Beyond the Genetics of HDL: Why Is HDL Cholesterol Inversely Related to Cardiovascular Disease?

There is unequivocal evidence that high-density lipoprotein (HDL) cholesterol levels in plasma are inversely associated with the risk of cardiovascular disease (CVD). Studies of families with inherited HDL disorders and genetic association studies in general (and patient) population samples have identified a large number of factors that control HDL cholesterol levels. However, they have not resolved why HDL cholesterol and CVD are inversely related. A growing body of evidence from nongenetic studies shows that HDL in patients at increased risk of CVD has lost its protective properties and that increasing the cholesterol content of HDL does not result in the desired effects. Hopefully, these insights can help improve strategies to successfully intervene in HDL metabolism. It is clear that there is a need to revisit the HDL hypothesis in an unbiased manner. True insights into the molecular mechanisms that regulate plasma HDL cholesterol and triglycerides or control HDL function could provide the handholds that are needed to develop treatment for, e.g., type 2 diabetes and the metabolic syndrome. Especially genome-wide association studies have provided many candidate genes for such studies. In this review we have tried to cover the main molecular studies that have been produced over the past few years. It is clear that we are only at the very start of understanding how the newly identified factors may control HDL metabolism. In addition, the most recent findings underscore the intricate relations between HDL, triglyceride, and glucose metabolism indicating that these parameters need to be studied simultaneously.

Gene • Dyslipidemia • Hyperalphalipoproteinemia • Hypoalphalipoproteinemia


Ever since plasma HDL cholesterol concentration was found to be inversely correlated with the risk of cardiovascular disease (CVD), there has been a strong interest in the biological mechanisms that can explain this correlation. From a large number of studies in humans, animals, and tissue culture, it has become clear that HDL exerts many beneficial functions with prominent roles in cellular cholesterol efflux and protection against inflammation. For recent overviews on this topic, see Luscher et al. (2014) and Rye and Barter (2014).

Paradoxically and not always recognized, however, is that rare inborn errors of HDL metabolism have illustrated that an almost complete loss of HDL or very high HDL cholesterol levels do not automatically translate in accelerated or protection from atherosclerosis, respectively. These observations may be related to the small numbers of patients available for studies or the absence/presence of concomitant established risk factors for CVD (such as increased LDL cholesterol, smoking, etc.) in these individuals. However, these findings by themselves indicate that the relation of HDL cholesterol with atherosclerosis is not as straightforward as for LDL cholesterol since in this case increases and decreases are always associated with increased and decreased risk, respectively.

Genetic approaches are frequently used to study whether changes in plasma HDL cholesterol concentration affect atherosclerosis. Such studies are conducted in families, larger patient population samples sharing large-impact mutations in HDL genes, as well as general population samples. Using candidate gene approaches, these studies mostly generated contrasting or confusing results [a short summary of these findings can be found in Chapman et al. (2011)]. Illustrative in this regard were investigations into variation at the locus encoding for the ATP-binding cassette transporter A1 (ABCA1). While a complete loss of ABCA1 function causes near HDL deficiency and often accelerated atherosclerosis in Tangier patients who are referred to the clinic, studies in general population samples indicated that ABCA1 gene variation is not necessarily related with plasma HDL cholesterol concentration and risk of CVD (for review, see Frikke-Schmidt (2011)). More recently, it has become possible to study the impact of whole-genome variation on complex diseases which has shed light on our understanding whether or not genes and their products are related to plasma lipid traits and the risk of CVD. In this regard, particularly Mendelian randomization studies showed that genetic variation associated with increased HDL cholesterol does not protect from atherosclerosis (Voight et al. 2012). In this case, it concerned a study of common variants in HDL candidate genes; however, more recently, it was also shown that low-frequency coding variants (frequencies between 0.1 and 2 %) with relatively large effects on HDL cholesterol and/or triglycerides were also not associated with risk for coronary heart disease (Peloso et al. 2014).

These and other studies have placed HDL cholesterol as a pharmaceutical target under heavy fire especially in the context of several large clinical trials that tested drugs which increased HDL cholesterol but did reduce atherosclerosis (for reviews on CETP inhibitors and the use of niacin: Ginsberg and Reyes-Soffer 2013; Rader and Degoma 2014). While there is still hope for HDL-related interventions as outlined in a recent review (van Capelleveen et al. 2014), it is clear that there is a need to revisit the mechanisms that have been put forward to explain the unequivocal relation between HDL cholesterol and risk of CVD in epidemiological studies.

To date, it is repeatedly been pointed out that a focus on the cholesterol content of HDL should maybe be replaced by a focus on the functions that are associated with this lipoprotein (Feig et al. 2014; Peloso et al. 2014; Luscher et al. 2014; Riwanto and Landmesser 2013), but unfortunately, HDL functionality studies have thus far not provided a solution to the problems encountered. So far it is not clear which of HDL properties should and could be targeted. There is evidence for a focus on HDL as an acceptor of cholesterol (Khera et al. 2011) but later studies were not able to confirm this (Li et al. 2013a, b). In other words, the association with CVD risk has only been firmly established for the concentration of cholesterol in HDL while at the same time there is little evidence of a causal relation between HDL and CVD (Vergeer et al. 2010). Thus, it is possible that HDL cholesterol is a proxy for an unknown correlating factor. A renewed focus on the clinical application of HDL-based strategies for certain indications on the basis of functional properties of HDL but also on significant preclinical and clinical data, as was recently suggested, may hopefully bring relief (Gordts et al. 2013).

In this light, the current chapter focuses on recent studies that have shed new light on how genes and/or their products affect HDL metabolism. The first section shortly describes established regulators of HDL metabolism as a general framework to help understand the new insights that are described in the second section.

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