesity, and hypertension. 1 With increasing prevalence of obesity in the US, the metabolic syndrome poses a major public health threat now affecting 22% of the adult population. 2 Atherosclerotic cardiovascular disease is a major clinical complication of the metabolic syndrome; patients with the syndrome have at least a 2-fold increase in risk for atherosclerosis compared with controls. 3 However, the mechanism(s) for the association between metabolic risk factors and atherogenesis are poorly understood. Several studies have attempted to map and identify genetic factors contributing to metabolic syndrome in humans, 4 -7 but these have met with limited success. Because of the inherent difficulties in carrying out linkage analysis in humans, many geneticists have successfully turned to animal models.Wild-type mice are resistant to atherosclerosis, developing only very small lesions when fed a diet high in fat and cholic acid. 8 Genetically-engineered models, such as the lowdensity lipoprotein receptor knock-out (Ldlr Ϫ/Ϫ ) and apolipoprotein E knock-out (apoE Ϫ/Ϫ ) mouse strains, develop larger, more complex lesions with structural ...

Quantitative Trait Loci Affecting Atherosclerosis at the Aortic Root Identified in an Intercross between DBA2J and 129S6 Apolipoprotein E-Null Mice

“…At this locus DBA and 129 show additive effects. This QTL also appears to be distinct from any of QTL previously mapped on mouse Chr 2: Athla1 [18], Ath28 [6], Ath39 [19] and Ath41 [8]. We name this novel QTL locus Ath45 .…”

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

“…The expression pattern of Hpx is similar between the two strains, however it is possible that these polymorphisms contribute to the observed difference in expression magnitude (Figure 1c). HPX also falls in two other independently mapped and overlapping QTL associated with variation in serum lipids in mice: Chldq4 identified in a MRL/MpJ × SJL/J cross (29), and Hdlcl1 identified in a C57BL/6J × PERA/EiJ cross (30). HPX is associated with triglycerides (31) in human subjects with diabetes, and with cholesterol in human subjects with coronary artery disease (15).…”

Genetic Analysis of Atherosclerosis and Glucose Homeostasis in an Intercross Between C57BL/6 and BALB/cJ Apolipoprotein E–Deficient Mice

“…The QTL on chromosome 2, named Ath41 , is close to Athla1 , an atherosclerosis susceptibility locus mapped in a (PERA×B6- Ldlr −/− )×B6- Ldlr −/− N 2 backcross mice 39 . Athla1 is located in a more distal region (69 cM), and it increases lesion size only when homozygous for the B6 allele.…”