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

Stephen Zewinger; Marcus E Kleber; Vinicius Tragante; Raymond O McCubrey; Amand F Schmidt; Kenan Direk; Ulrich Laufs; Christian Werner; Wolfgang Koenig; Dietrich Rothenbacher; Ute Mons; Lutz P Breitling; Herrmann Brenner; Richard T Jennings; Ioannis Petrakis; Sarah Triem; Mira Klug; Alexandra Filips; Stefan Blankenberg; Christoph Waldeyer; Christoph Sinning; Renate B Schnabel; Karl J Lackner; Efthymia Vlachopoulou; Ottar Nygård; Gard Frodahl Tveitevåg Svingen; Eva Ringdal Pedersen; Grethe S Tell; Juha Sinisalo; Markku S Nieminen; Reijo Laaksonen; Stella Trompet; Roelof A J Smit; Naveed Sattar; J Wouter Jukema; Heinrich V Groesdonk; Graciela Delgado; Tatjana Stojakovic; Anna P Pilbrow; Vicky A Cameron; A Mark Richards; Robert N Doughty; Yan Gong; Rhonda Cooper-DeHoff; Julie Johnson; Markus Scholz; Frank Beutner; Joachim Thiery; J Gustav Smith; Ragnar O Vilmundarson; Ruth McPherson; Alexandre F R Stewart; Sharon Cresci; Petra A Lenzini; John A Spertus; Oliviero Olivieri; Domenico Girelli; Nicola I Martinelli; Andreas Leiherer; Christoph H Saely; Heinz Drexel; Axel Mündlein; Peter S Braund; Christopher P Nelson; Nilesh J Samani; Daniel Kofink; Imo E Hoefer; Gerard Pasterkamp; Arshed A Quyyumi; Yi-An Ko; Jaana A Hartiala; Hooman Allayee; W H Wilson Tang; Stanley L Hazen; Niclas Eriksson; Claes Held; Emil Hagström; Lars Wallentin; Axel Åkerblom; Agneta Siegbahn; Igor Karp; Christopher Labos; Louise Pilote; James C Engert; James M Brophy; George Thanassoulis; Peter Bogaty; Wojciech Szczeklik; Marcin Kaczor; Marek Sanak; Salim S Virani; Christie M Ballantyne; Vei-Vei Lee; Eric Boerwinkle; Michael V Holmes; Benjamin D Horne; Aroon Hingorani; Folkert W Asselbergs; Riyaz S Patel; Bernhard K Krämer; Hubert Scharnagl; Danilo Fliser; Winfried März; Thimoteus Speer; GENIUS-CHD consortium

doi:10.1016/S2213-8587(17)30096-7

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

Standard

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; Rothenbacher, Dietrich; Mons, Ute; Breitling, Lutz P; Brenner, Herrmann; Jennings, Richard T; Petrakis, Ioannis; Triem, Sarah; Klug, Mira; Filips, Alexandra; Blankenberg, Stefan ; Waldeyer, Christoph ; Sinning, Christoph ; Schnabel, Renate B; Lackner, Karl J; Vlachopoulou, Efthymia; Nygård, Ottar; Svingen, Gard Frodahl Tveitevåg; Pedersen, Eva Ringdal; Tell, Grethe S; Sinisalo, Juha; Nieminen, Markku S; Laaksonen, Reijo; Trompet, Stella; Smit, Roelof A J; Sattar, Naveed; Jukema, J Wouter; Groesdonk, Heinrich V; Delgado, Graciela; Stojakovic, Tatjana; Pilbrow, Anna P; Cameron, Vicky A; Richards, A Mark; Doughty, Robert N; Gong, Yan; Cooper-DeHoff, Rhonda; Johnson, Julie; Scholz, Markus; Beutner, Frank; Thiery, Joachim; Smith, J Gustav; Vilmundarson, Ragnar O; McPherson, Ruth; Stewart, Alexandre F R; Cresci, Sharon; Lenzini, Petra A; Spertus, John A; Olivieri, Oliviero; Girelli, Domenico; Martinelli, Nicola I; Leiherer, Andreas; Saely, Christoph H; Drexel, Heinz; Mündlein, Axel; Braund, Peter S; Nelson, Christopher P; Samani, Nilesh J; Kofink, Daniel; Hoefer, Imo E; Pasterkamp, Gerard; Quyyumi, Arshed A; Ko, Yi-An; Hartiala, Jaana A; Allayee, Hooman; Tang, W H Wilson; Hazen, Stanley L; Eriksson, Niclas; Held, Claes; Hagström, Emil; Wallentin, Lars; Åkerblom, Axel; Siegbahn, Agneta; Karp, Igor; Labos, Christopher; Pilote, Louise; Engert, James C; Brophy, James M; Thanassoulis, George; Bogaty, Peter; Szczeklik, Wojciech; Kaczor, Marcin; Sanak, Marek; Virani, Salim S; Ballantyne, Christie M; Lee, Vei-Vei; Boerwinkle, Eric; Holmes, Michael V; Horne, Benjamin D; Hingorani, Aroon; Asselbergs, Folkert W; Patel, Riyaz S; Krämer, Bernhard K; Scharnagl, Hubert; Fliser, Danilo; März, Winfried; Speer, Thimoteus; GENIUS-CHD consortium.

