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

Günther Silbernagel; Hubert Scharnagl; Marcus E. Kleber; Graciela Delgado; Tatjana Stojakovic; Reijo Laaksonen; Jeanette Erdmann; Tuomo Rankinen; Claude Bouchard; Ulf Landmesser; Heribert Schunkert; Winfried März; Tanja B. Grammer

doi:10.1016/j.atherosclerosis.2018.12.024

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

Günther Silbernagel, Hubert Scharnagl^*, Marcus E. Kleber, Graciela Delgado, Tatjana Stojakovic, Reijo Laaksonen, Jeanette Erdmann, Tuomo Rankinen, Claude Bouchard, Ulf Landmesser, Heribert Schunkert, Winfried März, Tanja B. Grammer

^*Corresponding author for this work

43 Citations (Scopus)

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.

Original language	English
Journal	Atherosclerosis
Volume	282
Pages (from-to)	37-44
Number of pages	8
ISSN	0021-9150
DOIs	https://doi.org/10.1016/j.atherosclerosis.2018.12.024
Publication status	Published - 03.2019

Funding

Dr. Silbernagel reports grants and personal fees from Sanofi, grants and non-financial support from Amgen, grants from Numares, and non-financial support from Bayer, outside the submitted work. Dr. Landmesser reports personal fees from Sanofi, personal fees from Amgen, personal fees from Medicines Company, personal fees from Bayer, personal fees from Novartis, personal fees from Abbott, outside the submitted work. Dr. Laaksonen reports other from Zora Biosciences, outside the submitted work. Dr. März reports other from Synlab Services GmbH, other from Synlab Holding GmbH, grants and personal fees from Siemens Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from Amgen, grants and personal fees from Astrazeneca, grants and personal fees from Danone Research, grants and personal fees from Sanofi, personal fees from Hoffmann LaRoche, personal fees from MSD, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Synageva, grants and personal fees from BASF, grants from Abbott Diagnostics, grants and personal fees from Numares, outside the submitted work. Dr. Schunkert, Dr. Scharnagl, Dr. Kleber, Mrs. Delgado, Dr. Stojakovic, Dr. Erdmann, Dr. Rankinen, Dr. Bouchard, and Dr. Grammer have nothing to disclose. The LURIC study was supported by the 7th Framework Program (integrated projects AtheroRemo , Grant Agreement number 201668 and RiskyCAD , Project Number 305739 ) of the European Union, by the German Federal Ministry of Education and Research (project e:AtheroSysMed [Systems medicine of coronary heart disease and stroke], grant number 01ZX1313A-K ). The work was also supported as part of the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD) which is funded by the German Federal Ministry of Education and Research (grant number 01EA1411A ). The HERITAGE Family Study was funded by the National Institutes of Health (grant numbers HL-45670 , HL- 47323 , HL- 47317 , HL- 47327 , HL- 47321 ). C. Bouchard is partially supported by the John W. Barton Sr Chair in Genetics and Nutrition.

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Research Area: Medical Genetics

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10.1016/j.atherosclerosis.2018.12.024

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Silbernagel, G., Scharnagl, H., Kleber, M. E., Delgado, G., Stojakovic, T., Laaksonen, R., Erdmann, J., Rankinen, T., Bouchard, C., Landmesser, U., Schunkert, H., März, W., & Grammer, T. B. (2019). LDL triglycerides, hepatic lipase activity, and coronary artery disease: An epidemiologic and Mendelian randomization study. Atherosclerosis, 282, 37-44. https://doi.org/10.1016/j.atherosclerosis.2018.12.024

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

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. ",

author = "G{\"u}nther Silbernagel and Hubert Scharnagl and Kleber, \{Marcus E.\} and Graciela Delgado and Tatjana Stojakovic and Reijo Laaksonen and Jeanette Erdmann and Tuomo Rankinen and Claude Bouchard and Ulf Landmesser and Heribert Schunkert and Winfried M{\"a}rz and Grammer, \{Tanja B.\}",

year = "2019",

month = mar,

doi = "10.1016/j.atherosclerosis.2018.12.024",

language = "English",

volume = "282",

pages = "37--44",

journal = "Atherosclerosis",

issn = "0021-9150",

publisher = "Elsevier Ireland Ltd",

}

Silbernagel, G, Scharnagl, H, Kleber, ME, Delgado, G, Stojakovic, T, Laaksonen, R, Erdmann, J, Rankinen, T, Bouchard, C, Landmesser, U, Schunkert, H, März, W & Grammer, TB 2019, 'LDL triglycerides, hepatic lipase activity, and coronary artery disease: An epidemiologic and Mendelian randomization study', Atherosclerosis, vol. 282, pp. 37-44. https://doi.org/10.1016/j.atherosclerosis.2018.12.024

TY - JOUR

T1 - LDL triglycerides, hepatic lipase activity, and coronary artery disease: An epidemiologic and Mendelian randomization study

AU - Silbernagel, Günther

AU - Scharnagl, Hubert

AU - Kleber, Marcus E.

AU - Delgado, Graciela

AU - Stojakovic, Tatjana

AU - Laaksonen, Reijo

AU - Erdmann, Jeanette

AU - Rankinen, Tuomo

AU - Bouchard, Claude

AU - Landmesser, Ulf

AU - Schunkert, Heribert

AU - März, Winfried

AU - Grammer, Tanja B.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85060326687

U2 - 10.1016/j.atherosclerosis.2018.12.024

DO - 10.1016/j.atherosclerosis.2018.12.024

M3 - Journal articles

C2 - 30685440

AN - SCOPUS:85060326687

SN - 0021-9150

VL - 282

SP - 37

EP - 44

JO - Atherosclerosis

JF - Atherosclerosis

ER -

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

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