Plasma HDL Cholesterol and Risk of Myocardial Infarction: A Mendelian Randomization Study

Study Questions:

High plasma high-density lipoprotein cholesterol (HDL-C) is associated with reduced risk of myocardial infarction (MI), but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of nongenetic confounding, and are unmodified by disease processes, mendelian randomization can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Is the genetic predisposition to a higher level of HDL-C associated with a lower risk of MI?


The authors performed a case-control study using two mendelian randomization analyses. First, a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) related to HDL-C was tested in 20 studies (20,913 MI cases, 95,407 controls). Second, a genetic score consisting of 14 common SNPs that is exclusively associated with HDL-C was tested in up to 12,482 cases of MI and 41,331 controls. As a positive control, a genetic score of 13 common SNPs was used that is exclusively associated with LDL-C.


Carriers of the LIPG 396Ser allele (2.6% frequency) had higher HDL-C [0.14 mmol/L (5.41 mg/dl) higher, p = 8 × 10–13], but similar levels of other lipid and nonlipid risk factors for MI compared with noncarriers. This difference in HDL-C is expected to decrease risk of MI by 13% (odds ratio [OR], 0.87; 95% CI, 0.84-0.91). 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 [SD] in HDL-C was associated with reduced risk of MI (OR, 0.62; 95% CI, 0.58-0.66). However, a 1 SD 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). For LDL-C, the estimate from observational epidemiology (a 1 SD increase in LDL-C associated with OR, 1.54; 95% CI, 1.45-1.63) was concordant with that from genetic score (OR, 2.13; 95% CI, 1.69-2.69; p = 2 × 10–10).


Some genetic mechanisms that raise plasma HDL-C do not seem to lower risk of MI. These data challenge the concept that raising of plasma HDL-C will uniformly translate into reductions in risk of MI.


This wonderful genetic study took the cooperation of many investigative teams and yielded results that would have been surprising until recently. The findings are timely, considering the recent trials showing niacin + statins, and two different cholesterol ester transfer protein (CETP) inhibitors + statins that raised HDL-C significantly were not associated with a reduction in coronary event rates. Clearly the results should not discourage clinical trials designed to test the value of strategies that increase the HDL-C. Of interest, a common genetic variation of CETP reduced the incidence of MI by 4%, so there is hope for other outcome studies of CETP inhibitors.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Genetic Variation, Odds Ratio, Outcome Assessment (Health Care), Myocardial Infarction, Risk Reduction Behavior, Meiosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Factors, Incidence, Cholesterol, Lipase, Cholesterol Ester Transfer Proteins, Case-Control Studies, Polymorphism, Single Nucleotide, Biological Markers, Heterozygote, Genetic Predisposition to Disease, Cardiovascular Diseases, Niacin, Genotype, Lipoproteins, HDL

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