دورية أكاديمية
أعرض في EDS

Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci.

التفاصيل البيبلوغرافية
العنوان: Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci.
المؤلفون: Clark AD; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom., Nair N; Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester Manchester, United Kingdom; NIHR Manchester Musculoskeletal BRC, Manchester University NHS Foundation Trust, Manchester, United Kingdom., Anderson AE; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom., Thalayasingam N; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom., Naamane N; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom., Skelton AJ; Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom., Diboll J; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom., Barton A; Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester Manchester, United Kingdom; NIHR Manchester Musculoskeletal BRC, Manchester University NHS Foundation Trust, Manchester, United Kingdom., Eyre S; Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester Manchester, United Kingdom; NIHR Manchester Musculoskeletal BRC, Manchester University NHS Foundation Trust, Manchester, United Kingdom., Isaacs JD; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom; Musculoskeletal Services Directorate, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom., Pratt AG; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom; Musculoskeletal Services Directorate, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. Electronic address: arthur.pratt@ncl.ac.uk., Reynard LN; Newcastle University Biosciences Institute, Newcastle upon Tyne, United Kingdom.
المصدر: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2020 May; Vol. 145 (5), pp. 1438-1451. Date of Electronic Publication: 2020 Jan 13.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Mosby Country of Publication: United States NLM ID: 1275002 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-6825 (Electronic) Linking ISSN: 00916749 NLM ISO Abbreviation: J Allergy Clin Immunol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: St Louis, Mosby.
مواضيع طبية MeSH: B-Lymphocytes* , CD4-Positive T-Lymphocytes* , DNA Methylation* , Genetic Predisposition to Disease*, Arthritis, Rheumatoid/*genetics, Aged ; Arthritis, Rheumatoid/immunology ; Female ; Genetic Loci ; Genotype ; Humans ; Male ; Middle Aged
مستخلص: Background: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era.
Objectives: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies.
Methods: Whole-genome methylation and transcriptional data from isolated CD4 + T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources.
Results: We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4 + T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4 + T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally.
Conclusions: Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
References: PLoS Genet. 2014 Jun 26;10(6):e1004404. (PMID: 24968232)
PLoS Genet. 2016 Mar 25;12(3):e1005908. (PMID: 27015630)
BMC Genet. 2009 May 27;10:23. (PMID: 19473544)
Am J Hum Genet. 2018 Nov 1;103(5):654-665. (PMID: 30401456)
Nat Commun. 2018 Feb 23;9(1):804. (PMID: 29476079)
Nat Commun. 2017 Mar 23;8:14852. (PMID: 28332497)
Nat Commun. 2018 May 15;9(1):1921. (PMID: 29765031)
Nucleic Acids Res. 2017 Jan 4;45(D1):D896-D901. (PMID: 27899670)
Nat Commun. 2016 Nov 25;7:13507. (PMID: 27886173)
Genome Biol. 2014 Dec 03;15(12):503. (PMID: 25599564)
