TY - JOUR

T1 - HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease – Insights from randomized clinical trials and human genetics

AU - Kjeldsen, Emilie Westerlin

AU - Thomassen, Jesper Qvist

AU - Frikke-Schmidt, Ruth

N1 - Publisher Copyright: © 2021 The Authors

PY - 2022

Y1 - 2022

N2 - Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies.

AB - Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies.

KW - Atherosclerotic cardiovascular disease

KW - HDL cholesterol concentration

KW - HDL deficiency syndromes

KW - Mendelian randomization studies

U2 - 10.1016/j.bbalip.2021.159063

DO - 10.1016/j.bbalip.2021.159063

M3 - Review

C2 - 34637926

AN - SCOPUS:85117235176

VL - 1867

JO - B B A - Molecular and Cell Biology of Lipids

JF - B B A - Molecular and Cell Biology of Lipids

SN - 1388-1981

IS - 1

M1 - 159063

ER -