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16-05-2012 | Cardiometabolic | Article

Doubt cast over cardiovascular protective effect of raising HDL cholesterol


Free abstract

MedWire News: Raising plasma high-density lipoprotein (HDL) cholesterol may not necessarily reduce the risk for myocardial infarction (MI), show US research findings.

The mendelian randomization study indicates that genetic mechanisms that result in elevated HDL cholesterol levels do not seem to have any impact on MI risk.

"Just because an intervention raises HDL cholesterol, we cannot assume automatically that risk for heart attack will be lowered," lead author Sekar Kathiresan from Harvard Medical School in Boston told MedWire News.

"For those patients with low HDL cholesterol, we may want to specifically avoid giving drugs for the sole purpose of raising HDL cholesterol until such drugs have been proven to work in randomized controlled trials."

Despite the well established link between high plasma HDL cholesterol and reduced MI risk, the available evidence for the causal relevance of HDL cholesterol from randomized trials or mendelian diseases is scarce and inconsistent, explain Kathiresan and team in The Lancet.

"For a biomarker directly involved in disease pathogenesis, we expect a genetic variant that modulates the biomarker to likewise confer risk for disease," they remark.

To investigate, the researchers performed two mendelian randomization analyses to examine whether the association of plasma HDL cholesterol with myocardial infarction is causal.

The researchers tested a genetic variant in the endothelial lipase gene, LIPG Asn396Ser, which is known to specifically and substantially increase plasma HDL cholesterol, in 20 studies comprising a total of 20,913 MI cases and 95,407 controls.

"The LIPG 396Ser variant raises HDL cholesterol overall and also raises a subtype of HDL called large HDL," said Kathiresan.

In addition, the team tested a genetic risk score consisting of 14 common single nucleotide polymorphisms (SNPs) that are exclusively associated with HDL cholesterol, in almost 12,500 people.

The authors report that the LIPG 396Ser allele was associated with significant increases in HDL cholesterol, with an effect size that ranged from 0.8 mmol/L to 0.28 mmol/L per copy of the Ser allele.

Based on the associations between SNPs and HDL cholesterol, and those between HDL cholesterol and MI risk, the team estimated that carrying LIPG 396Ser should decrease risk for MI by 13%.

However, no such association between the variant and risk for MI was observed in 50,763 participants from six prospective cohort studies.

Whereas each standard deviation (SD) rise in HDL cholesterol was associated with a significant 48% reduction in odds for MI, there was no association between change in HDL cholesterol due to genetic score and MI risk.

The team says the data challenge several established views about plasma HDL cholesterol. The findings raise the possibility that "a specific means of raising of HDL cholesterol in human beings - namely, inhibition of endothelial lipase - will not reduce risk of myocardial infarction."

"Low HDL cholesterol tracks with a number of other factors including obesity, cigarette smoking, physical inactivity, increased cholesterol in remnant particles, increased small LDL particles, increased coagulation factors, insulin resistance, diabetes, among others," explained Kathiresen. "We hypothesize that the population association of low HDL with increased heart attack risk may be due to one of these other factors."

MedWire ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

By Sally Robertson