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HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics

  • Cardiovascular Genomics (TL Assimes, Section Editor)
  • Published:
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Abstract

Purpose of Review

Elevated high-density lipoprotein cholesterol levels in the blood (HDL-C) represent one of the strongest epidemiological surrogates for protection against coronary heart disease (CHD), but recent human genetic and pharmacological intervention studies have raised controversy about the causality of this relationship. Here, we review recent discoveries from human genome studies using new analytic tools as well as relevant animal studies that have both addressed, and in some cases, fueled this controversy.

Recent Findings

Methodologic developments in genotyping and sequencing, such as genome-wide association studies (GWAS), exome sequencing, and exome array genotyping, have been applied to the study of HDL-C and risk of CHD in large, multi-ethnic populations. Some of these efforts focused on population-wide variation in common variants have uncovered new polymorphisms at novel loci associated with HDL-C and, in some cases, CHD risk. Other efforts have discovered loss-of-function variants for the first time in genes previously implicated in HDL metabolism through common variant studies or animal models. These studies have allowed the genetic relationship between these pathways, HDL-C and CHD to be explored in humans for the first time through analysis tools such as Mendelian randomization. We explore these discoveries for selected key HDL-C genes CETP, LCAT, LIPG, SCARB1, and novel loci implicated from GWAS including GALNT2, KLF14, and TTC39B.

Summary

Recent human genetics findings have identified new nodes regulating HDL metabolism while reshaping our current understanding of known candidate genes to HDL and CHD risk through the study of critical variants across model systems. Despite their effect on HDL-C, variants in many of the reviewed genes were found to lack any association with CHD. These data collectively indicate that HDL-C concentration, which represents a static picture of a very dynamic and heterogeneous metabolic milieu, is unlikely to be itself causally protective against CHD. In this context, human genetics represent an extremely valuable tool to further explore the biological mechanisms regulating HDL metabolism and investigate what role, if any, HDL plays in the pathogenesis of CHD.

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Acknowledgements

This work was supported by grants HL055323, HL111398, and HL133502 from the National Institutes of Health. Additionally, SAK has been supported by a fellowship 5F30HL124967 from the National Institutes of Health and the Medical Scientist Training Program of the Perelman School of Medicine, University of Pennsylvania. The content is solely the responsibility of the authors and does not necessarily represent the official viewpoints of the NIH.

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  1. Perelman School of Medicine at the University of Pennsylvania, 11-162 TRC, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Cecilia Vitali, Sumeet A. Khetarpal & Daniel J. Rader

  2. Departments of Genetics and Medicine, Cardiovascular Institute, and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, 11-125 TRC, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Daniel J. Rader

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  1. Cecilia Vitali
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Cecilia Vitali and Sumeet A. Khetarpal declare that they have no conflict of interest. Daniel J. Rader serves as consultant to the following companies: Alnylam, CSL-Behring, DalCor, Eli Lilly, Novartis, and Pfizer.

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Vitali, C., Khetarpal, S.A. & Rader, D.J. HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics. Curr Cardiol Rep 19, 132 (2017). https://doi.org/10.1007/s11886-017-0940-0

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