In: LANCET DIABETES ENDO, Vol. 5, No. 7, 07.2017, p. 534-543.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Zewinger, S, Kleber, ME, Tragante, V, McCubrey, RO, Schmidt, AF, Direk, K, Laufs, U, Werner, C, Koenig, W, Rothenbacher, D, Mons, U, Breitling, LP, Brenner, H, Jennings, RT, Petrakis, I, Triem, S, Klug, M, Filips, A, Blankenberg, S , Waldeyer, C , Sinning, C , Schnabel, RB, Lackner, KJ, Vlachopoulou, E, Nygård, O, Svingen, GFT, Pedersen, ER, Tell, GS, Sinisalo, J, Nieminen, MS, Laaksonen, R, Trompet, S, Smit, RAJ, Sattar, N, Jukema, JW, Groesdonk, HV, Delgado, G, Stojakovic, T, Pilbrow, AP, Cameron, VA, Richards, AM, Doughty, RN, Gong, Y, Cooper-DeHoff, R, Johnson, J, Scholz, M, Beutner, F, Thiery, J, Smith, JG, Vilmundarson, RO, McPherson, R, Stewart, AFR, Cresci, S, Lenzini, PA, Spertus, JA, Olivieri, O, Girelli, D, Martinelli, NI, Leiherer, A, Saely, CH, Drexel, H, Mündlein, A, Braund, PS, Nelson, CP, Samani, NJ, Kofink, D, Hoefer, IE, Pasterkamp, G, Quyyumi, AA, Ko, Y-A, Hartiala, JA, Allayee, H, Tang, WHW, Hazen, SL, Eriksson, N, Held, C, Hagström, E, Wallentin, L, Åkerblom, A, Siegbahn, A, Karp, I, Labos, C, Pilote, L, Engert, JC, Brophy, JM, Thanassoulis, G, Bogaty, P, Szczeklik, W, Kaczor, M, Sanak, M, Virani, SS, Ballantyne, CM, Lee, V-V, Boerwinkle, E, Holmes, MV, Horne, BD, Hingorani, A, Asselbergs, FW, Patel, RS, Krämer, BK, Scharnagl, H, Fliser, D, März, W, Speer, T & GENIUS-CHD consortium 2017, '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', LANCET DIABETES ENDO, vol. 5, no. 7, pp. 534-543. https://doi.org/10.1016/S2213-8587(17)30096-7

APA

Zewinger, S., Kleber, M. E., Tragante, V., McCubrey, R. O., Schmidt, A. F., Direk, K., Laufs, U., Werner, C., Koenig, W., Rothenbacher, D., Mons, U., Breitling, L. P., Brenner, H., Jennings, R. T., Petrakis, I., Triem, S., Klug, M., Filips, A., Blankenberg, S., ... GENIUS-CHD consortium (2017). 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. LANCET DIABETES ENDO, 5(7), 534-543. https://doi.org/10.1016/S2213-8587(17)30096-7

