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HDL-cholesterol, genetics, and coronary artery disease: the myth of the 'good cholesterol'?

Coronary disease remains a leading cause of death and disability in developed countries, and development of more effective prevention and treatment strategies is of paramount importance. Lowering LDL-cholesterol by targeting HMG-CoA reductase (using statins), Niemann–Pick C1-Like 1 (NPC1L1) protein (by ezetimibe), or proprotein convertase subtilisin/kexin type 9 (PCSK9; by human monoclonal antibodies) has become a safe and effective approach to reduce risk of coronary disease as observed in large-scale clinical outcome studies. Of note, these therapeutic approaches reduce the plasma concentrations of LDL. Moreover, genetic studies have suggested that lifelong reduction of LDL-cholesterol is associated with a more profound, almost three-fold stronger reduction in risk of coronary disease as compared with effects observed in clincial outcome studies, strongly supporting the concept of ‘LDL burden’, i.e. cumulative exposure of the vasculature to increased LDL, rather than simply a one time LDL-cholesterol level, as a determinant and causal risk factor for the pathophysiology and progression of coronary disease. HDL-cholesterol has been considered as the so-called ‘good cholesterol’, largely based on epidemiological studies demonstrating an inverse relationship between reduced HDL-cholesterol levels and an increased risk of coronary disease and myocardial infarction. Several recent large-scale clinical studies testing HDL-cholesterolraising treatments have, however, failed to demonstrate a preventive effect on coronary disease. Notably, translational studies have suggested that potential vasoprotective effects of HDL from healthy subjects were markedly altered in HDL obtained from patients with coronary disease, that has been termed ‘HDL dysfunction’. Of note, Mendelian randomization genetic studies, including those using loss-of-function mutations of ABCA1 or a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser), have shown that genetically higher HDL-cholesterol levels were not associated with a reduced risk of myocardial infarction, in contrast to genetic scores associated with reduced LDL-cholesterol levels. These observations have further challenged the concept that there is a causal relationship between increased HDL-cholesterol levels and a reduced cardiovascular risk. In a recent publication by Zanoni et al. in 2016, the opposite has been suggested by a genetic study, i.e. that heterozygous carriers of the very rare P376L variant of SCARB1, the gene encoding scavenger receptor class B type 1 (SR-BI), had markedly increased levels of plasma HDL-cholesterol, but also an increased risk of coronary disease. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective cholesterol uptake from HDL that was elegantly shown in hepatocyte-like cells derived from induced pluripotent stem cells from a homozygous subject. The association between P376L carrier status and coronary disease was tested in the CARDIoGRAM Exome Consortium and the CHD Exomeþ Consortium in 137 995 individuals [across 49 846 coronary heart disease (CHD) cases and 88 149 CHD controls], and this analysis suggested an increased risk of coronary disease in P376L carriers. However, the P376L variant of SCARB1 is very rare and only 86 carriers could be identified, e.g. 1 in 1600 individuals. In the present issue of the European Heart Journal, Helgadottir et al. present a study from the large cohort of Icelanders who have whole genomes sequenced, and study the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-cholesterol also associate with increased risk of coronary disease (n = 36 886 cases, 306 268 controls). Thirteen SCARB1 mutations were identified and examined for association with HDL-cholesterol. Three different rare SCARB1 mutations, encoding PG319V, PV111M, and PV32M, were shown to be associated with increased HDL-cholesterol levels. However, in the present study, none of the SCARB1 variants was associated with an increased risk of coronary disease. In this large Icelandic cohort, 147 carriers of the above SCARB1 mutations were identified, with a combined allelic frequency of 0.2%. In further analyses, three additional HDL-cholesterol-raising common SCARB1 noncoding variants were examined and similarly were found not to be associated with increased risk for coronary disease.