New genetic research fails to support a causal association between higher concentrations of high-density lipoprotein (HDL) cholesterol and a lower risk of heart attack. The findings, published Online First in The Lancet, challenge the established view that raising HDL cholesterol will uniformly translate into reductions in heart attack risk.
"These results show that some ways of raising HDL cholesterol might not reduce risk of myocardial infarction [heart attack] in human beings. Therefore, if an intervention such as a drug raises HDL cholesterol, we cannot automatically assume that risk of myocardial infarction will be reduced", explains Sekar Kathiresan from Massachusetts General Hospital, Broad Institute, and Harvard Medical School in the USA, lead author of the study.
HDL cholesterol is known as "good" cholesterol because higher concentrations have been associated with lower risk of heart attacks in observational studies, but whether this association is causal is uncertain.
While lowering low-density lipoprotein or LDL ("bad" cholesterol) decreases the risk of heart attack, it has not been shown that raising HDL similarly reduces the risk of heart attack.
This new study used mendelian randomisation to compare heart attack risk in people with an inherited increase in HDL cholesterol (those carrying the LIPG 396Ser allele) who would be expected to have a reduced risk of heart attack.
In analysis of 20 913 heart attack cases and 95 407 controls from 20 studies, findings showed that people with a genetically-programmed tendency for higher HDL cholesterol concentrations did not have a lower susceptibility to heart attack.
The researchers then constructed a genetic risk score testing for 14 common genetic variants exclusively associated with HDL cholesterol in nearly 12 500 people with a history of heart attack and over 41 000 controls. The score was not associated with risk of heart attack, "suggesting that some genetic mechanisms that raise HDL cholesterol do not lower risk of myocardial infarction", say the authors.
They conclude: "Interventions (lifestyle or pharmacological) that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction."
In an accompanying Comment, Steve Humphries and colleagues from University College London, UK remark: "These findings are consistent with previous mendelian randomisation analyses that also refute a causal role of HDL cholesterol in coronary heart disease."
They add: "However, even if HDL cholesterol concentration is not validated as a causal factor, further investigation into the mechanisms of HDL cholesterol and its function in coronary heart disease is warranted."
Dr Sekar Kathiresan, Massachusetts General Hospital, Broad Institute, and Harvard Medical School, Boston, USA. T) +1 617 643 7995 E) skathiresan@partners.org
Professor Steve Humphries, University College London, London, UK. T) +44 (0) 207 679 6962 E) steve.humphries@ucl.ac.uk
Journal
The Lancet