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. 2009 Jun;2(3):220-8.
doi: 10.1161/CIRCGENETICS.108.792499.

Quantitative trait locus analysis of neointimal formation in an intercross between C57BL/6 and C3H/HeJ apolipoprotein E-deficient mice

Zuobiao Yuan  1 , Hong Pei, Drew J Roberts, Zhimin Zhang, Jessica S Rowlan, Alan H Matsumoto, Weibin Shi
Affiliations

Quantitative trait locus analysis of neointimal formation in an intercross between C57BL/6 and C3H/HeJ apolipoprotein E-deficient mice

Zuobiao Yuan et al. Circ Cardiovasc Genet. 2009 Jun.

Abstract

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(-/-)) and fed a Western diet. Quantitative trait locus (QTL) analysis was performed on an intercross between B6.apoE(-/-) and C3H.apoE(-/-) mice to determine genetic factors contributing to the phenotype.

Methods and results: Female B6.apoE(-/-) mice were crossed with male C3H.apoE(-/-) 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 MCP-1 levels. One significant QTL, named Nih1 (61cM, LOD score: 5.02), on chromosome 12 and a suggestive locus on chromosome 13 (35cM, LOD: 2.67) were identified to influence lesion size. One significant QTL on distal chromosome 1 accounted for major variations in plasma non-HDL cholesterol and triglyceride levels. Four suggestive QTLs 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.

Keywords: Mice; Neointimal hyperplasia; Quantitative trait locus; Restenosis.

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Figures

Figure 1
Figure 1
Representative cross-sections of the injured common carotid artery of B6.apoE−/− and C3H.apoE−/− mice fed a Western diet. Paraffin-embedded tissues were stained with van Gieson stain or specific antibodies against smooth muscle cells and macrophages. Note the distinct difference between the two strains in neointimal lesion size, the strong -actin positive arterial wall and neointimal lesions, and the focal accumulation of macrophages (arrow). Original magnification: 10 or 20×. Insets display magnified views of representative areas.
Figure 2
Figure 2
Distributions of square root-transformed neointimal lesion size, untransformed non-HDL cholesterol, triglyceride, and MCP-1 levels in 204 male F2 mice derived from B6.apoE−/−and C3H.apoE−/− mice. Mice were subject to endothelium denudation injury to the left common carotid artery and fed a Western diet for 1 week before and 4 weeks after injury.
Figure 3
Figure 3
A genome-wide scan with F2 mice to search for loci influencing neointimal lesion size. Chromosomes 1 through X are represented numerically on the X-axis. The relative width of the space allotted for each chromosome reflects the relative length of each chromosome. The Y-axis represents LOD score. Three dash lines on the plot represent LOD score thresholds for “suggestive (P=0.63)”, “significant (P=0.05)”, or “highly significant (P=0.01)” QTLs as calculated by permutation tests.
Figure 4
Figure 4
Likelihood plots for neointimal lesion size on chromosome 12 and chromosome 13. Plots were generated using the interval mapping function of Map Manager QTX, including a bootstrap test shown as a histogram estimating the confidence interval of a QTL. Vertical green lines on the plot represent significance thresholds for the likelihood-ratio statistic, indicating “suggestive (P=0.63)”, “significant (P=0.05)”, or “highly significant (P=0.01)” peaks as calculated by permutation analysis for the genome-wide significance thresholds. Black plots reflect the likelihood-ratio statistic calculated at 1-cM intervals. The red plot represents the additive regression coefficient and the blue plot represents the dominant regression coefficient, indicating effect of the B6 allele.
Figure 5
Figure 5
Genome-wide scans with F2 mice to search for loci affecting plasma levels of non-HDL cholesterol and triglyceride. Chromosomes 1 through X are numerically represented on the X-axis and the LOD scores represented on the Y-axis. The LOD score thresholds are shown on the figure.
Figure 6
Figure 6
Representative light photographs of immunohistochemical analysis of Yy1 and Pacs2 expression in the carotid arteries with or without endothelium denudation injury. Sections were stained with rabbit polyclonal antibodies against Yy1 and Pacs2. Original magnification: 20×. Insets display magnified views of representative areas.
Figure 7
Figure 7
Selected sequence traces of the promoter region of the Yy1 gene for B6 and C3H mice. Differences between the two strains in nucleotides are highlighted. Partial sequences of the Yy1 promoter region are not presented because no sequence difference has been found between the two strains.
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