Abstract
Carotid atherosclerosis is the primary cause of ischemic stroke. To identify genetic factors contributing to carotid atherosclerosis, we performed quantitative trait locus (QTL) analysis using female mice derived from an intercross between C57BL/6J (B6) and BALB/cJ (BALB) apolipoprotein E (Apoe−/−) mice. We started 266 F2 mice on a Western diet at 6 wk of age and fed them the diet for 12 wk. Atherosclerotic lesions in the left carotid bifurcation and plasma lipid levels were measured. We genotyped 130 microsatellite markers across the entire genome. Three significant QTLs, Cath1 on chromosome (Chr) 12, Cath2 on Chr5, and Cath3 on Chr13, and four suggestive QTLs on Chr6, Chr9, Chr17, and Chr18 were identified for carotid lesions. The Chr6 locus replicated a suggestive QTL and was named Cath4. Six QTLs for HDL, three QTLs for non-HDL cholesterol, and three QTLs for triglyceride were found. Of these, a significant QTL for non-HDL on Chr1 at 60.3 cM, named Nhdl13, and a suggestive QTL for HDL on ChrX were new. A significant locus for HDL (Hdlq5) was overlapping with a suggestive locus for carotid lesions on Chr9. A significant correlation between carotid lesion sizes and HDL cholesterol levels was observed in the F2 population (R = −0.153, P = 0.0133). Thus, we have identified several new QTLs for carotid atherosclerosis and the locus on Chr9 may exert effect through interactions with HDL.
Highlights
STROKE IS THE LEADING CAUSE of disability in adults and the fourth most common cause of death in the United States [33]
In an intercross derived from C57BL/6 (B6) and C3H/HeJ (C3H) ApoeϪ/Ϫ mice, we performed quantitative trait locus (QTL) analysis and identified the first significant locus for carotid atherosclerosis [19]
Genome-wide QTL analysis of either nontransformed carotid lesion sizes with the nonparametric mode or square root-transformed carotid lesion sizes with the parametric mode revealed three significant QTLs, located on chromosomes (Chr) 5, 12, and 13, and two suggestive QTLs, on Chr17 and Chr18, for carotid lesion sizes (Fig. 2)
Summary
STROKE IS THE LEADING CAUSE of disability in adults and the fourth most common cause of death in the United States [33]. Patients with noticeable carotid stenosis have severely impaired cerebral blood flow and markedly increased risk for ipsilateral stroke [24, 26]. For those with no obvious carotid stenosis, perspective studies show a close association between the intima-media thickening and the risk of stroke [21, 25, 48]. Genetic studies of twin pairs and families have demonstrated the heritability of carotid atherosclerosis or common and internal carotid artery intima media thickness [34, 44, 60]. We generated a F2 population from B6.ApoeϪ/Ϫ and BALB.ApoeϪ/Ϫ mice to search for new loci contributing to carotid atherosclerosis and associated lipid traits
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