Expert Review: Heart Failure, Lipid / Metabolic

Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomization study

The present study sought to assess whether there is a causal relationship between raising HDL and the risk for myocardial infarction (MI). Using a mendelian randomization, the authors found that in patients with genetically higher HDL the risk of MI was not lower than in those with normal HDL. These data question the concept that pharmacological therapies raising HDL can improve risk of MI. 


It is well known that LDL cholesterol is associated with cardiovascular risk, especially risk for MI. Moreover, it has been shown in both randomised trials of LDL-cholesterol-lowering treatments and from human mendelian diseases that LDL is causally linked to the risk of MI. Much less is known about a potential causal link between HDL and MI, although is has been shown that HDL cholesterol is inversely associated with its risk.

Knowledge Gap

It is not known if high HDL is causally linked to a lower risk of MI, and if measures to raise HDL may be beneficial for lowering the risk of MI in individuals.

Aim of the Study

The authors sought to assess whether genetically raised plasma HDL cholesterol may be protective for MI. They performed two mendelian randomization analyses in numerous patients from case-control studies and prospective cohort studies.


The authors determined the number of individuals carrying a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) in 20 studies (20,913 myocardial infarction cases, 95,407 controls). In addition, they applied a genetic scoring of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of MI and 41,331 controls.


Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol but similar levels of other lipid and non-lipid risk factors for MI compared with non-carriers. This difference in HDL cholesterol was expected to decrease risk of MI by 13%. However, the 396Ser allele was not associated with risk of MI (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 standard deviation in HDL cholesterol was associated with reduced risk of myocardial infarction. However, a 1 standard deviation increase in HDL-C due to genetic score was not associated with risk of MI (OR 0·93, 95% CI 0·68–1·26, p=0·63).


Genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of MI. This data questions the concept that raising plasma HDL cholesterol translates into reduction in risk of MI.

Perspective-Clinical Impact

The data from this interesting approach using two mendelian analyses cast doubt on the old concept that lowering LDL and raising HDL are both similarly and causally linked to the risk of MI.

Obviously, the risk of MI was not lower in individuals with a genetically higher HDL. These findings should lead to a more detailed exploration of mechanisms in HDL function in search of an explanation for this finding. Moreover, current therapeutic concepts of raising HDL in patients with high risk for MI may not be as efficient as previously thought. Finally, this study is a nice example on how to use genetic information from cohort studies to generate new pathophysiologic concepts.

Corresponding author from original paper

Dr Sekar Kathiresan, Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA,


Citation: The Lancet, Early Online Publication, 17 May 2012doi:10.1016/S0140-6736(12)60312-2

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