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Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Myasthenia Gravis and Ischemic Stroke: A Bidirectional Mendelian Randomization Study

Author(s): Chen Liu, Chengyuan Mao, Shen Li, Yun Su, Hongbing Liu, Xin Wang, Weishi Liu, Jiawei Zhao, Xuyang Liu and Yuming Xu*

Volume 20, Issue 2, 2023

Published on: 03 August, 2023

Page: [270 - 279] Pages: 10

DOI: 10.2174/1567202620666230703122140

Price: $65

Abstract

Background: Autoimmune diseases are associated with cardiovascular and cerebrovascular diseases. However, whether myasthenia gravis (MG) and ischemic stroke (IS) are causally related remains unclear.

Objectives: This study aimed to evaluate potential causal links between MG and IS using bidirectional Mendelian randomization (MR).

Methods: We conducted a two-sample MR analysis to assess the potential associations between MG and IS. Genetic variants associated with MG and IS as well as their subtypes were extracted from genome-wide association studies by meta-analysis. The inverse-variance weighted method was used for the main MR analysis. Sensitivity analyses, including the MREgger, simple mode, simple median, weighted mode, and weighted median approaches were applied to test the robustness of the results.

Results: The MR analyses indicated no causal effects of general MG on IS of all causes (odds ratio [OR] = 0.990, 95% confidence interval [CI]: 0.953-1.029, p = 0.615), large vessel atherosclerosis stroke (OR = 0.943, 95% CI: 0.856-1.039, p = 0.233), cardioembolic stroke (OR = 0.975, 95% CI: 0.867-1.096, p = 0.670), and small vessel occlusion stroke (OR = 1.059, 95% CI 0.974-1.150, p = 0.178). Subgroup analyses indicated no causal effects of early- or late-onset MG on IS and its subtypes (all p > 0.05). The reverse MR analysis showed no significant causal associations of IS on MG (all p > 0.05).

Conclusion: Bidirectional MR analysis did not provide evidence to support a causal relationship between genetically predicted MG and IS, although observational studies have found such a potential link.

