Role of genetics in peripheral arterial disease outcomes; significance of limb-salvage quantitative locus-1 genes

Emmanuel Okeke, Ayotunde Dokun

Research output: Contribution to journalArticle

Abstract

Peripheral artery disease is a major health care problem with significant morbidity and mortality. Humans with peripheral artery disease exhibit two major and differential clinical manifestations – intermittent claudication and critical limb ischemia. Individuals with intermittent claudication or critical limb ischemia have overlapping risk factors and objective measures of blood flow. Hence, we hypothesized that variation in genetic make-up may be an important determinant in the severity of peripheral artery disease. Previous studies have identified polymorphism in genes, contributing to extent of atherosclerosis but much less is known about polymorphisms associated with genes that can influence peripheral artery disease severity. This review outlines some of the progress made up-to-date to unravel the molecular mechanisms underlining differential peripheral artery disease severity. By exploring the recovery phenotype of different mouse strains following experimental peripheral artery disease, our group identified the limb salvage-associated quantitative trait locus 1 on mouse chromosome 7 as the first genetic modifier of perfusion recovery and tissue necrosis phenotypes. Furthermore, a number of genes within LSq-1, such as ADAM12, IL-21Rα, and BAG3 were identified as genetic modifiers of peripheral artery disease severity that function through preservation of endothelial and skeletal muscle cells during ischemia. Taken together, these studies suggest manipulation of limb salvage-associated quantitative trait locus 1 genes show great promise as therapeutic targets in the management of peripheral artery disease. Impact statement: Peripheral artery disease (PAD) is a major health care problem with significant morbidity and mortality. Individuals with similar atherosclerosis burden do display different severity of disease. This review outlines some of the progress made up-to-date in unraveling the molecular mechanisms underlining differential PAD severity with a focus on the role of the Limb Salvage-associated Quantitative trait locus 1 (LSq-1), a key locus in adaptation to ischemia in PAD.

Original languageEnglish (US)
Pages (from-to)190-197
Number of pages8
JournalExperimental Biology and Medicine
Volume243
Issue number2
DOIs
StatePublished - Jan 1 2018

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Salvaging
Limb Salvage
Peripheral Arterial Disease
Genes
Quantitative Trait Loci
Ischemia
Intermittent Claudication
Polymorphism
Health care
Atherosclerosis
Genetics
Extremities
Morbidity
Delivery of Health Care
Phenotype
Chromosomes, Human, Pair 7
Recovery
Mortality
Chromosomes
Muscle Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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Role of genetics in peripheral arterial disease outcomes; significance of limb-salvage quantitative locus-1 genes. / Okeke, Emmanuel; Dokun, Ayotunde.

In: Experimental Biology and Medicine, Vol. 243, No. 2, 01.01.2018, p. 190-197.

Research output: Contribution to journalArticle

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