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

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 SF; 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 LM; Anderson, Christopher; Levi, Christopher R; Satizabal, Claudia L; Palmer, Colin NA; 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 IW; 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 WK; Tatlisumak, Turgut; Thorsteinsdottir, Unnur; Thijs, Vincent NS; Longstreth, WT; Zhao, Wei; Chen, Wei-Min; Cheng, Yu-Ching

doi:10.1212/WNL.0000000000007091

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

Author:

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 SF ; 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 LM ; Anderson, Christopher ; Levi, Christopher R ; Satizabal, Claudia L ; Palmer, Colin NA ; 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 IW ; 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 WK ; Tatlisumak, Turgut ; Thorsteinsdottir, Unnur ; Thijs, Vincent NS ; Longstreth, WT ; Zhao, Wei ; Chen, Wei-Min ; Cheng, Yu-Ching

Keywords:

Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, DENSITY-LIPOPROTEIN CHOLESTEROL, RISK-FACTORS, HEART-DISEASE, GENETIC-VARIANTS, STATIN THERAPY, METAANALYSIS, SUBTYPES, PCSK9, BMI, Brain Ischemia, Causality, Cholesterol, LDL, Coronary Disease, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Hypolipidemic Agents, Mendelian Randomization Analysis, Stroke, METASTROKE Consortium of the ISGC,, DENSITY-LIPOPROTEIN-CHOLESTEROL, REDUCTION, 1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences, Neurology & Neurosurgery, 3202 Clinical sciences, 3209 Neurosciences

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 × 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. 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.