Abstract
Type 2 diabetes (T2D) is a major risk for atherosclerosis and its complications. Apoe-null (Apoe−/−) mouse strains exhibit a wide range of variations in susceptibility to T2D and carotid atherosclerosis, with the latter being a major cause of ischemic stroke. To identify genetic connections between T2D and carotid atherosclerosis, 145 male F2 mice were generated from LP/J and BALB/cJ Apoe−/− mice and fed 12 weeks of a Western diet. Atherosclerotic lesions in the carotid arteries, fasting, and non-fasting plasma glucose levels were measured, and genotyping was performed using miniMUGA arrays. Two significant QTL (quantitative trait loci) on chromosomes (Chr) 6 and 15 were identified for carotid lesions. The Chr15 QTL coincided precisely with QTL Bglu20 for fasting and non-fasting glucose levels. Carotid lesion sizes showed a trend toward correlation with fasting and non-fasting glucose levels in F2 mice. The Chr15 QTL for carotid lesions was suppressed after excluding the influence from fasting or non-fasting glucose. Likely candidate genes for the causal association were Tnfrsf11b, Deptor, and Gsdmc2. These results demonstrate a causative role for hyperglycemia in the development of carotid atherosclerosis in hyperlipidemic mice.
Highlights
Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries, such as the coronary artery and carotid artery, featured by the buildup of lipid-containing plaque in the arterial wall
Residuals generated from linear regression analysis of carotid lesion sizes with either fasting or non-fasting glucose in F2 mice were subject to quantitative trait locus (QTL) mapping as a new phenotype
We identified two significant QTLs on mouse chromosomes 6 and 15 for carotid atherosclerosis and a significant QTL on chromosome 15 for plasma glucose levels using a male F2 cohort derived from LP and BALB Apoe−/− mice
Summary
Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries, such as the coronary artery and carotid artery, featured by the buildup of lipid-containing plaque in the arterial wall. The latest meta-analysis of genome-wide association studies (GWAS) with Europeans from 17 studies identified 14 loci for cIMT and carotid plaque [6]. These loci only account for a small fraction of the variance in the traits of the examined subjects. Even though a SNP is found to be associated with both T2D and CHD, it is challenging to deduce their causal connections from human GWAS due to the small effect size of an individual variant, complex genetic structure, and environmental influences. Apoe−/− mice on certain genetic backgrounds develop T2D when fed a Western diet [14,23], providing a valuable model for finding common genetic loci shared between T2D and carotid atherosclerosis. We sought to determine whether T2D plays a causal role in the development of carotid atherosclerosis
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