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Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : A molecular and genetic association study

Zewinger, Stephen; Kleber, Marcus E; Tragante, Vinicius; McCubrey, Raymond O.; Schmidt, Amand F.; Direk, Kenan; Laufs, Ulrich; Werner, Christian; Koenig, Wolfgang and Rothenbacher, Dietrich, et al. (2017) In The Lancet Diabetes and Endocrinology 5(7). p.534-543
Abstract

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without... (More)

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

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The Lancet Diabetes and Endocrinology
volume
5
issue
7
pages
534 - 543
publisher
Elsevier
external identifiers
  • scopus:85019743146
  • wos:000403672400019
ISSN
2213-8587
DOI
10.1016/S2213-8587(17)30096-7
language
English
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yes
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090d445f-f2d3-40b8-b9c9-abe964a82c78
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2017-06-27 08:04:50
date last changed
2017-09-18 11:42:52
@article{090d445f-f2d3-40b8-b9c9-abe964a82c78,
  abstract     = {<p>Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.</p>},
  author       = {Zewinger, Stephen and Kleber, Marcus E and Tragante, Vinicius and McCubrey, Raymond O. and Schmidt, Amand F. and Direk, Kenan and Laufs, Ulrich and Werner, Christian and Koenig, Wolfgang and Rothenbacher, Dietrich and Mons, Ute and Breitling, Lutz P. and Brenner, Herrmann and Jennings, Richard T. and Petrakis, Ioannis and Triem, Sarah and Klug, Mira and Filips, Alexandra and Blankenberg, Stefan and Waldeyer, Christoph and Sinning, Christoph R. and Schnabel, Renate B and Lackner, Karl J. and Vlachopoulou, Efthymia and Nygård, Ottar and Svingen, Gard Frodahl Tveitevåg and Pedersen, Eva Ringdal and Tell, Grethe S. and Sinisalo, Juha and Nieminen, Markku S. and Laaksonen, Reijo and Trompet, Stella and Smit, Roelof A.J. and Sattar, Naveed and Jukema, J Wouter and Groesdonk, Heinrich V. and Delgado, Graciela and Stojakovic, Tatjana and Pilbrow, Anna P. and Cameron, Vicky A. and Richards, A. Mark and Doughty, Robert N. and Gong, Yan and Cooper-Dehoff, Rhonda M and Johnson, Julie A. and Scholz, Markus and Beutner, Frank and Thiery, Joachim and Smith, Gustav and Vilmundarson, Ragnar O. and McPherson, Ruth and Stewart, Alexandre F. R. and Cresci, Sharon and Lenzini, Petra A. and Spertus, John A. and Olivieri, Oliviero and Girelli, Domenico and Martinelli, Nicola I. and Leiherer, Andreas and Saely, Christoph H. and Drexel, Heinz and Mündlein, Axel and Braund, Peter S. and Nelson, Christopher P and Samani, Nilesh J. and Kofink, Daniel and Hoefer, Imo E and Pasterkamp, Gerard and Quyyumi, Arshed A. and Ko, Yi An and Hartiala, Jaana A. and Allayee, Hooman and Tang, W. H. Wilson and Hazen, Stanley L. and Eriksson, Niclas and Held, Claes and Hagström, Emil and Wallentin, Lars and Åkerblom, Axel and Siegbahn, Agneta and Karp, Igor and Labos, Christopher and Pilote, Louise and Engert, James C and Brophy, James M. and Thanassoulis, George and Bogaty, Peter and Szczeklik, Wojciech and Kaczor, Marcin and Sanak, Marek and Virani, Salim S. and Ballantyne, Christie M and Lee, Vei Vei and Boerwinkle, Eric and Holmes, Michael V and Horne, Benjamin D. and Hingorani, Aroon and Asselbergs, Folkert W. and Patel, Riyaz S. and Krämer, Bernhard K. and Scharnagl, Hubert and Fliser, Danilo and März, Winfried and Speer, Thimoteus},
  issn         = {2213-8587},
  language     = {eng},
  number       = {7},
  pages        = {534--543},
  publisher    = {Elsevier},
  series       = {The Lancet Diabetes and Endocrinology},
  title        = {Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : A molecular and genetic association study},
  url          = {http://dx.doi.org/10.1016/S2213-8587(17)30096-7},
  volume       = {5},
  year         = {2017},
}