Focus on HDL cholesterol and cardiovascular disease IAS HDL Workshop

Epidemiological evidence supports an association between HDL cholesterol and cardiovascular disease. Population-based genome studies and family linkage studies have been used to investigate this association further, although results have been mixed, as discussed at the IAS HDL Workshop, 17-20 May, Whistler, Canada. 

 

Sek Kathiresan MD, of the Broad Institute, Cambridge, MA, USA overviewed evidence from population-based genome studies. In studies investigating a link between genes for HDL cholesterol and risk for myocardial infarction (MI), only six of 15 common HDL single nucleotide polymorphisms (SNPs) were associated with increased MI risk. However, such findings could be limited by modest effect sizes of the SNPs on HDL cholesterol. For example, genome-wide association studies have identified variants of endothelial lipase variants that are associated with plasma HDL-C levels in humans. A meta-analysis across 5 cohorts demonstrated that the loss of function Asn396Ser variant was significantly associated with increased HDL-C (1). However, because of the modest effect size (~13%), the variant conferred no significant effect on MI risk. Moreover, it is likely to be difficult to show a significant effect against a background of pre-existing atherosclerosis, or due to confounding by lifestyle factors which are known to influence HDL cholesterol levels.

 

Pleiotropic or opposing effects of the individual variants on multiple lipid fractions could also contribute to this confusion. For example, variants of the CETP locus have been shown to increase both HDL cholesterol and lower LDL cholesterol. Alternatively, some ABCA1 variants have been shown to raise both HDL cholesterol and triglycerides.

 

Further, there is debate as to which is the most appropriate endpoint for such studies, with the suggestion that any cardiovascular disease event, evidence of atherosclerotic plaque, or even age at the onset of cardiovascular disease, might be more appropriate.

 

Instead, family-based linkage studies provide stronger evidence for a link between HDL cholesterol and cardiovascular risk, according to Professor John Kastelein, Academisch Medisch Centrum Amsterdam, The Netherlands. In such studies, conducted in individuals with either very low or very high plasma levels of HDL cholesterol, the effect size is substantially greater which, even in smaller studies, strengthens the likelihood of association.

 

Dr Kastelein highlighted evidence from family studies showing that genetic variants of apolipoprotein A-I (apoA-I) are associated with cardiovascular disease risk (2). Individuals heterozygous for the L178P variant had 50% lower plasma levels of apoA-I, 63% lower levels of HDL cholesterol and increased carotid intima-media thickness, and these changes were associated with a 24-fold increase in coronary artery disease risk. These data have been instrumental in the development of ApoA-I-based therapies aimed at reducing cardiovascular risk.

 

However, the data are also mixed, as is the case for studies which investigated ABCA1 variants. On the one hand, infusion of reconstituted HDL in subjects heterozygous for ABCA1 loss of function variants led to restoration of endothelial function (3). Another study, however, showed that individuals with another ABCA1 variant had lowered plasma levels of HDL cholesterol but no change in cardiovascular risk (4). The reasons for these conflicting data could relate to the size of the effect on HDL cholesterol (modest), as well as effects on other lipids such as LDL cholesterol which may offset the HDL effect. These data emphasise the need for studies evaluating SNPs that explain the large percentage of variation in a given trait.

 

Dr Kastelein highlighted the need for best body on body comparisons, sensitive assessment methodologies for atherosclerosis and studies using an increased number of cases to maximise the value of family linkage data. Such studies could provide more appropriate modelling of the effects of therapeutic intervention. Finally, the possibility that there are more appropriate HDL markers cannot be discounted.

 

Ultimately, outcome studies evaluating the effect of raising HDL cholesterol on cardiovascular risk, such as the dal-OUTCOMES study (5), are needed to resolve this ongoing controversy.

 

 

References

1. Edmondson AC, Brown RJ, Kathiresan S et al. Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J Clin Invest 2009; 119(4):1042-50.

2. Hovingh GK, Brownlie A, Bisoendial RJ et al. A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease. J Am Coll Cardiol 2004;44:1429-35.

3. van Dam MJ, De Groot E, Clee SM et al. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study. Lancet 2002;359:37-42.

4. Frikke-Schmidt R, Nordestgaard BG, Stene MC et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 2008; 299:2524-32.

5. Schwartz GG, Olsson AG, Ballantyne CM et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009; 58:896-901.