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Current Cardiology Reports
Erschienen in: Current Cardiology Reports 12/2017

01.12.2017 | Cardiovascular Genomics (TL Assimes, Section Editor)

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

verfasst von: Cecilia Vitali, Sumeet A. Khetarpal, Daniel J. Rader

Erschienen in: Current Cardiology Reports | Ausgabe 12/2017

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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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Metadaten
Titel
HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics
verfasst von
Cecilia Vitali
Sumeet A. Khetarpal
Daniel J. Rader
Publikationsdatum
01.12.2017
Verlag
Springer US
Erschienen in
Current Cardiology Reports / Ausgabe 12/2017
Print ISSN: 1523-3782
Elektronische ISSN: 1534-3170
DOI
https://doi.org/10.1007/s11886-017-0940-0

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