New quantitative trait loci for carotid atherosclerosis identified in an intercross derived from apolipoprotein E-deficient mouse strains

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.

Genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice

“…Similar findings have been observed with other mouse crosses [15,23,30]. These findings are consistent with the observation made from Mendelian randomization studies of HDL for role in human coronary heart disease [31,32].…”

Associations between pig adiponectin (ADIPOQ) genotype and serum lipid levels are modulated by age-specific modifiers1

“…In the case of CHOL190, heterozygous individuals displayed lower means than the 2 homozygous genotypes. This pattern of underdominance is difficult to explain from a functional perspective because the molecular basis of dominance is not yet fully understood, but similar results have been obtained in mouse, where underdominant QTL for serum lipids (Lawson et al, 2010) and carotid atherosclerosis (Rowlan et al, 2013) have been reported so far. Previous data obtained in humans provided evidence that adiponectin levels are negatively correlated with LDL concentrations (Kantartzis et al, 2006) and LDL particle size (Lara-Castro et al, 2006).…”

Genetic linkage of hyperglycemia and dyslipidemia in an intercross between BALB/cJ and SM/J Apoe-deficient mouse strains

“…Bglu17 on Chr9 has been mapped in 3 separate intercrosses, including previously reported C57BLKS x DBA/2 [ 35 ] and B6- Apoe −/− x BALB- Apoe −/− crosses [ 21 ]. Hdlq17 on Chr9 has been mapped in multiple crosses, including B6 x 129, B6 x CAST/EiJ, B6- Apoe −/− x C3H- Apoe −/− , and B6- Apoe −/− x BALB- Apoe −/− crosses [ 24 , 27 , 31 , 32 , 36 – 38 ]. We conducted haplotype analyses using Sanger SNP database to prioritize positional candidate genes for both QTLs.…”