Vancouver

Zewinger S, Kleber ME, Tragante V, McCubrey RO, Schmidt AF, Direk K et al. 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. LANCET DIABETES ENDO. 2017 Jul;5(7):534-543. https://doi.org/10.1016/S2213-8587(17)30096-7

Bibtex

@article{0a02346c46fe4decb12d94c671421075,

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",

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 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 f{\"u}r Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.",

keywords = "Biomarkers/blood, Cohort Studies, Coronary Disease/blood, Europe/epidemiology, Female, Genetic Association Studies, Humans, Lipoprotein(a)/blood, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, Survival Rate",

author = "Stephen Zewinger and Kleber, {Marcus E} and Vinicius Tragante and McCubrey, {Raymond O} and Schmidt, {Amand F} and Kenan Direk and Ulrich Laufs and Christian Werner and Wolfgang Koenig and Dietrich Rothenbacher and Ute Mons and Breitling, {Lutz P} and Herrmann Brenner and Jennings, {Richard T} and Ioannis Petrakis and Sarah Triem and Mira Klug and Alexandra Filips and Stefan Blankenberg and Christoph Waldeyer and Christoph Sinning and Schnabel, {Renate B} and Lackner, {Karl J} and Efthymia Vlachopoulou and Ottar Nyg{\aa}rd and Svingen, {Gard Frodahl Tveitev{\aa}g} and Pedersen, {Eva Ringdal} and Tell, {Grethe S} and Juha Sinisalo and Nieminen, {Markku S} and Reijo Laaksonen and Stella Trompet and Smit, {Roelof A J} and Naveed Sattar and Jukema, {J Wouter} and Groesdonk, {Heinrich V} and Graciela Delgado and Tatjana Stojakovic and Pilbrow, {Anna P} and Cameron, {Vicky A} and Richards, {A Mark} and Doughty, {Robert N} and Yan Gong and Rhonda Cooper-DeHoff and Julie Johnson and Markus Scholz and Frank Beutner and Joachim Thiery and Smith, {J Gustav} and Vilmundarson, {Ragnar O} and Ruth McPherson and Stewart, {Alexandre F R} and Sharon Cresci and Lenzini, {Petra A} and Spertus, {John A} and Oliviero Olivieri and Domenico Girelli and Martinelli, {Nicola I} and Andreas Leiherer and Saely, {Christoph H} and Heinz Drexel and Axel M{\"u}ndlein and Braund, {Peter S} and Nelson, {Christopher P} and Samani, {Nilesh J} and Daniel Kofink and Hoefer, {Imo E} and Gerard Pasterkamp and Quyyumi, {Arshed A} and Yi-An Ko and Hartiala, {Jaana A} and Hooman Allayee and Tang, {W H Wilson} and Hazen, {Stanley L} and Niclas Eriksson and Claes Held and Emil Hagstr{\"o}m and Lars Wallentin and Axel {\AA}kerblom and Agneta Siegbahn and Igor Karp and Christopher Labos and Louise Pilote and Engert, {James C} and Brophy, {James M} and George Thanassoulis and Peter Bogaty and Wojciech Szczeklik and Marcin Kaczor and Marek Sanak and Virani, {Salim S} and Ballantyne, {Christie M} and Vei-Vei Lee and Eric Boerwinkle and Holmes, {Michael V} and Horne, {Benjamin D} and Aroon Hingorani and Asselbergs, {Folkert W} and Patel, {Riyaz S} and Kr{\"a}mer, {Bernhard K} and Hubert Scharnagl and Danilo Fliser and Winfried M{\"a}rz and Thimoteus Speer and {GENIUS-CHD consortium}",

