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

By Benjamin F. Voight, G. Peloso, M. Orho-Melander, R. Frikke-Schmidt, M. Barbalić, M. Jensen, G. Hindy, H. Hólm, E. Ding, T. Johnson and 116 more. The Lancet, 2012

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Summary Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol 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). Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

Subfields: Cardiology and Cardiovascular Medicine, Endocrinology, Diabetes and Metabolism, Genetics

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Citations in the corpus

2016 European Guidelines on cardiovascular disease prevention in clinical practice (2016, background): “Recommendation for influenza vaccination Recommendation Classa Levelb Ref c Annual vaccination may be considered in patients with established CVD. IIb C 151–154 aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations.”
Atherosclerosis: Process, Indicators, Risk Factors and New Hopes (2014, background): “indicated that high HDL cholesterol concentrations do not usually protect against future risk of coronary heart disease or diabetes.([30,31]) Along with providing ample evidence that high concentrations of serum ApoA‐1 can also lose antioxidant and atheroprotective functions relative to cardiometabo”
2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. (2019, methodology): “A meta-analysis of observational studies has shown that higher TC is associated with increased CAD mortality at all ages.(62,394) However, since the absolute risk of CAD is higher in older persons, Box 6 Management of dyslipidaemia in women”
Hyperlipidemia as a Risk Factor for Cardiovascular Disease (2012, background): “A recently published trial comparing genetic mutations that confer high HDL versus low HDL has called into question the well established belief that HDL-C protects against CVD (45).”
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. (2016, background): “The causative role of HDL-C for protection against CVD has been questioned in several studies utilizing Mendelian randomization.(87,89,91,92) Recent studies suggest that HDL has a complex role in atherogenesis and that the presence of dysfunctional HDL may be more relevant to the ESC/EAS Guidelines ”
Meta-analysis methods for genome-wide association studies and beyond (2013, background): “…a large Mendelian randomization study based on a GWAS meta-analysis managed to demonstrate conclusively that high-density lipoprotein (HDL) is not causally related to coronary artery disease, as variants that affect specifically HDL levels do not have an impact on coronary artery disease risk 91 .”
2016 European Guidelines on cardiovascular disease prevention in clinical practice. (2016, background): “Recommendation for influenza vaccination Recommendation Classa Levelb Ref c Annual vaccination may be considered in patients with established CVD. IIb C 151–154 aClass of recommendation. bLevel of evidence. cReference(s) supporting recommendations.”
Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator (2016, background): “…contrary, although HDL-c is observationally inversely associated with CAD risk, interventions to raise HDL-c concentrations (Schwartz et al., 2012) and focused Mendelian randomization investigations (Voight et al., 2012) suggest that there is not even a moderate causal effect of HDL-c on CAD risk.”
Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects (2015, positive): “Efforts to elucidate causal relationships using genetic variants in a Mendelian randomization approach have indicated that LDL-C plays a causal role in increasing the risk of CHD (22) and have suggested a null causal effect of HDL-C on CHD risk (23).”