Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant

Qiang Wang; Marta Martínez-Bonet; Taehyeung Kim; Jeffrey A Sparks; Kazuyoshi Ishigaki; Xiaoting Chen; Marc Sudman; Vitor Aguiar; Sangwan Sim; Marcos Chiñas Hernandez; Darren J Chiu; Alexandra Wactor; Brian Wauford; Miranda C Marion; Maria Gutierrez-Arcelus; John Bowes; Stephen Eyre; Ellen Nordal; Sampath Prahalad; Marite Rygg; Vibeke Videm; Soumya Raychaudhuri; Matthew T Weirauch; Carl D Langefeld; Susan D Thompson; Peter A Nigrovic

doi:10.1016/j.xgen.2023.100420

Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant

Cell Genom. 2023 Oct 16;3(11):100420. doi: 10.1016/j.xgen.2023.100420. eCollection 2023 Nov 8.

Authors

Qiang Wang¹, Marta Martínez-Bonet^{2

3}, Taehyeung Kim¹, Jeffrey A Sparks², Kazuyoshi Ishigaki², Xiaoting Chen⁴, Marc Sudman⁴, Vitor Aguiar¹, Sangwan Sim¹, Marcos Chiñas Hernandez¹, Darren J Chiu², Alexandra Wactor¹, Brian Wauford¹, Miranda C Marion⁵, Maria Gutierrez-Arcelus^{1

4}, John Bowes^{6

7}, Stephen Eyre^{6

7}, Ellen Nordal⁸, Sampath Prahalad⁹, Marite Rygg^{10

11}, Vibeke Videm¹⁰, Soumya Raychaudhuri^{2

6

12

13

14}, Matthew T Weirauch^{4

15

16}, Carl D Langefeld⁵, Susan D Thompson^{4

16}, Peter A Nigrovic^{1

2}

Affiliations

¹ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Laboratory of Immune-regulation, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
⁴ Center of Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁵ Department of Biostatistics and Data Science, and Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁶ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Oxford Road, Manchester, UK.
⁷ NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁸ University Hospital of North Norway and UIT The Arctic University of Norway, Tromsø, Norway.
⁹ Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, GA, USA.
¹⁰ Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
¹¹ Department of Pediatrics, St. Olav's University Hospital, Trondheim, Norway.
¹² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Center for Data Science, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
¹⁵ Divisions of Human Genetics, Biomedical Informatics, and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁶ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Abstract

TRAF1/C5 was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using Immunochip data from 3,939 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of TRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-related antigen 2 (FRA2), encoded by FOSL2, resulting in reduced TRAF1 expression and enhanced tumor necrosis factor (TNF) production. Conditioning on this JIA variant eliminated attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding functional variant drives risk of inflammatory arthritis in children and adults.

Keywords: C5; FRA2; TNF; TRAF1; genome-wide association study; juvenile idiopathic arthritis; monocyte; non-coding variant; rheumatoid arthritis.

Abstract

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