Relative effects of LDL-C on ischemic stroke and coronary disease:: a Mendelian randomization study

Elsa Valdes-Marquez; Sarah Parish; Robert Clarke; Traiani Stari; Bradford B. Worrall; Jemma C. Hopewell; Agnieszka Slowik; Albert Hofman; Ale Algra; Alex P. Reiner; Alexander S. F. Doney; Andreas Gschwendtner; Andreea Ilinca; Anne-Katrin Giese; Arne Lindgren; Astrid M. Vicente; Bo Norrving; Borge G. Nordestgaard; Braxton D. Mitchell; Bruce M. Psaty; Cara L. Carty; Cathie L. M. Sudlow; Christopher Anderson; Christopher R. Levi; Claudia L. Satizabal; Colin N. A. Palmer; Dale M. Gamble; Daniel Woo; Danish Saleheen; E. Bernd Ringelstein; Einar M. Valdimarsson; Elizabeth G. Holliday; Gail Davies; Ganesh Chauhan; Gerard Pasterkamp; Giorgio B. Boncoraglio; Gregor Kuhlenbaeumer; Gudmar Thorleifsson; Guido J. Falcone; Guillaume Pare; Helena Schmidt; Hossein Delavaran; Hugh S. Markus; Hugo J. Aparicio; Ian Deary; Ioana Cotlarciuc; Israel Fernandez-Cadenas; James F. Meschia; Jingmin Liu; Joan Montaner; Joanna Pera; John Cole; John R. Attia; Jonathan Rosand; Jose M. Ferro; Joshua C. Bis; Karen Furie; Kari Stefansson; Klaus Berger; Konstantinos Kostulas; Kristiina Rannikmae; M. Arfan Ikram; Marianne Benn; Martin Dichgans; Massimo Pandolfo; Matthew Traylor; Matthew Walters; Michele Sale; Michael A. Nalls; Myriam Fornage; Natalie R. van Zuydam; Pankaj Sharma; Patricia Abrantes; Paul I. W. de Bakker; Peter Higgins; Peter Lichtner; Peter M. Rothwell; Philippe Amouyel; Qiong Yang; Rainer Malik; Reinhold Schmidt; Robin Lemmens; Sander W. van der Laan; Sara L. Pulit; Sherine Abboud; Sofia A. Oliveira; Solveig Gretarsdottir; Stephanie Debette; Stephen R. Williams; Steve Bevan; Steven J. Kittner; Sudha Seshadri; Thomas Mosley; Thomas W. K. Battey; Turgut Tatlisumak; Unnur Thorsteinsdottir; Vincent N. S. Thijs; W. T. Longstreth; Wei Zhao; Wei-Min Chen; Yu-Ching Cheng

doi:10.1212/WNL.0000000000007091

Relative effects of LDL-C on ischemic stroke and coronary disease: a Mendelian randomization study

Elsa Valdes-Marquez, Sarah Parish, Robert Clarke, Traiani Stari, Bradford B. Worrall, Jemma C. Hopewell, Agnieszka Slowik, Albert Hofman, Ale Algra, Alex P. Reiner, Alexander S. F. Doney, Andreas Gschwendtner, Andreea Ilinca, Anne-Katrin Giese, Arne Lindgren, Astrid M. Vicente, Bo Norrving, Borge G. Nordestgaard, Braxton D. Mitchell, Bruce M. PsatyCara L. Carty, Cathie L. M. Sudlow, Christopher Anderson, Christopher R. Levi, Claudia L. Satizabal, Colin N. A. Palmer, Dale M. Gamble, Daniel Woo, Danish Saleheen, E. Bernd Ringelstein, Einar M. Valdimarsson, Elizabeth G. Holliday, Gail Davies, Ganesh Chauhan, Gerard Pasterkamp, Giorgio B. Boncoraglio, Gregor Kuhlenbaeumer, Gudmar Thorleifsson, Guido J. Falcone, Guillaume Pare, Helena Schmidt, Hossein Delavaran, Hugh S. Markus, Hugo J. Aparicio, Ian Deary, Ioana Cotlarciuc, Israel Fernandez-Cadenas, James F. Meschia, Jingmin Liu, Joan Montaner, Joanna Pera, John Cole, John R. Attia, Jonathan Rosand, Jose M. Ferro, Joshua C. Bis, Karen Furie, Kari Stefansson, Klaus Berger, Konstantinos Kostulas, Kristiina Rannikmae, M. Arfan Ikram, Marianne Benn, Martin Dichgans, Massimo Pandolfo, Matthew Traylor, Matthew Walters, Michele Sale, Michael A. Nalls, Myriam Fornage, Natalie R. van Zuydam, Pankaj Sharma, Patricia Abrantes, Paul I. W. de Bakker, Peter Higgins, Peter Lichtner, Peter M. Rothwell, Philippe Amouyel, Qiong Yang, Rainer Malik, Reinhold Schmidt, Robin Lemmens, Sander W. van der Laan, Sara L. Pulit, Sherine Abboud, Sofia A. Oliveira, Solveig Gretarsdottir, Stephanie Debette, Stephen R. Williams, Steve Bevan, Steven J. Kittner, Sudha Seshadri, Thomas Mosley, Thomas W. K. Battey, Turgut Tatlisumak, Unnur Thorsteinsdottir, Vincent N. S. Thijs, W. T. Longstreth, Wei Zhao, Wei-Min Chen, Yu-Ching Cheng

