- July 14, 2025
- Matthew Brown, Huji Xu, et al. Kings College London, Shanghai Changzheng Hospital
Topic/Product:
Immunology, Inflammation, Inflammation Panel 250
Disease Area:
Ankylosing Spondylitis
Sample Type:
Serum
Abstract
We report the largest genome-wide association study meta-analysis in ankylosing spondylitis (AS) to date (25,645 cases, 71,224 controls), identifying 27 novel loci and 86 independent genetic associations. Variations in FUT2 (non-secretor status) and ABO (blood group A) increase AS risk, with Mendelian randomisation (MR) linking non-secretor status to increased AS risk from reduced gut carriage of Ruminococcus torques. Associations with three telomerase maintenance genes (TERT, TERC, RTEL1), and MR analysis, suggest increased telomere length causally increases AS susceptibility. Fine-mapping prioritised likely causal variants at multiple loci. Transcriptome- and proteome-wide association studies implicated 644 genes, highlighting immune-related pathways. Lower genetically-determined IL-6 and IL-12, and similar IL-23, levels were found in AS cases, offering a genetic explanation for the failure of IL-6, IL-12, and IL-23 inhibition in AS treatment. Finally, multi-omic analyses showed chromosome 2p15 association acts via reduced B3GNT2 expression. These findings deepen understanding of AS pathogenesis, highlighting new pathways and therapeutic opportunities.
Authors & Affiliations
Matthew Brown1, Zhixiu Li2, Xin Wu3 , Nicholas Harvey4, Jose Garrido-Mesa5, Xiaobing Wang6, Zhihao Xu2, Geng Wang7, Helena Marzo-Ortega8, Dennis McGonagle9, Ann Morgan10, Nurullah Akkoc11, Gokce Kenar Artin12, Gary Macfarlane13, Gareth Jones14, Linda Bradbury15, Paul Leo16, Kate Zimmerman17, Emma Duncan18, Julia Brown19, Tony Merriman20, Simon Stebbings21, Mahdi Mahmoudi22, Ahmadreza Jamshidi22, Elham Farhadi22, Nigil Haroon23, Robert Inman23, Maxime Breban24, Gensler Lianne25, Michael Ward26, B. Wordsworth27, Michael Weisman28, David Evans18, Tony Kenna15, Tae-Hwan Kim29, John Reveille30, Huji Xu31
1 King’s College London,
2 School of Public Health and Emergency Management, Southern University of Science and Technology,
3 Department of Rhuematology and Immunology, Shanghai Changzeng Hospital, The Second Military Medical University, China.,
4 Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King’s College London,
5 Unidad investigación clínica de cáncer de pulmón, H12O-CNIO, Instituto de Investigación Hospital 12 de Octubre/Centro Nacional de Investigaciones Oncológica,
6 Department of Rheumatology and Immunology, National key laboratory for Immunity and Inflammation, Shanghai Changzheng Hospital, Naval Medical University,
7 The University of Queensland,
8 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds,
9 Leeds Institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, University of Leeds,
10 Leeds University,
11 Dokuz Eylül University,
12 School of Medicine, Division of Rheumatology, Dokuz Eylül University,
13 School of Medicine and Dentistry, University of Aberdeen,
14 University of Aberdeen,
15 Queensland University of Technology,
16 QUT,
17 School of Biomedical Sciences, Queensland University of Technology,
18 University of Queensland,
19 College of Medicine and Dentistry, James Cook University,
20 University of Alabama at Birmingham,
21 Department of Medicine, Dunedin School of Medicine, University of Otago,
22 Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences and Rheumatology Research Center, Tehran University of Medical Sciences,
23 Division of Rheumatology, Department of Medicine, University Health Network, University of Toronto, Schroeder Arthritis Institute,
24 UMR1173, Université Paris Saclay, Université de Versailles St Quentin en Yvelines, Inserm, Infection et Inflammation,
25 University of California, San Francisco,
26 National Institutes of Health,
27 Botnar Research Centre,
28 Stanford University,
29 Hanyang University Hospital for Rheumatic Diseases,
30 Memorial Hermann Texas Medical Centre,
31 Department of Rheumatology and Immunology, National Key Laboratory for Immunity and Inflammation, Shanghai Changzheng Hospital, Naval Medical University