Cardioprotective effect of high HDL cholesterol queried
MedWire News: Raising plasma high-density lipoprotein (HDL) cholesterol may not necessarily reduce the risk for myocardial infarction (MI), research shows.
A mendelian randomization study indicates that genetic mechanisms that raise HDL cholesterol do not seem to have any impact on MI risk.
"Hence, interventions that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction," write Sekar Kathiresan (Massachusetts General Hospital, Boston) and colleagues in The Lancet.
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, explains the team.
"For a biomarker directly involved in disease pathogenesis, we expect a genetic variant that modulates the biomarker to likewise confer risk for disease," remark Kathiresan et al.
To investigate, the researchers performed two mendelian randomization analyses to examine whether the association of plasma HDL cholesterol with MI 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. In addition, they tested a genetic risk score consisting of 14 common single nucleotide polymorphisms (SNPs) 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 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 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."
By Joanna Lyford