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Abstract

To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.MethodsWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.ResultsA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 × 10^-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10^-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10^-3) when compared with that for CHD.ConclusionsIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.

Original language	English
Pages (from-to)	E1176-E1187
Number of pages	13
Journal	Neurology
Volume	Vol. 92
Issue number	n.º 11
DOIs	https://doi.org/10.1212/WNL.0000000000007091
Publication status	Published - 12 Mar 2019

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Valdes-Marquez, E., Parish, S., Clarke, R., Stari, T., Worrall, B. B., Hopewell, J. C., Slowik, A., Hofman, A., Algra, A., Reiner, A. P., Doney, A. S. F., Gschwendtner, A., Ilinca, A., Giese, A-K., Lindgren, A., Vicente, A. M., Norrving, B., Nordestgaard, B. G., Mitchell, B. D., ... Cheng, Y-C. (2019). Relative effects of LDL-C on ischemic stroke and coronary disease: a Mendelian randomization study. Neurology, Vol. 92(n.º 11), E1176-E1187. https://doi.org/10.1212/WNL.0000000000007091

@article{2915156077f4466fb88efa59fd35ea1b,

title = "Relative effects of LDL-C on ischemic stroke and coronary disease:: a Mendelian randomization study",

abstract = "To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.MethodsWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.ResultsA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10-3) when compared with that for CHD.ConclusionsIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.",

author = "Elsa Valdes-Marquez and Sarah Parish and Robert Clarke and Traiani Stari and Worrall, {Bradford B.} and Hopewell, {Jemma C.} and Agnieszka Slowik and Albert Hofman and Ale Algra and Reiner, {Alex P.} and Doney, {Alexander S. F.} and Andreas Gschwendtner and Andreea Ilinca and Anne-Katrin Giese and Arne Lindgren and Vicente, {Astrid M.} and Bo Norrving and Nordestgaard, {Borge G.} and Mitchell, {Braxton D.} and Psaty, {Bruce M.} and Carty, {Cara L.} and Sudlow, {Cathie L. M.} and Christopher Anderson and Levi, {Christopher R.} and Satizabal, {Claudia L.} and Palmer, {Colin N. A.} and Gamble, {Dale M.} and Daniel Woo and Danish Saleheen and Ringelstein, {E. Bernd} and Valdimarsson, {Einar M.} and Holliday, {Elizabeth G.} and Gail Davies and Ganesh Chauhan and Gerard Pasterkamp and Boncoraglio, {Giorgio B.} and Gregor Kuhlenbaeumer and Gudmar Thorleifsson and Falcone, {Guido J.} and Guillaume Pare and Helena Schmidt and Hossein Delavaran and Markus, {Hugh S.} and Aparicio, {Hugo J.} and Ian Deary and Ioana Cotlarciuc and Israel Fernandez-Cadenas and Meschia, {James F.} and Jingmin Liu and Joan Montaner and Joanna Pera and John Cole and Attia, {John R.} and Jonathan Rosand and Ferro, {Jose M.} and Bis, {Joshua C.} and Karen Furie and Kari Stefansson and Klaus Berger and Konstantinos Kostulas and Kristiina Rannikmae and Ikram, {M. Arfan} and Marianne Benn and Martin Dichgans and Massimo Pandolfo and Matthew Traylor and Matthew Walters and Michele Sale and Nalls, {Michael A.} and Myriam Fornage and {van Zuydam}, {Natalie R.} and Pankaj Sharma and Patricia Abrantes and {de Bakker}, {Paul I. W.} and Peter Higgins and Peter Lichtner and Rothwell, {Peter M.} and Philippe Amouyel and Qiong Yang and Rainer Malik and Reinhold Schmidt and Robin Lemmens and {van der Laan}, {Sander W.} and Pulit, {Sara L.} and Sherine Abboud and Oliveira, {Sofia A.} and Solveig Gretarsdottir and Stephanie Debette and Williams, {Stephen R.} and Steve Bevan and Kittner, {Steven J.} and Sudha Seshadri and Thomas Mosley and Battey, {Thomas W. K.} and Turgut Tatlisumak and Unnur Thorsteinsdottir and Thijs, {Vincent N. S.} and Longstreth, {W. T.} and Wei Zhao and Wei-Min Chen and Yu-Ching Cheng",

