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Valdes-Marquez, Elsa; Parish, Sarah; Clarke, Robert; Stari, Traiani; Worrall, Bradford B.; Hopewell, Jemma C.; Slowik, Agnieszka; Hofman, Albert; Algra, Ale; Reiner, Alex P.; Doney, Alexander S. F.; Gschwendtner, Andreas; Ilinca, Andreea; Giese, Anne-Katrin; Lindgren, Arne; Vicente, Astrid M.; Norrving, Bo; Nordestgaard, Borge G.; Mitchell, Braxton D.; Psaty, Bruce M.; Carty, Cara L.; Sudlow, Cathie L. M.; Anderson, Christopher; Levi, Christopher R.; Satizabal, Claudia L.; Palmer, Colin N. A.; Gamble, Dale M.; Woo, Daniel; Saleheen, Danish; Ringelstein, E. Bernd; Valdimarsson, Einar M.; Holliday, Elizabeth G.; Davies, Gail; Chauhan, Ganesh; Pasterkamp, Gerard; Boncoraglio, Giorgio B.; Kuhlenbaeumer, Gregor; Thorleifsson, Gudmar; Falcone, Guido J.; Pare, Guillaume; Schmidt, Helena; Delavaran, Hossein; Markus, Hugh S.; Aparicio, Hugo J.; Deary, Ian; Cotlarciuc, Ioana; Fernandez-Cadenas, Israel; Meschia, James F.; Liu, Jingmin; Montaner, Joan; Pera, Joanna; Cole, John; Attia, John R.; Rosand, Jonathan; Ferro, Jose M.; Bis, Joshua C.; Furie, Karen; Stefansson, Kari; Berger, Klaus; Kostulas, Konstantinos; Rannikmae, Kristiina; Ikram, M. Arfan; Benn, Marianne; Dichgans, Martin; Pandolfo, Massimo; Traylor, Matthew; Walters, Matthew; Sale, Michele; Nalls, Michael A.; Fornage, Myriam; van Zuydam, Natalie R.; Sharma, Pankaj; Abrantes, Patricia; de Bakker, Paul I. W.; Higgins, Peter; Lichtner, Peter; Rothwell, Peter M.; Amouyel, Philippe; Yang, Qiong; Malik, Rainer; Schmidt, Reinhold; Lemmens, Robin; van der Laan, Sander W.; Pulit, Sara L.; Abboud, Sherine; Oliveira, Sofia A.; Gretarsdottir, Solveig; Debette, Stephanie; Williams, Stephen R.; Bevan, Steve; Kittner, Steven J.; Seshadri, Sudha; Mosley, Thomas; Battey, Thomas W. K.; Tatlisumak, Turgut; Thorsteinsdottir, Unnur; Thijs, Vincent N. S.; Longstreth, W. T.; Zhao, Wei; Chen, Wei-Min; Cheng, Yu-Ching (2019): Relative effects of LDL-C on ischemic stroke and coronary disease A Mendelian randomization study. In: Neurology, Vol. 92, No. 11, E1176-E1187
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Abstract

Objective 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. Methods We 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. Results A 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 x 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 x 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 x 10(-3)) when compared with that for CHD. Conclusions In 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.

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