Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross Between C57BL/6 and C3H Apolipoprotein E–Deficient Mice

Li, Qiongzhen; Li, Yuhua; Zhang, Zhimin; Gilbert, Timothy R.; Matsumoto, Alan H.; Dobrin, Seth; Shi, Weibin

doi:10.1161/strokeaha.107.492165

Cited by 24 publications

(53 citation statements)

References 47 publications

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“…These findings are consistent with the observation made from Mendelian randomization studies of HDL for role in human coronary heart disease [31,32]. Although Mendelian randomization studies of blood lipids have suggested a role for triglyceride and LDL cholesterol in human coronary heart disease, no significant correlations with atherosclerotic lesions were observed in the present cross or previous crosses [13,33]. …”

Section: Discussionsupporting

confidence: 92%

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

Grainger

Jones

et al. 2016

Atherosclerosis

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Background and aims: Recent genome-wide association studies (GWAS) have identified over 50 significant loci containing common variants associated with coronary artery disease. However, these variants explain only 26% of the genetic heritability of the disease, suggesting that many more variants remain to be discovered. Here, we examined the genetic basis underlying the marked difference between SM/J-Apoe−/− and BALB/cJ-Apoe−/−mice in atherosclerotic lesion formation. Methods: 206 female F2 mice generated from an intercross between the two Apoe–/- strains were fed 12 weeks of western diet. Atherosclerotic lesion sizes in the aortic root were measured and 149 genetic markers genotyped across the entire genome. Results: A significant locus, named Ath49 (LOD score: 4.18), for atherosclerosis was mapped to the H2 complex [mouse major histocompatibility complex (MHC)] on chromosome 17. Bioinformatic analysis identified 12 probable candidate genes, including Tnfrsf21, Adgrf1, Adgrf5, Mep1a, and Pla2g7. Corresponding human genomic regions of Ath49 showed significant association with coronary heart disease. Five suggestive loci on chromosomes 1, 4, 5, and 8 for atherosclerosis were also identified. Atherosclerotic lesion sizes were significantly correlated with HDL but not with non-HDL cholesterol, triglyceride or glucose levels in the F2 cohort. Conclusions: We have identified the MHC as a major genetic determinant of atherosclerosis, highlighting the importance of inflammation in atherogenesis.

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Section: Discussionsupporting

confidence: 92%

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

Grainger

Jones

et al. 2016

Atherosclerosis

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“…A significant QTL on chromosome 12 near D12Mit97 (47cM) had a significant LOD of 4.0 and accounted for 9% of the variance in non-HDL cholesterol levels. This QTL overlapped with Nhdlq12 , recently mapped in a female BXH F 2 cross 13. A suggestive QTL for non-HDL near D4Mit192 (6.3cM; LOD: 2.18) corresponded to Chol8 , identified in a 129S1/SvImJXCAST/Ei intercross,14 and a QTL near D7Mit330 (57.5cM, LOD: 2.13) corresponded to Chldq4 , mapped in a MRL/MpJXSJL/J intercross 15.…”

Section: Resultsmentioning

confidence: 65%

“…The chromosome 12 QTL mapped to the distal region (61 cM), and the B6 allele conferred the increased neointimal lesion formation at the locus. This locus did not overlap with any atherosclerosis QTLs mapped in genetic crosses derived from B6 and C3H mice,12,13,18–20 suggesting that neointimal hyperplasia and atherosclerosis are controlled by separate genetic factors. Indeed, the pathology of these two vascular disorders is quite different: the neointimal lesion consists largely of vascular smooth muscle cells, although macrophages are also present (Figure 1), whereas macrophages are the major cellular component ofatherosclerotic lesions at all stages and smooth muscle cellsonly become prominent in the advanced stage 22…”

Section: Discussionmentioning

confidence: 85%

Quantitative Trait Locus Analysis of Neointimal Formation in an Intercross Between C57BL/6 and C3H/HeJ Apolipoprotein E–Deficient Mice