year = "2019",

month = mar,

day = "12",

doi = "10.1212/WNL.0000000000007091",

language = "English",

volume = "Vol. 92",

pages = "E1176--E1187",

journal = "Neurology",

issn = "0028-3878",

publisher = "American Academy of Neurology (AAN) | Lippincott, Williams & Wilkins",

number = "n.º 11",

}

Valdes-Marquez, E, Parish, S, Clarke, R, Stari, T, Worrall, BB, Hopewell, JC, Slowik, A, Hofman, A, Algra, A, Reiner, AP, Doney, ASF, Gschwendtner, A, Ilinca, A, Giese, A-K, Lindgren, A, Vicente, AM, Norrving, B, Nordestgaard, BG, Mitchell, BD, Psaty, BM, Carty, CL, Sudlow, CLM, Anderson, C, Levi, CR, Satizabal, CL, Palmer, CNA, Gamble, DM, Woo, D, Saleheen, D, Ringelstein, EB, Valdimarsson, EM, Holliday, EG, Davies, G, Chauhan, G, Pasterkamp, G, Boncoraglio, GB, Kuhlenbaeumer, G, Thorleifsson, G, Falcone, GJ, Pare, G, Schmidt, H, Delavaran, H, Markus, HS, Aparicio, HJ, Deary, I, Cotlarciuc, I, Fernandez-Cadenas, I, Meschia, JF, Liu, J, Montaner, J, Pera, J, Cole, J, Attia, JR, Rosand, J, Ferro, JM, Bis, JC, Furie, K, Stefansson, K, Berger, K, Kostulas, K, Rannikmae, K, Ikram, MA, Benn, M, Dichgans, M, Pandolfo, M, Traylor, M, Walters, M, Sale, M, Nalls, MA, Fornage, M, van Zuydam, NR, Sharma, P, Abrantes, P, de Bakker, PIW, Higgins, P, Lichtner, P, Rothwell, PM, Amouyel, P, Yang, Q, Malik, R, Schmidt, R, Lemmens, R, van der Laan, SW, Pulit, SL, Abboud, S, Oliveira, SA, Gretarsdottir, S, Debette, S, Williams, SR, Bevan, S, Kittner, SJ, Seshadri, S, Mosley, T, Battey, TWK, Tatlisumak, T, Thorsteinsdottir, U, Thijs, VNS, Longstreth, WT, Zhao, W, Chen, W-M & Cheng, Y-C 2019, 'Relative effects of LDL-C on ischemic stroke and coronary disease: a Mendelian randomization study', Neurology, vol. Vol. 92, no. n.º 11, pp. E1176-E1187. https://doi.org/10.1212/WNL.0000000000007091

TY - JOUR

T1 - Relative effects of LDL-C on ischemic stroke and coronary disease:

T2 - a Mendelian randomization study

AU - Valdes-Marquez, Elsa

AU - Parish, Sarah

AU - Clarke, Robert

AU - Stari, Traiani

AU - Worrall, Bradford B.