year = "2017",

month = jul,

doi = "10.1016/S2213-8587(17)30096-7",

language = "English",

volume = "5",

pages = "534--543",

journal = "LANCET DIABETES ENDO",

issn = "2213-8587",

publisher = "Elsevier BV",

number = "7",

}

RIS

TY - JOUR

T1 - 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

AU - Zewinger, Stephen

AU - Kleber, Marcus E

AU - Tragante, Vinicius

AU - McCubrey, Raymond O

AU - Schmidt, Amand F

AU - Direk, Kenan

AU - Laufs, Ulrich

AU - Werner, Christian

AU - Koenig, Wolfgang

AU - Rothenbacher, Dietrich

AU - Mons, Ute

AU - Breitling, Lutz P

AU - Brenner, Herrmann

AU - Jennings, Richard T

AU - Petrakis, Ioannis

AU - Triem, Sarah

AU - Klug, Mira

AU - Filips, Alexandra

AU - Blankenberg, Stefan

AU - Waldeyer, Christoph

AU - Sinning, Christoph

AU - Schnabel, Renate B

AU - Lackner, Karl J

AU - Vlachopoulou, Efthymia

AU - Nygård, Ottar

AU - Svingen, Gard Frodahl Tveitevåg

AU - Pedersen, Eva Ringdal

AU - Tell, Grethe S

AU - Sinisalo, Juha

AU - Nieminen, Markku S

AU - Laaksonen, Reijo

AU - Trompet, Stella

AU - Smit, Roelof A J

AU - Sattar, Naveed

AU - Jukema, J Wouter

AU - Groesdonk, Heinrich V

AU - Delgado, Graciela

AU - Stojakovic, Tatjana

AU - Pilbrow, Anna P

AU - Cameron, Vicky A

AU - Richards, A Mark

AU - Doughty, Robert N

AU - Gong, Yan

AU - Cooper-DeHoff, Rhonda

AU - Johnson, Julie

AU - Scholz, Markus

AU - Beutner, Frank

AU - Thiery, Joachim

AU - Smith, J Gustav

AU - Vilmundarson, Ragnar O

AU - McPherson, Ruth

AU - Stewart, Alexandre F R

AU - Cresci, Sharon

AU - Lenzini, Petra A

AU - Spertus, John A

AU - Olivieri, Oliviero

AU - Girelli, Domenico

AU - Martinelli, Nicola I

AU - Leiherer, Andreas

AU - Saely, Christoph H

AU - Drexel, Heinz

AU - Mündlein, Axel

AU - Braund, Peter S

AU - Nelson, Christopher P

AU - Samani, Nilesh J

AU - Kofink, Daniel

AU - Hoefer, Imo E

AU - Pasterkamp, Gerard

AU - Quyyumi, Arshed A

AU - Ko, Yi-An

AU - Hartiala, Jaana A

AU - Allayee, Hooman

AU - Tang, W H Wilson

AU - Hazen, Stanley L

AU - Eriksson, Niclas

AU - Held, Claes

AU - Hagström, Emil

AU - Wallentin, Lars

AU - Åkerblom, Axel

AU - Siegbahn, Agneta

AU - Karp, Igor

AU - Labos, Christopher

AU - Pilote, Louise

AU - Engert, James C

AU - Brophy, James M

AU - Thanassoulis, George

AU - Bogaty, Peter

AU - Szczeklik, Wojciech

AU - Kaczor, Marcin

AU - Sanak, Marek

AU - Virani, Salim S

AU - Ballantyne, Christie M

AU - Lee, Vei-Vei

AU - Boerwinkle, Eric

AU - Holmes, Michael V

AU - Horne, Benjamin D

AU - Hingorani, Aroon

AU - Asselbergs, Folkert W

AU - Patel, Riyaz S

AU - Krämer, Bernhard K

AU - Scharnagl, Hubert

AU - Fliser, Danilo

AU - März, Winfried

AU - Speer, Thimoteus

AU - GENIUS-CHD consortium

PY - 2017/7

Y1 - 2017/7

N2 - 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.

AB - 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.

KW - Biomarkers/blood

KW - Cohort Studies

KW - Coronary Disease/blood

KW - Europe/epidemiology

KW - Female

KW - Genetic Association Studies

KW - Humans

KW - Lipoprotein(a)/blood

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - Risk Factors

KW - Survival Rate

U2 - 10.1016/S2213-8587(17)30096-7

DO - 10.1016/S2213-8587(17)30096-7

M3 - SCORING: Journal article

C2 - 28566218

VL - 5

SP - 534

EP - 543

JO - LANCET DIABETES ENDO

JF - LANCET DIABETES ENDO

SN - 2213-8587

IS - 7

ER -