Yuan

Pei

Roberts

et al. 2009

Circ Cardiovasc Genet

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Background-Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in neointimal formation after arterial injury when deficient in apolipoprotein E (apoE Ϫ/Ϫ ) and fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE Ϫ/Ϫ and C3H.apoE Ϫ/Ϫ mice to determine genetic factors contributing to the phenotype. Methods and Results-Female B6.apoE Ϫ/Ϫ mice were crossed with male C3H.apoE Ϫ/Ϫ mice to generate F 1 s, which were intercrossed to generate 204 male F 2 progeny. At 10 weeks of age, F 2 s underwent endothelium denudation injury to the left common carotid artery. Mice were fed a Western diet for 1 week before and 4 weeks after injury and analyzed for neointimal lesion size, plasma lipid, and membrane cofactor protein (MCP)-1 levels. One significant quantitative trait locus, named Nih1 (61 cM; LOD score, 5.02), on chromosome 12 and a suggestive locus on chromosome 13 (35 cM; LOD score, 2.67) were identified to influence lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma non-high-density lipoprotein cholesterol and triglyceride levels. Four suggestive quantitative trait locis on chromosomes 1, 2, and 3 were detected for circulating MCP-1 levels. No correlations were observed between neointimal lesion size and plasma lipid levels or between lesion size and plasma MCP-1 levels. Conclusions-Neointimal formation is controlled by genetic factors independent of those affecting plasma lipid levels and circulating MCP-1 levels in the B6 and C3H mouse model. (Circ Cardiovasc Genet. 2009;2:220-228.)

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“…The reason for this is unknown. Previous studies of F 2 mice derived from B6.apoE −/− and C3H.apoE −/− mice showed that multiple loci contribute to atherosclerotic lesion formation and alleles derived from C3H may contribute to the susceptibility to atherosclerosis while alleles derived from B6 may contribute to the resistance to atherosclerosis 21, 27, 28. Thus, it is likely that genes outside the H2 region protect against radiation-enhanced atherosclerosis in B6.apoE −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Genes Within the MHC Region Have a Dramatic Influence on Radiation-Enhanced Atherosclerosis in Mice

Shi

Zhang

Chen

et al. 2010

Circ Cardiovasc Genet

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Background— C3H/HeJ (C3H) mice develop much smaller atherosclerotic lesions than C57BL/6 (B6) mice when deficient in apolipoprotein E (apoE −/− ) or fed an atherogenic diet. The 2 strains differ in H2 haplotypes, with B6 having H2 b and C3H having H2 k . C3.SW-H2 b /SnJ (C3.SW) is a congenic strain of C3H/HeJ in which H2 k is replaced with H2 b . Methods and Results— We performed bone marrow transplantation and found that atherosclerosis-resistant C3.SW.apoE −/− mice reconstituted with bone marrow from either C3.SW.apoE −/− or B6.apoE −/− mice after lethal irradiation had significantly larger atherosclerotic lesions than B6.apoE −/− mice receiving identical treatments and much larger lesions than C3H.apoE −/− mice reconstituted with syngeneic bone marrow. For syngeneic transplantation, C3.SW.apoE −/− mice exhibited a 21-fold increase in lesion size over C3H.apoE −/− mice (152 800±21 937 versus 7060±2290 μm 2 /section) and a near 4-fold increase over B6.apoE −/− mice (40 529±4675 μm 2 /section). C3.SW.apoE −/− mice reconstituted with syngeneic marrow exhibited enhanced lesion formation relative to those reconstituted with B6 marrow (152 800±21 937 versus 107 000±9374 μm 2 /section; P =0.067). Sublethal irradiation led to a 6-fold increase of lesion size in C3.SW.apoE −/− mice (9795±2804 versus 1550±607 μm 2 /section; P =0.008). Wild-type C3.SW mice reconstituted with apoE +/+ or apoE −/− bone marrow had significantly larger atherosclerotic lesions than C3H mice receiving identical treatments on an atherogenic diet. Conclusions— These results indicate that gene(s) within the H2 region have a dramatic impact on radiation-enhanced atherosclerosis, and their effect is conveyed partially through bone marrow–derived cells.

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Quantitative Trait Locus Analysis of Carotid Atherosclerosis in an Intercross Between C57BL/6 and C3H Apolipoprotein E–Deficient Mice

Cited by 24 publications

References 47 publications

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

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

Quantitative Trait Locus Analysis of Neointimal Formation in an Intercross Between C57BL/6 and C3H/HeJ Apolipoprotein E–Deficient Mice

Genes Within the MHC Region Have a Dramatic Influence on Radiation-Enhanced Atherosclerosis in Mice

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