Clinical Research
Cardiometabolic Risk
Remnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease

https://doi.org/10.1016/j.jacc.2012.08.1026Get rights and content
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Objectives

The aim of this study was to test the hypothesis that elevated nonfasting remnant cholesterol is a causal risk factor for ischemic heart disease independent of reduced high-density lipoprotein (HDL) cholesterol.

Background

Elevated remnant cholesterol is associated with elevated levels of triglyceride-rich lipoproteins and with reduced HDL cholesterol, and all are associated with ischemic heart disease.

Methods

A total of 73,513 subjects from Copenhagen were genotyped, of whom 11,984 had ischemic heart disease diagnosed between 1976 and 2010. Fifteen genetic variants were selected, affecting: 1) nonfasting remnant cholesterol alone; 2) nonfasting remnant cholesterol and HDL cholesterol combined; 3) HDL cholesterol alone; or 4) low-density lipoprotein (LDL) cholesterol alone as a positive control. The variants were used in a Mendelian randomization design.

Results

The causal odds ratio for a 1 mmol/l (39 mg/dl) genetic increase of nonfasting remnant cholesterol was 2.8 (95% confidence interval [CI]: 1.9 to 4.2), with a corresponding observational hazard ratio of 1.4 (95% CI: 1.3 to 1.5). For the ratio of nonfasting remnant cholesterol to HDL cholesterol, corresponding values were 2.9 (95% CI: 1.9 to 4.6) causal and 1.2 (95% CI 1.2 to 1.3) observational for a 1-U increase. However, for HDL cholesterol, corresponding values were 0.7 (95% CI: 0.4 to 1.4) causal and 1.6 (95% CI: 1.4 to 1.7) observational for a 1 mmol/l (39 mg/dl) decrease. Finally, for LDL cholesterol, corresponding values were 1.5 (95% CI: 1.3 to 1.6) causal and 1.1 (95% CI: 1.1 to 1.2) observational for a 1 mmol/l (39 mg/dl) increase.

Conclusions

A nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for ischemic heart disease, independent of reduced HDL cholesterol. This implies that elevated cholesterol content of triglyceride-rich lipoprotein particles causes ischemic heart disease. However, because pleiotropic effects of the genetic variants studied cannot be totally excluded, these findings need to be confirmed using additional genetic variants and/or randomized intervention trials.

Key Words

atherosclerosis
cardiovascular disease
lipoproteins
myocardial infarction

Abbreviations and Acronyms

CI
confidence interval
HDL
high-density lipoprotein
LDL
low-density lipoprotein

Cited by (0)

This study was supported by the Danish Medical Research Council, the Danish Heart Foundation, Herlev Hospital, Copenhagen University Hospital, Copenhagen County Foundation, and Chief Physician Johan Boserup and Lise Boserup's Fund, Denmark. Dr. Nordestgaard has received lecture and/or consultancy honoraria from AstraZeneca, Merck, Pfizer, Karo Bio, Omthera, Abbott, Sanofi-Aventis, Regeneron, and ISIS Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.