PLoS Genet. 2007 Sep;3(9):1724-35. (PMID: 17907809)
PLoS Genet. 2014 Sep 18;10(9):e1004663. (PMID: 25233095)
Cell. 2016 Nov 17;167(5):1398-1414.e24. (PMID: 27863251)
Hum Mol Genet. 2015 Dec 20;24(25):7432-44. (PMID: 26464490)
Epigenetics. 2006 Jul-Sep;1(3):127-30. (PMID: 17965610)
BMC Bioinformatics. 2012 May 08;13:86. (PMID: 22568884)
Genome Res. 2012 Sep;22(9):1798-812. (PMID: 22955990)
PLoS Genet. 2017 Mar 1;13(3):e1006643. (PMID: 28248954)
Nat Genet. 2017 Jul;49(7):1120-1125. (PMID: 28553958)
J Allergy Clin Immunol. 2018 Jun;141(6):2282-2286.e6. (PMID: 29374573)
Nat Genet. 2005 May;37(5):478-85. (PMID: 15838509)
Ann Rheum Dis. 2012 Dec;71(12):1984-90. (PMID: 22661644)
Science. 2017 May 5;356(6337):. (PMID: 28473536)
Bioinformatics. 2012 May 15;28(10):1353-8. (PMID: 22492648)
PLoS Genet. 2014 May 15;10(5):e1004383. (PMID: 24830394)
Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792)
Nat Biotechnol. 2016 Oct;34(10):1060-1065. (PMID: 27571369)
Nature. 2014 Feb 20;506(7488):376-81. (PMID: 24390342)
Genome Res. 2014 Jan;24(1):1-13. (PMID: 24196873)
Cell. 2013 Nov 7;155(4):934-47. (PMID: 24119843)
PLoS Genet. 2009 Jun;5(6):e1000529. (PMID: 19543373)
BMC Med Genet. 2014 May 04;15:53. (PMID: 24886551)
Nature. 2012 Sep 6;489(7414):91-100. (PMID: 22955619)
FEBS J. 2014 Jul;281(14):3193-205. (PMID: 24854865)
PLoS Genet. 2015 Jan 29;11(1):e1004958. (PMID: 25634236)
Nature. 2015 Feb 19;518(7539):317-30. (PMID: 25693563)
Cell. 2016 Nov 17;167(5):1369-1384.e19. (PMID: 27863249)
PLoS Genet. 2010 May 13;6(5):e1000952. (PMID: 20485568)
Genome Biol. 2016 Dec 12;17(1):255. (PMID: 27955697)
Nat Genet. 2017 Jan;49(1):139-145. (PMID: 27918533)
Rheumatology (Oxford). 2019 Jul 1;58(7):1268-1273. (PMID: 30753709)
J Autoimmun. 2013 Mar;41:6-16. (PMID: 23306098)
Nat Genet. 2019 Jan;51(1):187-195. (PMID: 30478440)
Bioinformatics. 2016 Jan 15;32(2):286-8. (PMID: 26424855)
Nature. 2015 Feb 19;518(7539):337-43. (PMID: 25363779)
Ann Rheum Dis. 2018 May;77(5):736-743. (PMID: 29437559)
Nat Rev Genet. 2012 May 29;13(7):484-92. (PMID: 22641018)
Epigenomics. 2016 Feb;8(2):209-24. (PMID: 26556652)
Arthritis Rheum. 2010 Sep;62(9):2569-81. (PMID: 20872595)
Arthritis Rheumatol. 2018 Mar;70(3):361-370. (PMID: 29193869)
Science. 2009 Sep 4;325(5945):1246-50. (PMID: 19644074)
Nat Biotechnol. 2013 Feb;31(2):142-7. (PMID: 23334450)
Genome Biol. 2016 Mar 31;17:61. (PMID: 27036880)
Nat Methods. 2011 Dec 04;9(2):179-81. (PMID: 22138821)
Nature. 2015 Apr 23;520(7548):558-62. (PMID: 25686607)
Nat Commun. 2016 Nov 16;7:13426. (PMID: 27848966)
Mod Rheumatol. 2017 May;27(3):441-447. (PMID: 27585642)
Hum Mol Genet. 2017 Jul 15;26(14):2803-2811. (PMID: 28475762)
معلومات مُعتمدة: G1001518 United Kingdom MRC_ Medical Research Council; MR/P020941/1 United Kingdom MRC_ Medical Research Council; 21754 United Kingdom VAC_ Versus Arthritis; United Kingdom DH_ Department of Health; MR/K015346/1 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust
فهرسة مساهمة: Keywords: B cell; CD4(+) T cell; DNA methylation; Rheumatoid arthritis; adaptive immunity; expression quantitative trait locus; genetics; immune-mediated disease; methylation quantitative trait locus; pathogenesis
تواريخ الأحداث: Date Created: 20200117 Date Completed: 20210215 Latest Revision: 20220129
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC7201180
DOI: 10.1016/j.jaci.2019.12.910
PMID: 31945409
قاعدة البيانات: MEDLINE
الوصف
تدمد:1097-6825
DOI:10.1016/j.jaci.2019.12.910