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LDL triglycerides, hepatic lipase activity, and coronary artery disease: An epidemiologic and Mendelian randomization study

  • Günther Silbernagel
    Affiliations
    Division of Angiology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Department of Cardiology, Charité Berlin (CBF), Berlin Institute of Health (BIH), And DZHK (German Research Centre for Cardiovascular Research), Partner Site Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
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  • Hubert Scharnagl
    Correspondence
    Corresponding author.
    Affiliations
    Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
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  • Marcus E. Kleber
    Affiliations
    Department of Internal Medicine 5 (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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  • Graciela Delgado
    Affiliations
    Department of Internal Medicine 5 (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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  • Tatjana Stojakovic
    Affiliations
    Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
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  • Reijo Laaksonen
    Affiliations
    Zora Biosciences Oy, Espoo, Finland

    Finnish Cardiovascular Research Center Tampere, University of Tampere, Finland

    Finnish Clinical Biobank, University Hospital of Tampere, Finland
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  • Jeanette Erdmann
    Affiliations
    Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany

    DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany

    University Heart Center Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany
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  • Tuomo Rankinen
    Affiliations
    Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA, 70808, United States
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  • Claude Bouchard
    Affiliations
    Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA, 70808, United States
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  • Ulf Landmesser
    Affiliations
    Department of Cardiology, Charité Berlin (CBF), Berlin Institute of Health (BIH), And DZHK (German Research Centre for Cardiovascular Research), Partner Site Berlin, Hindenburgdamm 30, 12203, Berlin, Germany
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  • Heribert Schunkert
    Affiliations
    Department of Cardiology, German Heart Center Munich, Technical University Munich and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Lazarettstraße 36, 80636, Munich, Germany
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  • Winfried März
    Affiliations
    Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Synlab Academy, Synlab Holding Germany GmbH, P5, 7, 68167, Mannheim, Germany

    Department of Internal Medicine 5 (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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  • Tanja B. Grammer
    Affiliations
    Mannheim Institute of Public Health, Mannheim Medical Faculty, University of Heidelberg, Ludolf-Krehl-Straße 7-11, 68167, Mannheim, Germany
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      Highlights

      • High LDL triglycerides are associated with increased cardiovascular mortality, both in males and females.
      • LDL triglycerides are strongly associated with variants in the hepatic lipase region, both in males and females.
      • Low hepatic lipase acitivity implicates high LDL triglycerides.
      • Low hepatic lipase activity appears to be a causal cardiovascular risk factor.

      Abstract

      Background and aims

      High concentrations of low density lipoprotein (LDL) triglycerides have been associated with prevalent angiographic coronary artery disease. The present analysis was designed to investigate the association of LDL triglycerides with cardiovascular mortality and to explore possible mechanisms that may link LDL triglycerides to cardiovascular risk.

      Methods

      LDL triglycerides were measured in 3140 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. They were prospectively followed for cardiovascular mortality (median duration 9.9 years). Genome wide association data for LDL triglycerides were available for 2900 LURIC participants. Genetic data and measurements of hepatic lipase activity were available for 478 participants of the HERITAGE Family study. Genome wide association data for cardiovascular disease were available for 184,305 participants of the CARDIoGRAMplusC4D consortium.

      Results

      There was a continuous positive association between LDL triglycerides and cardiovascular mortality (hazard ratio for 5th vs. 1st quintile = 2.53, p < 0.001) and this association was similar in males and females. Genome wide association analysis in LURIC revealed that LDL triglycerides were strongly associated with variation in the hepatic lipase region (p < 10−15 for rs1800588 and rs10468017). The LDL triglyceride raising alleles in rs1800588 and rs10468017 were associated with low hepatic lipase activity in HERITAGE and increased cardiovascular risk in CARDIoGRAMplusC4D. Two-sample Mendelian randomization analysis (HERITAGE and CARDIoGRAMplusC4D) using rs1800588 and rs10468017 as instrumental variable suggested that low hepatic lipase activity may cause increased cardiovascular risk (p = 0.013).

      Conclusions

      Low hepatic lipase activity may link high LDL triglycerides to increased cardiovascular risk.

      Keywords

      Abbreviations:

      HDL (high density lipoprotein), HERITAGE (Health Risk Factors Exercise Training and Genetics), IDL (intermediate density lipoprotein), LDL (low density lipoprotein), LURIC (Ludwigshafen Risk and Cardiovascular Health), SNP (single nucleotide polymorphism), VLDL (very low density lipoprotein)
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