Elucidating the Genetic Basis of Peripheral Arterial Disease

Abstract

Using sophisticated tools of mouse genetics and bioinformatics, a multidisciplinary group of scientists, Dokun et al,1 have shown that a region of chromosome 7 of a C57BL/6 mouse strain contributes a dominant protective allele (or alleles) that increases limb perfusion and reduces limb necrosis after induction of experimental hindlimb ischemia. The investigators hope that the application of these methods will lead to the identification of genes that might predict the risk of critical limb ischemia in patients with peripheral arterial disease (PAD). Beyond providing the potential to learn more about the genetic and molecular basis of PAD, the genetic and bioinformatics approaches taken by this multidisciplinary team of scientists provide a pathway that could have broader applications to advance the study of many aspects of cardiovascular diseases. Article p 1207 The mouse remains the most powerful experimental model to study the genetic basis of human disease.2,3 The techniques used in this study represent an evolution from those that were first used in the early 1900s with the development of inbred strains of mice. Subsequently, the ability to analyze the function of single-gene mutations by knockout or knock-in techniques and by regulatable site-specific gene expression in inbred strains of mice has allowed many major advances in understanding the molecular basis of human disease. Despite their power, these techniques have remained limited to studies that analyzed the function of a single gene. In contrast, quantitative trait loci analysis permits the study of phenotypes that vary within a population and are influenced by multiple genes. Since most common human diseases result from such quantitative traits, the phenotype observed often results from the compound effects of multiple genes, the interactions of these genes with other genes, and then the effect of the environment on their collective expression. Thus, it is likely that …