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13 June 2016
Genetic study provides support for targeting atherogenic cholesterol beyond that carried by LDL particles to reduce residual cardiovascular risk
Genetic risk score for non-high-density lipoprotein cholesterol (non-HDL-C) confers coronary risk beyond low-density lipoprotein cholesterol (LDL-C).
Helgadottir A, Gretarsdottir S, Thorleifsson G, Hjartarson E, Sigurdsson A, Magnusdottir A, Jonasdottir A, Kristjansson H, Sulem P, Oddsson A, Sveinbjornsson G, Steinthorsdottir V, Rafnar T, Masson G, Jonsdottir I, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Daneshpour MS, Khalili D, Azizi F, Swinkels DW, Kiemeney L, Quyyumi AA, Levey AI, Patel RS, Hayek SS, Gudmundsdottir IJ, Thorgeirsson G, Thorsteinsdottir U, Gudbjartsson DF, Holm H, Stefansson K. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet 2016 May 2. doi: 10.1038/ng.3561. [Epub ahead of print]
Objective: To identify novel rare and low-frequency lipid-associated variants that may be potential therapeutic targets to prevent coronary artery disease (CAD). The investigators also used information for rare and common variants to dissect the relationship between lipid traits and CAD.
Study design: Population-based resource of whole-genome sequence data
Study population: Genome sequence data for up to 119,146 Icelanders were combined with a population-based data set, which was tested for association with non-HDL-C, HDL?C, and triglycerides. Results for LDL-C (n=53,841) were available for comparison.
Key outcomes: ·       Rare (allele frequency <1%) and low-frequency (allele frequency 1–5%) genetic variants associated with non-HDL-C, HDL-C, LDL-C and triglycerides.

·       Genetic risk scores for these lipid fractions and their association with CAD.

Methods: Lipid-associated variants were tested for association with CAD among 33,090 cases and 236,254 controls. Individual-level genetic risk scores were constructed for each lipid trait based on rare and low-frequency lipid-associated variants, and common and low-frequency lipid-associated variants identified in the study.  Causality analysis was used to investigate the association of each risk score with CAD. Results were compared with summary-level data using weighted multiple regression.
Main results: ·       The study identified 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants.

·       Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associated with CAD.

·       Genetic risk scores were based on 27 rare and low-frequency variants reported in this study combined with 185 known lipid-associated variants.

·       The genetic risk score for non-HDL-C associated most strongly with CAD (p=2.7 x 10-28), the effects were beyond those of LDL-C.  After adjustment for non-HDL-C, no other risk score associated with CAD.

Authors’ conclusion: The genetic risk score for non-HDL-C confers CAD risk beyond that of LDL-C, suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.


Non-HDL-C is defined as total cholesterol minus HDL-C, and thus incorporates the cholesterol from triglyceride-rich lipoproteins (which encompasses very low-density lipoprotein, chylomicrons, and their cholesterol-enriched remnants), as well as LDL-C. In this study, causality analysis using genetic risk scores based on 27 rare and low-frequency variants showed an effect of non-HDL-C, but not HDL-C or triglycerides, on CAD risk. These findings are consistent with the Emerging Risk Factors Collaboration.1 Moreover, re-analysis of data from a previous genetic study which reported an association between triglycerides and CAD,2 showed that this could be explained by the effect of cholesterol carried within triglyceride-rich lipoproteins, notably remnant cholesterol,3 which is captured by non-HDL-C.  However, as a cautionary note, the authors comment that while general causal relationships between HDL-C or triglycerides and CAD are not supported, there is the possibility that other mechanisms that affect these variables may have a role in the pathogenesis of the disease. Indeed, in this study, an APOA1 variant (affecting HDL-C levels and reverse cholesterol transport) and an ANGPTL4 variant (affecting plasma triglycerides) had substantial effects on CAD. This might suggest that the products of these genes may represent potential therapeutic targets.

 The recent Sixth Joint Task Force for Cardiovascular Disease Prevention has reinforced the value of non-HDL-C as an alternative target for lipid lowering interventions.4 As this measure does not require fasting, there are obvious practical advantages. Moreover, the results of this study indicating that non-HDL-C confers CAD risk beyond that of LDL-C, suggests that it may be a preferable marker in assessment of residual cardiovascular risk, including that remaining in patients receiving lipid-lowering therapy according to current standards of care.


1. Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:993–2000.

2. Do R et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015;518:102–6.

3. Varbo A, Benn M, Tybjaerg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–36.

4. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016; DOI: ehw106 First published online: 23 May 2016

Key words non-HDL cholesterol; atherogenic lipoproteins; coronary risk; genetic study; remnant cholesterol; residual cardiovascular risk