Genetics of Lipid Traits and Relationship to Coronary Artery Disease

Abstract

Despite the critical importance of plasma lipoproteins in the development of atherosclerosis, varying degrees of evidence surround the causal associations of lipoproteins with coronary artery disease (CAD). These causal contributions can be assessed by employing genetic variants as unbiased proxies for lipid levels. A relatively large number of low-density lipoprotein cholesterol (LDL-C) variants strongly associate with CAD, confirming the causal impact of this lipoprotein on atherosclerosis. Although not as firmly established, genetic evidence supporting a causal role of triglycerides (TG) in CAD is growing. Conversely, high-density lipoprotein cholesterol (HDL-C) variants not associated with LDL-C or TG have not yet been shown to be convincingly associated with CAD, raising questions about the causality of HDL-C in atherosclerosis. Finally, genetic variants at the LPA locus associated with lipoprotein(a) [Lp(a)] are decisively linked to CAD, indicating a causal role for Lp(a). Translational investigation of CAD-associated lipid variants may identify novel regulatory pathways with therapeutic potential to alter CAD risk.

Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression

“…Many studies have demonstrated that LDL induces dysfunction of endothelium (Yu et al, 2013), causes vascular wall inflammation (Fenyo and Gafencu, 2013;Wang et al, 2013), promotes vasospasm (Miwa, 2003) and ischemic heart disease (Keenan and Rader, 2013). However, the underlying molecular mechanisms how LDL leads to vasospasm and ischemic cerebro-and cardiovascular diseases are not fully understood yet.…”

Lipid metabolism genes and predisposition to ischemic heart disease

“…К настоящему времени идентифицировано множество полиморфных вариантов генов, ассоциированных с риском развития полигенных форм ИБС [11]. Наиболее выраженными эффектами в отношении риска развития болезни обладали такие гены, как PCSK9 [11][12][13][14], LPA [10], NPC1L1 [15], ST3GAL4 [16], генный кластер APOE-C1-C2-C4 [17], COBLL1 [15], LRP4 [10], STARD3 [18], ABCA1 [10,19], SCARB1 [20][21][22], CETP [23,24], PLTP [25,26], LCAT [10]. Продукты экспрессии идентифицированных генов не ограничены влияниями на липидный обмен, а вовлечены в разнообразные молекулярные механизмы развития ИБС.…”

“…Ген PCSK9 -высоко полиморфный. Установлена ассоциация полиморфного варианта rs17111503 гена PCSK9 с развитием атеросклеротических поражений сосудов у китайцев [13,14]. Также показано, что носители полиморфного варианта требуют специальной тактики для коррекции уровня холестерина в крови [29].…”

Genome-wide association studies and contribution to cardiovascular physiology

“…Circulating blood lipid levels are important risk factors for cardiovascular disease, and the GWAS approach has yielded numerous variants associated with lipid traits and coronary artery disease (34). A recent study has reported genotyping of the exome array (Box 1) with lipid traits (24).…”