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

Abstract

SummaryBackgroundHigh 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.MethodsWe 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.FindingsCarriers 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).InterpretationSome 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.FundingUS National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

Genetics: Implications for Prevention and Management of Coronary Artery Disease

“…RCTs of statin and antihypertensive drug therapies (98,(109)(110)(111). In a comprehensive MR study involving 9 LDL-related SNPs in 6 genomic regions, as well as a meta-analysis of multiple studies involving >300,000 individuals and thousands of events, Ference et al documented that individuals inheriting LDL lowering experience a marked reduction in cardiac morbidity and mortality over their lifetime (111).…”

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

“…Reverse cholesterol transport is the process whereby cholesterol is taken from peripheral tissues, like macrophages in the arterial wall, and brought back to the liver for excretion by a direct pathway involving HDL particles and an indirect pathway involving low‐density lipoprotein particles in humans. Because mendelian randomization has not been able to establish a strong causal link between HDL cholesterol (HDL‐C) levels and cardiovascular events,1 HDL functionality, rather than HDL‐C, is regarded as a biomarker of cardiovascular risk. Cholesterol efflux capacity (CEC) to HDL particles is the first step of reverse cholesterol transport, and that capacity of plasma HDL represents a key feature of their functionality.…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…4,5 Moreover, in several inborn errors of human HDL metabolism and genetic mouse models with altered HDL metabolism, the changes in HDL-cholesterol levels were not associated with the opposite changes in cardiovascular risk and atherosclerotic plaque load, respectively, expected from epidemiological studies. 3,6 Because of these controversial data, the causal role and hence suitability as a therapeutic target of HDL has been increasingly questioned.…”

“…5,11,12 Of note, many physiological as well as pathological components and modifications are present at concentrations which are several orders of magnitude lower than the concentration of HDL-cholesterol or even HDL particles and hence reflected by measurements of neither HDL-cholesterol, nor apoA-I, nor HDLparticle concentrations. 5 In the search for biomarkers that reflect the functionality of HDL 6 better than these high-throughput markers, bioassays have been developed for clinical studies as well as for discovery of functional biomarkers by proteomics and lipidomics.…”