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 languageEnglish
Pages (from-to)E1176-E1187
Number of pages13
JournalNeurology
VolumeVol. 92
Issue numbern.º 11
DOIs
Publication statusPublished - 12 Mar 2019

Cite this

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