[1]
Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42(2): 517-84.
[http://dx.doi.org/10.1161/STR.0b013e3181fcb238] [PMID: 21127304]
[2]
Boehme AK, Esenwa C, Elkind MSV. Stroke risk factors, genetics, and prevention. Circ Res 2017; 120(3): 472-95.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.308398] [PMID: 28154098]
[3]
Iadecola C, Anrather J. The immunology of stroke: From mechanisms to translation. Nat Med 2011; 17(7): 796-808.
[http://dx.doi.org/10.1038/nm.2399] [PMID: 21738161]
[4]
Anrather J, Iadecola C. Inflammation and stroke: An overview. Neurotherapeutics 2016; 13(4): 661-70.
[http://dx.doi.org/10.1007/s13311-016-0483-x] [PMID: 27730544]
[5]
Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: An independent prognostic factor. Stroke 2001; 32(4): 917-24.
[http://dx.doi.org/10.1161/01.STR.32.4.917] [PMID: 11283392]
[6]
Sobowale OA, Parry-Jones AR, Smith CJ, Tyrrell PJ, Rothwell NJ, Allan SM. Interleukin-1 in stroke. Stroke 2016; 47(8): 2160-7.
[http://dx.doi.org/10.1161/STROKEAHA.115.010001] [PMID: 26931154]
[7]
Whiteley W, Jackson C, Lewis S, et al. Inflammatory markers and poor outcome after stroke: A prospective cohort study and systematic review of interleukin-6. PLoS Med 2009; 6(9): e1000145.
[http://dx.doi.org/10.1371/journal.pmed.1000145] [PMID: 19901973]
[8]
Arkema EV, Svenungsson E, Von Euler M, Sjöwall C, Simard JF. Stroke in systemic lupus erythematosus: A Swedish population-based cohort study. Ann Rheum Dis 2017; 76(9): 1544-9.
[http://dx.doi.org/10.1136/annrheumdis-2016-210973] [PMID: 28400384]
[9]
Yazdany J, Pooley N, Langham J, et al. Systemic lupus erythematosus; stroke and myocardial infarction risk: A systematic review and meta-analysis. RMD Open 2020; 6(2): e001247.
[http://dx.doi.org/10.1136/rmdopen-2020-001247] [PMID: 32900883]
[10]
Wiseman SJ, Ralston SH, Wardlaw JM. Cerebrovascular disease in Rheumatic diseases. Stroke 2016; 47(4): 943-50.
[http://dx.doi.org/10.1161/STROKEAHA.115.012052] [PMID: 26917565]
[11]
Palladino R, Marrie RA, Majeed A, Chataway J. Evaluating the risk of macrovascular events and mortality among people with multiple sclerosis in England. JAMA Neurol 2020; 77(7): 820-8.
[http://dx.doi.org/10.1001/jamaneurol.2020.0664] [PMID: 32364569]
[12]
Punga AR, Maddison P, Heckmann JM, Guptill JT, Evoli A. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol 2022; 21(2): 176-88.
[http://dx.doi.org/10.1016/S1474-4422(21)00297-0] [PMID: 35065040]
[13]
Wang Z, Yan Y. Immunopathogenesis in myasthenia gravis and neuromyelitis optica. Front Immunol 2017; 8: 1785.
[http://dx.doi.org/10.3389/fimmu.2017.01785]
[14]
Gilhus NE. Myasthenia Gravis. N Engl J Med 2016; 375(26): 2570-81.
[http://dx.doi.org/10.1056/NEJMra1602678] [PMID: 28029925]
[15]
Uzawa A, Kuwabara S, Suzuki S, et al. Roles of cytokines and T cells in the pathogenesis of myasthenia gravis. Clin Exp Immunol 2021; 203(3): 366-74.
[http://dx.doi.org/10.1111/cei.13546] [PMID: 33184844]
[16]
Cavalcante P, Cufi P, Mantegazza R, Berrih-Aknin S, Bernasconi P, Le Panse R. Etiology of myasthenia gravis: Innate immunity signature in pathological thymus. Autoimmun Rev 2013; 12(9): 863-74.
[http://dx.doi.org/10.1016/j.autrev.2013.03.010] [PMID: 23535157]
[17]
Conrad N, Verbeke G, Molenberghs G, et al. Autoimmune diseases and cardiovascular risk: A population-based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UK. Lancet 2022; 400(10354): 733-43.
[http://dx.doi.org/10.1016/S0140-6736(22)01349-6] [PMID: 36041475]
[18]
Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24(1): 35-41.
[http://dx.doi.org/10.1161/01.STR.24.1.35] [PMID: 7678184]
[19]
Zabor EC, Kaizer AM, Hobbs BP. Randomized controlled trials. Chest 2020; 158(1): S79-87.
[http://dx.doi.org/10.1016/j.chest.2020.03.013] [PMID: 32658656]
[20]
Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey Smith G. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med 2008; 27(8): 1133-63.
