7,918
Views
0
CrossRef citations to date
0
Altmetric
Research Article

Mendelian randomization study on causal association of IL-6 signaling with pulmonary arterial hypertension

, , , , , , & ORCID Icon show all
Article: 2183963 | Received 28 Sep 2022, Accepted 18 Feb 2023, Published online: 05 Mar 2023

References

  • Vazquez ZGS, Klinger JR.Guidelines for the treatment of pulmonary arterial hypertension. Lung. 2020;198(4):581–9. doi:10.1007/s00408-020-00375-w.
  • Coons JC, Pogue K, Kolodziej AR, Hirsch GA, George MP.Pulmonary arterial hypertension: a pharmacotherapeutic update. Curr Cardiol Rep. 2019;21(11):141. doi:10.1007/s11886-019-1235-4.
  • Ivy DD, Abman SH, Barst RJ, Berger RM, Bonnet D, Fleming TR, Haworth SG, Raj JU, Rosenzweig EB, Schulze Neick I, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D117–26. doi:10.1016/j.jacc.2013.10.028.
  • Galie N, Channick RN, Frantz RP, Grunig E, Jing ZC, Moiseeva O, Preston IR, Pulido T, Safdar Z, Tamura Y, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. 2019;53(1):1. doi:10.1183/13993003.01889-2018.
  • Hu Y, Chi L, Kuebler WM, Goldenberg NM, et al. Perivascular inflammation in pulmonary arterial hypertension. Cells. 2020;9:11. doi:10.3390/cells9112338.
  • Durham GA, Palmer TM.Is there a role for prostanoid-mediated inhibition of IL-6 trans-signalling in the management of pulmonary arterial hypertension? Biochem Soc Trans. 2019;47(4):1143–56.doi:10.1042/BST20190046.
  • Pullamsetti SS, Seeger W, Classical SR.IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension. J Clin Invest. 2018;128(5):1720–23. doi:10.1172/JCI120415.
  • Arita Y, Sakata Y, Sudo T, Maeda T, Matsuoka K, Tamai K, Higuchi K, Shioyama W, Nakaoka Y, Kanakura Y, et al. The efficacy of tocilizumab in a patient with pulmonary arterial hypertension associated with Castleman’s disease. Heart Vessels. 2010;25(5):444–47. doi:10.1007/s00380-009-1215-5.
  • Furuya Y, Satoh T, Kuwana M, et. al. Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol. 2010;2010:720305.doi:10.1155/2010/720305.
  • Toshner M, Church C, Harbaum L, Rhodes C, Villar Moreschi SS, Liley J, Jones R, Arora A, Batai K, Desai AA, et al. Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. Eur Respir J. 2022;59:3.
  • Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masaki T, Minami M, Inagaki T, Miyagawa S, Sawa Y, et al. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2015;112(20):E2677–86. doi:10.1073/pnas.1424774112.
  • Gao R, Xu Y, Zhu G, Zhou S, Li H, Han G, Su W, Wang R, et al. Genetic variation associated with COVID-19 is also associated with endometrial cancer. J Infect. 2022;84(5):e85–e6.doi:10.1016/j.jinf.2022.01.026.
  • Wang R.Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis. J Transl Med. 2022;20(1):3. doi:10.1186/s12967-021-03205-6.
  • Wang R.Genetic variation of interleukin-1 receptor type 1 is associated with severity of COVID-19 disease. J Infect. 2022;84(2):e19–e21. doi:10.1016/j.jinf.2021.12.010.
  • Xu Y, Gao R, Zhu G, Zhou S, Li H, Su W, Han G, Wang R, et al. Genetic variation of allergic disease is associated with the susceptibility to COVID-19. J Infect. 2022;84(5):e92–e3. doi:10.1016/j.jinf.2022.01.015.
  • Zhou S, Zhu G, Xu Y, Gao R, Li H, Han G, et al. Mendelian randomization study on the putative causal effects of Omega-3 fatty acids on low back pain. Front Nutr. 2022;9:819635.
  • Zhu G, Zhou S, Xu Y, Gao R, Li H, Su W, et al. Mendelian randomization study on the causal effects of COVID-19 on childhood intelligence. J Med Virol. 2022;94(7):3233–39. doi:10.1002/jmv.27736.
  • Zhu G, Zhou S, Xu Y, Gao R, Li H, Zhai B, Liu X, He Y, Wang X, Han G, et al. Mendelian randomization study on the causal effects of omega-3 fatty acids on rheumatoid arthritis. Clin Rheumatol. 2022;41(5):1305–12. doi:10.1007/s10067-022-06052-y.
  • Hong J, Qu Z, Ji X, Li C, Zhang G, Jin C, Wang J, Zhang Y, Shen Y, Meng J, et al. Genetic associations between IL-6 and the development of autoimmune arthritis are gender-specific. Front Immunol. 2021;12:707617.
  • Rosa M, Chignon A, Li Z, Boulanger MC, Arsenault BJ, Bosse Y, Thériault S, Mathieu P, et al. A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity. NPJ Genom Med. 2019;4:23.
  • Kappelmann N, Arloth J, Georgakis MK, Czamara D, Rost N, Ligthart S, Khandaker GM, Binder EB, et al. Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms: A genetic correlation and 2-sample mendelian randomization study. JAMA Psychiatry. 2021;78(2):161–70. doi:10.1001/jamapsychiatry.2020.3436.
  • Georgakis MK, Malik R, Gill D, Franceschini N, Sudlow A, Cathie LM, Dichgans M, Lindstrom S, Wang L, Smith EN, et al. Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: A mendelian randomization study. Circulation: Genomic and Precision Medicine. 2020;13(3):e002872. doi:10.1161/CIRCGEN.119.002872.
  • Ligthart S, Vaez A, Vosa U, Stathopoulou MG, de Vries PS, Prins BP, Van der Most PJ, Tanaka T, Naderi E, Rose LM, et al. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. Am J Hum Genet. 2018;103(5):691–706. doi:10.1016/j.ajhg.2018.09.009.
  • Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, Burgess S, Jiang T, Paige E, Surendran P, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73–79. doi:10.1038/s41586-018-0175-2.
  • Jostock T, Mullberg J, Ozbek S, Atreya R, Blinn G, Voltz N, Fischer M, Neurath MF, Rose-John S, et al. Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem. 2001;268(1):160–67. doi:10.1046/j.1432-1327.2001.01867.x.
  • 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):693–98. doi:10.1038/s41588-018-0099-7.
  • Bowden J, Davey Smith G, Haycock PC, Burgess S.Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14. doi:10.1002/gepi.21965.
  • Burgess S, Thompson SG.Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377–89. doi:10.1007/s10654-017-0255-x.
  • Yavorska OO, Burgess S.Mendelian randomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol. 2017;46(6):1734–39. doi:10.1093/ije/dyx034.
  • Greco MF, Minelli C, Sheehan NA, Thompson JR.Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med. 2015;34(21):2926–40.doi:10.1002/sim.6522.
  • Liu G, Zhang S, Cai Z, Ma G, Zhang L, Jiang Y, Feng R, Liao M, Chen Z, Zhao B, et al. PICALM gene rs3851179 polymorphism contributes to Alzheimer’s disease in an Asian population. Neuromolecular Med. 2013;15(2):384–88. doi:10.1007/s12017-013-8225-2.
  • Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. In: Elife. 2018;7:e34408. doi:10.7554/eLife.34408.
  • Harroud A, Richards JB.Mendelian randomization in multiple sclerosis: A causal role for vitamin D and obesity? Mult Scler. 2018;24(1):80–85. doi:10.1177/1352458517737373.
  • Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M.IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2012;122(4):143–59. doi:10.1042/CS20110340.
  • Jasiewicz M, Knapp M, Waszkiewicz E, Ptaszynska-Kopczynska K, Szpakowicz A, Sobkowicz B, Musial WJ, Kaminski KA, et al. Enhanced IL-6 trans-signaling in pulmonary arterial hypertension and its potential role in disease-related systemic damage. Cytokine. 2015;76(2):187–92.doi:10.1016/j.cyto.2015.06.018.
  • Maston LD, Jones DT, Giermakowska W, Resta TC, Ramiro-Diaz J, Howard TA, Jernigan NL, Herbert L, Maurice AA, Gonzalez Bosc LV, et al. Interleukin-6 trans-signaling contributes to chronic hypoxia-induced pulmonary hypertension. Pulm Circ. 2018;8(3):2045894018780734. doi:10.1177/2045894018780734.
  • Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182(9):1171–77. doi:10.1164/rccm.201001-0123OC.
  • Toshner M, Rothman AIL-6, et al. in pulmonary hypertension: why novel is not always best. Eur Respir J. 2020;55:4. doi:10.1183/13993003.00314-2020.
  • Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;151(5):1628–31. doi:10.1164/ajrccm.151.5.7735624.
  • Maston LD, Jones DT, Giermakowska W, Howard TA, Cannon JL, Wang W, Wei Y, Xuan W, Resta TC, Gonzalez Bosc LV, et al. Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2017;312(5):L609–L24. doi:10.1152/ajplung.00531.2016.
  • Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res. 2009;10(1):6. doi:10.1186/1465-9921-10-6.
  • Davies RJ, Holmes AM, Deighton J, Long L, Yang X, Barker L, Walker C, Budd DC, Upton PD, Morrell NW, et al. BMP type II receptor deficiency confers resistance to growth inhibition bTGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol. 2012;302(6):L604–15. doi:10.1152/ajplung.00309.2011.
  • Lissilaa R, Buatois V, Magistrelli G, Williams AS, Jones GW, Herren S, Shang L, Malinge P, Guilhot F, Chatel L, et al. Although IL-Trans -Signaling Is Sufficient To Drive Local Immune Responses, Classical IL-6 Signaling Is Obligate for the Induction of T Cell-Mediated Autoimmunity. J Immunol. 2010;185(9):5512–21. doi:10.4049/jimmunol.1002015.
  • Hunter CA, Jones SAIL-6.IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–57.doi:10.1038/ni.3153.
  • Lauder SN, Jones E, Smart K, Bloom A, Williams AS, Hindley JP, Ondondo B, Taylor PR, Clement M, Fielding C, et al. Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Eur J Immunol. 2013;43(10):2613–25. doi:10.1002/eji.201243018.
  • Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW.Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994;83(1):113–18. doi:10.1182/blood.V83.1.113.113.
  • Beaman MH, Hunter CA, Remington JS.Enhancement of intracellular replication of Toxoplasma gondii by IL-6 Interactions with IFN-gamma and TNF-alpha. J Immunol 1994;153(10):4583–87.
  • Nagabhushanam V, Solache A, Ting L-M, Escaron CJ, Zhang JY, Ernst JD, Nagabhushanam V, Solache A, LM T, Cj E, et al.Innate Inhibition of Adaptive Immunity: Mycobacterium tuberculosis -Induced IL-6 Inhibits Macrophage Responses to IFN-γ. J Immunol. 2003;171(9):4750–57. doi:10.4049/jimmunol.171.9.4750.
  • Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, Ernst M, Saris CJM, O’Shea JJ, Hunter CA, et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol. 2007;8(12):1363–71.doi:10.1038/ni1537.
  • McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8(12):1390–97. doi:10.1038/ni1539.