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|Objective||To evaluate whether elevated non-fasting remnant cholesterol, defined as non-fasting total cholesterol – (HDL-C + low-density lipoprotein cholesterol [LDL-C]) is a causal risk factor for IHD, independent of low HDL-C.|
|Study design||Mendelian randomization design based on observational and genetic data from the Copenhagen General Population Study (CGPS), Copenhagen City Heart Study (CCHS) and the Copenhagen Ischemic Heart Disease Study (CIHDS). Fifteen genetic variants affecting remnant cholesterol alone, remnant cholesterol/HDL-C, LDL-C, or HDL-C were selected.|
In total, 73,513 subjects were genotyped, of whom 11,984 had IHD diagnosed between 1976 and 2010. Characteristics of subjects in each study are summarized.
HDL-C, LDL-C and triglycerides
For combined control data, Cox proportional hazards regression models were used to estimate hazard ratios for IHD by lipoprotein quintile. Multivariate adjustment was performed for age, sex, smoking, hypertension, time since last meal, time of day for blood sampling, and lipid-lowering therapy. Correction for regression dilution bias was performed using lipoprotein values from 4,253 individuals without lipid-lowering therapy from the CCHS.
One-way analysis of variance was used to compare lipoprotein levels as a function of genotypes in the CGPS, CCHS, and CIHDS controls combined. The following genotypes were combined in 4 groups:
Logistic regression was used to evaluate the association of genotypes with observed risk for IHD based on the combined data.
The key findings are summarized.
The higher causal odds ratio for remnant cholesterol suggests that lifelong exposure through genetically elevated levels has a larger effect on risk than that suggested from observational data alone
Recent consensus1 has highlighted the importance of triglyceride-rich lipoproteins, typically manifest as elevated plasma triglycerides, often in association with low HDL-C, in atherosclerosis and cardiovascular disease. Failure to show outcome benefits associated with raising HDL-C in recent trials,2 implicates remnant cholesterol in triglyceride-rich lipoproteins rather than HDL-C, in causal risk.
The current study provides direct causal evidence of this association. Based on genotype analysis, each 1 mmol/L (39 mg/dL) genetic increase in remnant cholesterol was associated with a 2.8-fold causal risk for IHD, independent of reduced HDL C. These results support considerable mechanistic evidence that remnant lipoproteins are atherogenic; these lipoproteins are able to cross the endothelial barrier, and are taken up by scavenger receptors into the subendothelial space to promote foam cell formation.3‑5
The study is strengthened by a number of features, including the large number of subjects, lack of bias (due to the nature of the sample, all white subjects of Danish descent), and inclusion of a positive control (LDL-C). The use of a Mendelian randomisation design is another strength. This is a method for testing for a causal effect from observational data in the presence of confounding factors, corresponding to a ‘natural’ randomised trial. However, it is acknowledged6 that because pleiotropic effects of the genetic variants cannot be excluded, the findings need to be confirmed in further studies with additional genetic variants and/or randomized intervention trials.
The study findings are clearly consistent with the focus of the R3i on atherogenic dyslipidemia as an important contributor to cardiovascular risk beyond LDL-C. Moreover, this study adds to emerging consensus that it is elevated triglyceride-rich lipoproteins – rather than low HDL-C- that is the key contributor to this residual cardiovascular risk. The results of this study also lend support to the view7 that alternative lipid targets that better reflect the burden of triglyceride-rich lipoproteins in patients with atherogenic dyslipidemia– such as non-HDL‑C – may be preferable to LDL-C.
1. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61