[http://dx.doi.org/10.1002/sim.3034] [PMID: 17886233]
[21]
Chia R, Saez-Atienzar S, Murphy N, et al. Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: A genome-wide association study. Proc Natl Acad Sci USA 2022; 119(5): e2108672119.
[http://dx.doi.org/10.1073/pnas.2108672119] [PMID: 35074870]
[22]
Glanville KP, Coleman JRI, O’Reilly PF, Galloway J, Lewis CM. Investigating Pleiotropy between depression and autoimmune diseases using the UK Biobank. Bio Psych Global Open Sci 2021; 1(1): 48-58.
[http://dx.doi.org/10.1016/j.bpsgos.2021.03.002] [PMID: 34278373]
[23]
Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet 2018; 50(4): 524-37.
[http://dx.doi.org/10.1038/s41588-018-0058-3] [PMID: 29531354]
[24]
Auton A, Abecasis GR, Altshuler DM, et al. A global reference for human genetic variation. Nature 2015; 526(7571): 68-74.
[http://dx.doi.org/10.1038/nature15393] [PMID: 26432245]
[25]
Yavorska OO, Burgess S. MendelianRandomization: An R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol 2017; 46(6): 1734-9.
[http://dx.doi.org/10.1093/ije/dyx034] [PMID: 28398548]
[26]
Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50(5): 693-8.
[http://dx.doi.org/10.1038/s41588-018-0099-7] [PMID: 29686387]
[27]
Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife 2018; 7: e34408.
[28]
Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44(2): 512-25.
[http://dx.doi.org/10.1093/ije/dyv080] [PMID: 26050253]
[29]
Fisman GK, Kott HS. Myasthenia gravis mimicking stroke in elderly patients. Mayo Clin Proc 1998; 73(11): 1077-8.
[http://dx.doi.org/10.4065/73.11.1077] [PMID: 9818042]
[30]
Libman R, Benson R, Einberg K. Myasthenia mimicking vertebrobasilar stroke. J Neurol 2002; 249(11): 1512-4.
[http://dx.doi.org/10.1007/s00415-002-0858-2] [PMID: 12420089]
[31]
Marie I, Maurey G, Hervé F, Hellot M-F, Levesque H. Intravenous immunoglobulin-associated arterial and venous thrombosis; report of a series and review of the literature. Br J Dermatol 2006; 155(4): 714-21.
[http://dx.doi.org/10.1111/j.1365-2133.2006.07390.x] [PMID: 16965420]
[32]
Jin PH, Shin SC, Dhamoon MS. Risk of thrombotic events after inpatient intravenous immunoglobulin or plasma exchange for neurologic disease: A case‐crossover study. Muscle Nerve 2020; 62(3): 327-32.
[http://dx.doi.org/10.1002/mus.26884] [PMID: 32270520]
[33]
Rogers MAM, Wei MY, Kim C, Lee JM. Sex differences in autoimmune multimorbidity in type 1 diabetes mellitus and the risk of cardiovascular and renal disease: A longitudinal study in the United States, 2001–2017. J Womens Health 2020; 29(4): 511-9.
[http://dx.doi.org/10.1089/jwh.2019.7935] [PMID: 32320330]
[34]
Huda R. Inflammation and autoimmune myasthenia gravis. Front Immunol 2023; 14: 1110499.
[http://dx.doi.org/10.3389/fimmu.2023.1110499]
[35]
Yasuda K, Takeuchi Y, Hirota K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol 2019; 41(3): 283-97.
[http://dx.doi.org/10.1007/s00281-019-00733-8]
[36]
Wang Z, Wang W, Chen Y, Wei D. T helper type 17 cells expand in patients with myasthenia-associated thymoma. Scand J Immunol 2012; 76(1): 54-61.
[http://dx.doi.org/10.1111/j.1365-3083.2012.02703.x] [PMID: 22486891]
[37]
Xie Y, Li H-f, Jiang B, et al. Elevated plasma interleukin-17A in a subgroup of Myasthenia Gravis patients. Cytokine 2016; 78(1): 44-6.
[http://dx.doi.org/10.1016/j.cyto.2015.06.011]
[38]
Çebi M, Durmus H, Aysal F, et al. CD4 T cells of myasthenia gravis patients Are characterized by increased IL-21, IL-4, and IL-17A productions and higher presence of PD-1 and ICOS. Front Immunol 2020; 11: 809.
[39]
Shekhar S, Cunningham MW, Pabbidi MR, et al. Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches. Eur J Pharmacol 2018; 833: 531-44.
[40]
Balandina A, Lécart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 2005; 105(2): 735-41.
