Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease.

التفاصيل البيبلوغرافية
العنوان:	Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease.
المؤلفون:	Guyatt A; Department of Health Sciences, University of Leicester, Leicester, UK., John C; Department of Health Sciences, University of Leicester, Leicester, UK cj153@leicester.ac.uk., Williams AT; Department of Health Sciences, University of Leicester, Leicester, UK., Shrine N; Department of Health Sciences, University of Leicester, Leicester, UK., Reeve NF; Department of Health Sciences, University of Leicester, Leicester, UK., Sayers I; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.; NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK., Hall I; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.; NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK., Wain LV; Department of Health Sciences, University of Leicester, Leicester, UK.; NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK., Sheehan N; Department of Health Sciences, University of Leicester, Leicester, UK., Dudbridge F; Department of Health Sciences, University of Leicester, Leicester, UK., Tobin MD; Department of Health Sciences, University of Leicester, Leicester, UK.; NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.
مؤلفون مشاركون:	SpiroMeta consortium
المصدر:	Thorax [Thorax] 2023 May; Vol. 78 (5), pp. 496-503. Date of Electronic Publication: 2022 May 10.
نوع المنشور:	Journal Article; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: British Medical Assn Country of Publication: England NLM ID: 0417353 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-3296 (Electronic) Linking ISSN: 00406376 NLM ISO Abbreviation: Thorax Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: London : British Medical Assn.
مواضيع طبية MeSH:	Pulmonary Disease, Chronic Obstructive/complications , Asthma/complications, Humans ; Eosinophils ; Genome-Wide Association Study ; Forced Expiratory Volume ; Lung
مستخلص:	Rationale: Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood. Objectives: We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections. Methods: We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils. Measurements and Main Results: Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) and FEV 1 (weighted median estimator, SD FEV 1 /FVC: -0.054 (95% CI -0.078 to -0.029), effect only prominent in individuals with asthma). Conclusions: Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD. Competing Interests: Competing interests: MDT and LVW receive funding from GSK for collaborative research projects outside of the submitted work. IH has funded research collaborations with GSK, Boehringer Ingelheim and Orion. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
References:	Genet Epidemiol. 2016 May;40(4):304-14. (PMID: 27061298) Nat Genet. 2019 Mar;51(3):481-493. (PMID: 30804560) Lancet Respir Med. 2016 Jul;4(7):549-556. (PMID: 27177493) Hum Genet. 2020 Jan;139(1):121-136. (PMID: 31134333) Eur Respir J. 2018 Apr 19;51(4):. (PMID: 29563173) Elife. 2018 May 30;7:. (PMID: 29846171) Ther Adv Chronic Dis. 2016 Jan;7(1):34-51. (PMID: 26770668) Ann Med. 2021 Dec;53(1):1118-1128. (PMID: 34259107) Lancet Respir Med. 2019 Jan;7(1):20-34. (PMID: 30552067) Cell. 2016 Nov 17;167(5):1415-1429.e19. (PMID: 27863252) Stat Med. 2021 Nov 10;40(25):5434-5452. (PMID: 34338327) Expert Rev Respir Med. 2013 Feb;7(1):33-42. (PMID: 23362813) Eur Respir J. 2019 Aug 1;54(2):. (PMID: 31073084) N Engl J Med. 2009 Mar 5;360(10):973-84. (PMID: 19264686) Cell. 2020 Sep 3;182(5):1214-1231.e11. (PMID: 32888494) Int J Epidemiol. 2018 Feb 1;47(1):226-235. (PMID: 29040562) Nat Genet. 2011 Sep 25;43(11):1082-90. (PMID: 21946350) Twin Res Hum Genet. 2018 Apr;21(2):89-100. (PMID: 29506594) Am J Epidemiol. 2015 Feb 15;181(4):290-1. (PMID: 25660081) BMJ. 2018 Jul 12;362:k601. (PMID: 30002074) Am J Epidemiol. 2015 Feb 15;181(4):251-60. (PMID: 25632051) Genet Epidemiol. 2016 Nov;40(7):597-608. (PMID: 27625185) Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: 26050253) Nat Genet. 2018 May;50(5):693-698. (PMID: 29686387) Lancet. 2012 Aug 18;380(9842):651-9. (PMID: 22901886) Hum Mol Genet. 2014 Sep 15;23(R1):R89-98. (PMID: 25064373) Nature. 2018 Oct;562(7726):203-209. (PMID: 30305743) Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 1):1646-52. (PMID: 7952628) Nat Genet. 2019 Mar;51(3):494-505. (PMID: 30804561) N Engl J Med. 2017 Oct 26;377(17):1613-1629. (PMID: 28893134)
معلومات مُعتمدة:	MC_PC_19004 United Kingdom MRC_ Medical Research Council; MC_PC_17228 United Kingdom MRC_ Medical Research Council; MR/S037055/1 United Kingdom MRC_ Medical Research Council; MR/P00167X/1 United Kingdom MRC_ Medical Research Council; AA/18/3/34220 United Kingdom BHF_ British Heart Foundation; MR/N011317/1 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; MC_QA137853 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة:	Investigator: JP Cook; IJ Deary; S Enroth; R Ewert; C Gieger; U Gyllensten; SE Harris; C Hayward; G Homuth; J Hui; M Imboden; AL James; MR Jarvelin; PK Joshi; M Kahonen; S Karrasch; KA Kentistou; SM Kerr; M Kumari; C Langenberg; T Lehtimaki; L Lind; J Luan; A Mahajan; J Marten; AP Morris; O Polasek; DJ Porteous; NM Probst-Hensch; OT Raitakari; R Rawal; I Rudan; H Schulz; BH Smith; DP Strachan; B Stubbe; I Surakka; PR Timmers; V Vitart; N Wareham; S Weiss; M Wielscher; JF Wilson; E Zeggini; JH Zhao Keywords: Asthma Epidemiology; Asthma Genetics; Asthma Mechanisms; COPD epidemiology; COPD exacerbations mechanisms; Eosinophil Biology; Respiratory Infection
تواريخ الأحداث:	Date Created: 20220510 Date Completed: 20230417 Latest Revision: 20230816
رمز التحديث:	20230816
مُعرف محوري في PubMed:	PMC10176352
DOI:	10.1136/thoraxjnl-2021-217993
PMID:	35537820
قاعدة البيانات:	MEDLINE

Find this article in full text from ProQuest

Full Text Finder

الوصف
تدمد:	1468-3296
DOI:	10.1136/thoraxjnl-2021-217993