• Anette Varbo, Marianne Benn, Anne Tybjærg-Hansen, Anders B Jørgensen, Ruth Frikke-Schmidt, and Børge G Nordestgaard.
• Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
• J. Am. Coll. Cardiol. 2013 Jan 29; 61 (4): 427-436.

ObjectivesThe 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.BackgroundElevated remnant cholesterol is associated with elevated levels of triglyceride-rich lipoproteins and with reduced HDL cholesterol, and all are associated with ischemic heart disease.MethodsA 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.ResultsThe 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.ConclusionsA 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.Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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