Zhao, S.S., Mackie, S.L. orcid.org/0000-0003-2483-5873, Larsson, S.C. et al. (2 more authors) (2025) Modifiable risk factors and inflammation-related proteins in polymyalgia rheumatica: genome-wide meta-analysis and Mendelian randomization. Rheumatology, 64 (5). pp. 3012-3018. ISSN 1462-0324
Abstract
Objective
PMR is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR.
Methods
We meta-analysed genetic association data from 8156 cases of PMR (defined using diagnostic codes and self-report) and 416 495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55 792 individuals), using the inverse variance weighted and pleiotropy robust methods.
Results
We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08–1.60; P = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10–1.37; P = 3.10 × 10‾⁴) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signalling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; P = 1.89 × 10‾³²), serum amyloid A2 (OR 1.06, 9.91 × 10‾¹⁰) and CXCL6 (OR 1.09, P = 4.85 × 10‾⁷) retained significance after correction for multiple testing.
Conclusion
Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | genome-wide meta-analysis, IL-1, smoking, obesity, adiposity, PMR |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Jun 2025 08:57 |
Last Modified: | 04 Jun 2025 08:57 |
Published Version: | https://academic.oup.com/rheumatology/article/64/5... |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Identification Number: | 10.1093/rheumatology/keae308 |
Related URLs: | |
Sustainable Development Goals: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:227376 |
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