[http://dx.doi.org/10.1182/blood-2003-11-3900] [PMID: 15454488]
[41]
Thiruppathi M, Rowin J, Ganesh B, Sheng JR, Prabhakar BS, Meriggioli MN. Impaired regulatory function in circulating CD4+CD25highCD127low/− T cells in patients with myasthenia gravis. Clin Immunol 2012; 145(3): 209-23.
[http://dx.doi.org/10.1016/j.clim.2012.09.012] [PMID: 23110942]
[42]
Wang H, Ye J, Cui L, Chu S, Chen N. Regulatory T cells in ischemic stroke. Acta Pharmacol Sin 2022; 43(1): 1-9.
[http://dx.doi.org/10.1038/s41401-021-00641-4] [PMID: 33772140]
[43]
Kleinschnitz C, Kraft P, Dreykluft A, et al. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood 2013; 121(4): 679-91.
[http://dx.doi.org/10.1182/blood-2012-04-426734] [PMID: 23160472]
[44]
Rahman J, Singh P, Merle NS, et al. Complement’s favourite organelle-Mitochondria? Br J Pharmacol 2021; 178(14): 2785.
[http://dx.doi.org/10.1111/bph.15238]
[45]
Gavriilaki M, Kimiskidis VK, Gavriilaki E. Precision medicine in neurology: The inspirational paradigm of complement therapeutics. Pharmaceuticals (Basel) 2020; 13(11): 341.
[http://dx.doi.org/10.3390/ph13110341] [PMID: 33114553]
[46]
Clarke AR, Christophe BR, Khahera A, et al. Therapeutic modulation of the complement cascade in stroke. Front Immunol 2019; 10: 1723.
[http://dx.doi.org/10.3389/fimmu.2019.01723]
[47]
Howard JF Jr, Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis. JAMA Neurol 2020; 77(5): 582-92.
[http://dx.doi.org/10.1001/jamaneurol.2019.5125] [PMID: 32065623]
[48]
Hamza FN, Daher S, Fakhoury HMA, Grant WB, Kvietys PR, Al-Kattan K. Immunomodulatory properties of Vitamin D in the Intestinal and respiratory systems. Nutrients 2023; 15(7): 1696.
[http://dx.doi.org/10.3390/nu15071696] [PMID: 37049536]
[49]
Li H, Xie X, Bai G, et al. Vitamin D deficiency leads to the abnormal activation of the complement system. Immunol Res 2023; 71(1): 29-38.
[http://dx.doi.org/10.1007/s12026-022-09324-6] [PMID: 36178657]
[50]
Bonaccorso G. Myasthenia gravis and Vitamin D serum levels: A systematic review and meta-analysis. CNS Neurol Disord Drug Targets 2023; 22(5): 752-60.
[http://dx.doi.org/10.2174/1871527321666220707111344] [PMID: 35796450]
[51]
Zhou R, Wang M, Huang H, Li W, Hu Y, Wu T. Lower Vitamin D Status is associated with an increased risk of ischemic stroke: A systematic review and meta-analysis. Nutrients 2018; 10(3): 277.
[http://dx.doi.org/10.3390/nu10030277] [PMID: 29495586]
[52]
Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol 2015; 14(10): 1023-36.
[http://dx.doi.org/10.1016/S1474-4422(15)00145-3] [PMID: 26376969]
[53]
Ferrandi PJ, Khan MM, Paez HG, Pitzer CR, Alway SE, Mohamed JS. Transcriptome Analysis of skeletal muscle reveals altered proteolytic and neuromuscular junction associated gene expressions in a mouse model of cerebral ischemic stroke. Genes 2020; 11(7): 726.
[http://dx.doi.org/10.3390/genes11070726] [PMID: 32629989]
[54]
Turin TC, Kita Y, Rumana N, et al. Ischemic stroke subtypes in a Japanese population: Takashima Stroke Registry, 1988-2004. Stroke 2010; 41(9): 1871-6.
[http://dx.doi.org/10.1161/STROKEAHA.110.581033] [PMID: 20689083]
[55]
Tsai CF, Thomas B, Sudlow CLM. Epidemiology of stroke and its subtypes in Chinese vs white populations: A systematic review. Neurology 2013; 81(3): 264-72.
[http://dx.doi.org/10.1212/WNL.0b013e31829bfde3] [PMID: 23858408]
[56]
Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: Incidence, recurrence, and long-term survival in ischemic stroke subtypes: A population-based study. Stroke 2001; 32(12): 2735-40.
[http://dx.doi.org/10.1161/hs1201.100209] [PMID: 11739965]
[57]
Tu WJ, Zhao Z, Yin P, et al. Estimated burden of stroke in china in 2020. JAMA Netw Open 2023; 6(3): e231455.
[http://dx.doi.org/10.1001/jamanetworkopen.2023.1455] [PMID: 36862407]

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