Identifying novel genes for atherosclerosis through mouse-human comparative genetics

Abstract

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait-locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat-diet model only, 9 in a sensitized model (apolipoprotein E- or LDL [low-density lipoprotein] receptor-deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease.

Figure 1

Chromosome map of human QTLs for atherosclerotic diseases. Chromosomes are drawn to scale, on the basis of the length of each from the Ensembl Human Genome Browser. Each bar to the right of a chromosome represents a human atherosclerosis QTL from one population (see table 1). The size of the QTL is determined either as a 1.5-LOD CI or as ±10 Mb on either side of the peak marker when the information on CI is unavailable. Candidate genes are listed to the left of the chromosomes. Human homologous regions of mouse QTLs that fall within the human QTLs are represented by red stars.

Figure 2

Chromosome map of mouse atherosclerosis QTLs. Each chromosome is represented by a vertical line (centromeres at the top). Genetic distances (in cM) from the centromere are drawn to scale (scale shown at lower left of the figure. Chromosomes are drawn to scale, on the basis of the estimated cM position of the most distally mapped locus on the Mouse Genome Informatics (MGI) Web site. Mouse atherosclerosis QTLs are represented by the bars to the right of each chromosome (interacting QTLs are not shown). Each bar represents a QTL from one cross (sharing the same parental strains, regardless of the breeding strategy) in the specified mouse model (see table 2). The size of the QTL is determined either as a 95% CI or as ±10 cM on either side of the LOD score peak when the information on CI is unavailable. Candidate genes are listed to the left of the chromosomes. Mouse homologous regions of human QTLs that fall within mouse QTLs are represented by red stars.

Figure 3

Comparison of mouse atherosclerosis QTLs found in high-fat and sensitized models (Apoe^−/− and Ldlr^−/− mice), shown in different colors. The number of QTLs concordant with human QTLs is also shown.