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  • Hypomethylation of miR-17-92 cluster in lupus T cells and no significant role for genetic factors in the lupus-associated DNA methylation signature

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Systemic lupus erythematosus
Hypomethylation of miR-17-92 cluster in lupus T cells and no significant role for genetic factors in the lupus-associated DNA methylation signature
  1. Patrick Coit1,2,
  2. Xiavan Roopnarinesingh3,4,
  3. Lourdes Ortiz-Fernández1,
  4. Kathleen McKinnon-Maksimowicz5,
  5. Emily E Lewis6,
  6. Joan T Merrill4,
  7. W Joseph McCune6,
  8. Jonathan D Wren4,7,
  9. Amr H Sawalha1,8,9,10
  1. 1 Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  2. 2 Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA
  3. 3 Graduate Program, Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  4. 4 Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  5. 5 Division of Rheumatology, Henry Ford Health System, Detroit, Michigan, USA
  6. 6 Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  7. 7 Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  8. 8 Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  9. 9 Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  10. 10 Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Amr H Sawalha, Rheumatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; asawalha{at}pitt.edu

Abstract

Objectives Lupus T cells demonstrate aberrant DNA methylation patterns dominated by hypomethylation of interferon-regulated genes. The objective of this study was to identify additional lupus-associated DNA methylation changes and determine the genetic contribution to epigenetic changes characteristic of lupus.

Methods Genome-wide DNA methylation was assessed in naïve CD4+ T cells from 74 patients with lupus and 74 age-matched, sex-matched and race-matched healthy controls. We applied a trend deviation analysis approach, comparing methylation data in our cohort with over 16 500 samples. Methylation quantitative trait loci (meQTL) analysis was performed by integrating methylation profiles with genome-wide genotyping data.

Results In addition to the previously reported epigenetic signature in interferon-regulated genes, we observed hypomethylation in the promoter region of the miR-17-92 cluster in patients with lupus. Members of this microRNA cluster play an important role in regulating T cell proliferation and differentiation. Expression of two microRNAs in this cluster, miR-19b1 and miR-18a, showed a significant positive correlation with lupus disease activity. Among miR-18a target genes, TNFAIP3, which encodes a negative regulator of nuclear factor kappa B, was downregulated in lupus CD4+ T cells. MeQTL identified in lupus patients showed overlap with genetic risk loci for lupus, including CFB and IRF7. The lupus risk allele in IRF7 (rs1131665) was associated with significant IRF7 hypomethylation. However, <1% of differentially methylated CpG sites in patients with lupus were associated with an meQTL, suggesting minimal genetic contribution to lupus-associated epigenotypes.

Conclusion The lupus defining epigenetic signature, characterised by robust hypomethylation of interferon-regulated genes, does not appear to be determined by genetic factors. Hypomethylation of the miR-17-92 cluster that plays an important role in T cell activation is a novel epigenetic locus for lupus.

  • lupus erythematosus, systemic
  • polymorphism, genetic
  • autoimmunity

Data availability statement

Data are available on reasonable request. All relevant data used to generate the results presented, are included in supplementary tables associated with this submission.

http://dx.doi.org/10.1136/annrheumdis-2022-222656

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    Data availability statement

    Data are available on reasonable request. All relevant data used to generate the results presented, are included in supplementary tables associated with this submission.

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    Footnotes

    • Handling editor Josef S Smolen

    • PC and XR contributed equally.

    • Correction notice This article has been corrected since it published Online First. The wording in the 'Naïve CD4+ T cell methylation quantitative trait loci in patients with lupus' section has been amended.

    • Contributors All authors fulfilled the following criteria: substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data. Drafting the work or revising it critically for important intellectual content. Final approval of the version published. Dr. Sawalha accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.

    • Funding This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) grant number R01 AI097134 to AHS. JDW is supported by NIH grants number P30 AG050911 and P20 GM103636.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.