AU - Hopewell, Jemma C.

AU - Slowik, Agnieszka

AU - Hofman, Albert

AU - Algra, Ale

AU - Reiner, Alex P.

AU - Doney, Alexander S. F.

AU - Gschwendtner, Andreas

AU - Ilinca, Andreea

AU - Giese, Anne-Katrin

AU - Lindgren, Arne

AU - Vicente, Astrid M.

AU - Norrving, Bo

AU - Nordestgaard, Borge G.

AU - Mitchell, Braxton D.

AU - Psaty, Bruce M.

AU - Carty, Cara L.

AU - Sudlow, Cathie L. M.

AU - Anderson, Christopher

AU - Levi, Christopher R.

AU - Satizabal, Claudia L.

AU - Palmer, Colin N. A.

AU - Gamble, Dale M.

AU - Woo, Daniel

AU - Saleheen, Danish

AU - Ringelstein, E. Bernd

AU - Valdimarsson, Einar M.

AU - Holliday, Elizabeth G.

AU - Davies, Gail

AU - Chauhan, Ganesh

AU - Pasterkamp, Gerard

AU - Boncoraglio, Giorgio B.

AU - Kuhlenbaeumer, Gregor

AU - Thorleifsson, Gudmar

AU - Falcone, Guido J.

AU - Pare, Guillaume

AU - Schmidt, Helena

AU - Delavaran, Hossein

AU - Markus, Hugh S.

AU - Aparicio, Hugo J.

AU - Deary, Ian

AU - Cotlarciuc, Ioana

AU - Fernandez-Cadenas, Israel

AU - Meschia, James F.

AU - Liu, Jingmin

AU - Montaner, Joan

AU - Pera, Joanna

AU - Cole, John

AU - Attia, John R.

AU - Rosand, Jonathan

AU - Ferro, Jose M.

AU - Bis, Joshua C.

AU - Furie, Karen

AU - Stefansson, Kari

AU - Berger, Klaus

AU - Kostulas, Konstantinos

AU - Rannikmae, Kristiina

AU - Ikram, M. Arfan

AU - Benn, Marianne

AU - Dichgans, Martin

AU - Pandolfo, Massimo

AU - Traylor, Matthew

AU - Walters, Matthew

AU - Sale, Michele

AU - Nalls, Michael A.

AU - Fornage, Myriam

AU - van Zuydam, Natalie R.

AU - Sharma, Pankaj

AU - Abrantes, Patricia

AU - de Bakker, Paul I. W.

AU - Higgins, Peter

AU - Lichtner, Peter

AU - Rothwell, Peter M.

AU - Amouyel, Philippe

AU - Yang, Qiong

AU - Malik, Rainer

AU - Schmidt, Reinhold

AU - Lemmens, Robin

AU - van der Laan, Sander W.

AU - Pulit, Sara L.

AU - Abboud, Sherine

AU - Oliveira, Sofia A.

AU - Gretarsdottir, Solveig

AU - Debette, Stephanie

AU - Williams, Stephen R.

AU - Bevan, Steve

AU - Kittner, Steven J.

AU - Seshadri, Sudha

AU - Mosley, Thomas

AU - Battey, Thomas W. K.

AU - Tatlisumak, Turgut

AU - Thorsteinsdottir, Unnur

AU - Thijs, Vincent N. S.

AU - Longstreth, W. T.

AU - Zhao, Wei

AU - Chen, Wei-Min

AU - Cheng, Yu-Ching

PY - 2019/3/12

Y1 - 2019/3/12

N2 - To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.MethodsWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.ResultsA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10-3) when compared with that for CHD.ConclusionsIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.

AB - To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.MethodsWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.ResultsA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10-3) when compared with that for CHD.ConclusionsIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.

UR - https://n.neurology.org/content/92/11/e1176.long

U2 - 10.1212/WNL.0000000000007091

DO - 10.1212/WNL.0000000000007091

M3 - Article

C2 - 30787162

SN - 0028-3878

VL - Vol. 92

SP - E1176-E1187

JO - Neurology

JF - Neurology

IS - n.º 11

ER -

Relative effects of LDL-C on ischemic stroke and coronary disease: a Mendelian randomization study

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