Editors' ChoiceCardiovascular Disease

The remnants of coronary heart disease

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Science Translational Medicine  18 May 2016:
Vol. 8, Issue 339, pp. 339ec78
DOI: 10.1126/scitranslmed.aaf9191

Atherosclerosis and associated coronary heart disease (CHD) remain the largest cause of mortality in developed countries. Statins have been life-saving drugs for many, but CHD-associated mortality and morbidity have only been modestly reduced, demonstrating a clear need for additional therapeutic strategies. Although atherosclerosis is a lipid-driven disease, it’s not clear which lipid or lipoprotein subclass should be targeted with new drugs. Now, Helgadottir et al. provide provocative human genetic evidence that targeting cholesterol-enriched apolipoprotein B (apoB)–containing “remnant” lipoproteins holds more promise than traditional approaches aimed at modifying high-density lipoprotein (HDL).

Helgadottir and colleagues focused on low-frequency (1 to 5%) and rare (<1%) sequence variants with large effects on blood lipid levels in a unique Icelandic population with limited allele diversity. Although many of the lipid-associated variants mapped to genes known to directly regulate lipid and lipoprotein metabolism, 13 new rare and low-frequency variants were identified, including a previously unknown rare gain-of-function variant of the gene encoding apolipoprotein A1. Of the 27 variants identified [13 new and 14 confirmed from previous genome-wide association studies (GWAS)], only five were associated with CHD risk. The authors then constructed genetic risk scores for each lipid trait such as triglycerides, HDL, and non-HDL cholesterol, and determined association with CHD risk and overall lifespan. Collectively, this analysis suggested that apoB-containing remnant lipoproteins, but not HDL or total triglycerides, are involved in the pathogenesis of CHD. These findings provide critical new information for CHD drug discovery in the post-statin era, refocusing future lipid-modifying therapies less on raising HDL, and more on lowering levels of cholesterol-rich and triglyceride-poor apoB-containing remnant lipoproteins. Such GWAS can provide important clues into causal factors underlying human disease, but ultimately the hypothesis presented here will require mechanistic studies in animal models to establish true causality and to identify novel points of therapeutic intervention.

A. Helgadottir et al., Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat. Genet. 10.1038/ng.3561 (2016). [Abstract]

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