Genetic and genomic insights into the molecular basis of atherosclerosis

Abstract

Atherosclerosis is a complex disease involving genetic and environmental risk factors, acting on their own or in synergy. Within the general population, polymorphisms within genes in lipid metabolism, inflammation, and thrombogenesis are probably responsible for the wide range of susceptibility to myocardial infarction, a fatal consequence of atherosclerosis. Genetic linkage studies have been carried out in both humans and mouse models to identify these polymorphisms. Approximately 40 quantitative trait loci for atherosclerotic disease have been found in humans, and approximately 30 in mice. Recently, genome-wide association studies have been used to identify atherosclerosis-susceptibility polymorphisms. Although discovering new atherosclerosis genes through these approaches remains challenging, the pace at which these polymorphisms are being found is accelerating due to rapidly improving bioinformatics resources and biotechnologies. The outcome of these efforts will not only unveil the molecular basis of atherosclerosis but also facilitate the discovery of drug targets and individualized medication against the disease.

Figure 1

Chromosome map of human and mouse concordant QTLs for atherosclerotic diseases. Human HDL-C QTLs are represented by bars to the left of each chromosome. Each bar represents a QTL from one population as shown in Table 1. QTL sizes are given either as 1.5-LOD drop intervals (if LOD score figures are available), or ± 15 cM centered around the LOD score peak (when LOD score figures are unavailable). Human homologues of mouse HDL-C QTLs are represented by red bars to the right of each chromosome, and the chromosome numbers of these mouse QTLs are to their right.

Figure 2

Chromosome map of mouse and human concordant atherosclerosis QTLs. A vertical black line represents each chromosome, with the centromere at the top. Genetic distances in Mb from the centromere are shown by the scale at the lower left of the figure. Mouse atherosclerosis QTLs are represented by bars to the left of each chromosome. Each bar represents a QTL from one cross as shown in Table 2. QTL sizes are given either as 95% confidence intervals (CIs), 1.5-LOD drop intervals (if 95% CIs are not available but LOD score figures are available), or ± 10 cM centered around the LOD score peak (when neither CIs nor LOD score figures are available). To change cM into Mb, we found MIT markers at the cM positions in MGI (informatics.jax.org) and retrieved their Mb positions in Ensembl Mouse Genome Server NCBI m36. Mouse homologues of human HDL-C QTLs are represented by red bars to the right of each chromosome, and the chromosome numbers of these human QTLs are to their right.