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

Valdes-Marquez, Elsa and Parish, Sarah and Clarke, Robert and Stari, Traiani and Worrall, Bradford B and Hopewell, Jemma C and Slowik, Agnieszka and Hofman, Albert and Algra, Ale and Reiner, Alex P and Doney, Alexander SF and Gschwendtner, Andreas and Ilinca, Andreea and Giese, Anne-Katrin and Lindgren, Arne and Vicente, Astrid M and Norrving, Bo and Nordestgaard, Borge G and Mitchell, Braxton D and Psaty, Bruce M and Carty, Cara L and Sudlow, Cathie LM and Anderson, Christopher and Levi, Christopher R and Satizabal, Claudia L and Palmer, Colin NA and Gamble, Dale M and Woo, Daniel and Saleheen, Danish and Ringelstein, Bernd E and Valdimarsson, Einar M and Holliday, Elizabeth G and Davies, Gail and Chauhan, Ganesh and Pasterkamp, Gerard and Boncoraglio, Giorgio B and Kuhlenbaeumer, Gregor and Thorleifsson, Gudmar and Falcone, Guido J and Pare, Guillaume and Schmidt, Helena and Delavaran, Hossein and Markus, Hugh S and Aparicio, Hugo J and Deary, Ian and Cotlarciuc, Ioana and Fernandez-Cadenas, Israel and Meschia, James F and Liu, Jingmin and Montaner, Joan and Pera, Joanna and Cole, John and Attia, John R and Rosand, Jonathan and Ferro, Jose M and Bis, Joshua C and Furie, Karen and Stefansson, Kari and Berger, Klaus and Kostulas, Konstantinos and Rannikmae, Kristiina and Ikram, Arfan M and Benn, Marianne and Dichgans, Martin and Pandolfo, Massimo and Traylor, Matthew and Walters, Matthew and Sale, Michele and Nalls, Michael A and Fornage, Myriam and van Zuydam, Natalie R and Sharma, Pankaj and Abrantes, Patricia and de Bakker, Paul IW and Higgins, Peter and Lichtner, Peter and Rothwell, Peter M and Amouyel, Philippe and Yang, Qiong and Malik, Rainer and Schmidt, Reinhold and Lemmens, Robin and van der Laan, Sander W and Pulit, Sara L and Abboud, Sherine and Oliveira, Sofia A and Gretarsdottir, Solveig and Debette, Stephanie and Williams, Stephen R and Bevan, Steve and Kittner, Steven J and Seshadri, Sudha and Mosley, Thomas and Battey, Thomas WK and Tatlisumak, Turgut and Thorsteinsdottir, Unnur and Thijs, Vincent NS and Longstreth, WT and Zhao, Wei and Chen, Wei-Min and Cheng, Yu-Ching (2019) Relative effects of LDL-C on ischemic stroke and coronary disease A Mendelian randomization study. In: NEUROLOGY, 92 (11). E1176-E1187.

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Official URL: https://doi.org/10.1212/WNL.0000000000007091

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.

Item Type: Journal Article
Additional Information: Copyright of this article belongs to LIPPINCOTT WILLIAMS & WILKINS.
Keywords: DENSITY-LIPOPROTEIN-CHOLESTEROL; RISK-FACTORS; HEART-DISEASE; GENETIC-VARIANTS; STATIN THERAPY; METAANALYSIS; SUBTYPES; PCSK9; REDUCTION; BMI
Department/Centre: Autonomous Societies / Centres > Centre for Brain Research
Depositing User: Ms Ranganayaki RS
Date Deposited: 20 May 2019 07:38
Last Modified: 20 May 2019 07:38
URI: http://eprints.iisc.ac.in/id/eprint/62554

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