Genetic Susceptibility to Peripheral Arterial Disease: A Dark Corner in Vascular Biology

Abstract

Abstract-Peripheral arterial disease (PAD) is characterized by reduced blood flow to the limbs, usually as a consequence of atherosclerosis, and affects Ϸ12 million Americans. It is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. Similar to other atherosclerotic diseases, such as coronary artery disease, PAD is the result of the complex interplay between injurious environmental stimuli and genetic predisposing factors of the host. Genetic susceptibility to PAD is likely contributed by sequence variants in multiple genes, each with modest effects. Although many of these variants probably alter susceptibility both to PAD and to coronary artery disease, it is likely that there exists a set of variants specifically to alter susceptibility to PAD. Despite the prevalence of PAD and its high societal burden, relatively little is known about such genetic variants. This review summarizes our limited present knowledge and gives an overview of recent, more powerful approaches to elucidating the genetic basis of PAD. We discuss the advantages and limitations of genetic studies and highlight the need for collaborative networks of PAD investigators for shedding light on this dark corner of vascular biology. (Arterioscler Thromb Vasc

Identification of Evidence Suggestive of an Association with Peripheral Arterial Disease at the OSBPL10 Locus by Genome-Wide Investigation in the Japanese Population

“…This study is still in the screening stage and needs a replication study using an independent panel of cases (PAD patients) and controls in the future. To date, several genes susceptible to PAD have been reported in a case-control study with sample sizes ranging from ~100 to 1300 subjects 7) , but we could not confirm these genes as candidate genes in our study. Thus, we speculate that our genome-wide association study still cannot cover all the genes for PAD.…”

“…Despite its prevalence and the high social cost attributed to PAD 6) , the genetic basis of PAD and the factors that determine its responsiveness to treatment are yet to be understood. There are no genetic tests available that reliably identify the subset of subjects carrying inherited risk factors for developing PAD on a large scale 7) ; however, three family studies to date have reported estimates of heritability of PAD and thus its heritability could be suggested [8][9][10] . A logical next step is to perform a more comprehensive and unbiased scan of variations in all genes or in the entire genome using what is commonly referred to as a genome-wide association study (GWAS).…”

Additive Effect of ANRIL and BRAP Polymorphisms on Ankle-Brachial Index in a Taiwanese Population

“…34 Genes encoding for interleukin-6 (IL-6), fibrinogen (FGB) and intercellular adhesion molecule-1 (ICAM-1) have been reported to be associated with PAD risks. 35 The present study showed that both ANRIL and BRAP are risk genes for lower ABI values. In addition to the main effects of BRAP and ANRIL, we also demonstrated an additive effect of these 2 genes on ABI.…”

Elucidating the Genetic Basis of Peripheral Arterial Disease

“…10 Recently, Knowles and colleagues reviewed what is known of the genetic susceptibility to PAD and concluded that our understanding of the genetic basis of PAD is quite limited. 11 Neither linkage analysis nor linkage associations studies have convincingly uncovered any genes that either identify patients at risk for PAD or predict their clinical course. The major weakness of these published studies is the small number of patients studied.…”