Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: a cross-sectional study
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Abstract
BACKGROUND: Rheumatoid arthritis is a chronic inflammatory autoimmune disease that is associated with reduced life expectancy. The disease is heritable and an extensive repertoire of genetic variants have been identified. The gut microbiota might represent an environmental risk factor for rheumatoid arthritis. We aimed to assess whether known rheumatoid arthritis risk alleles were associated with the gut microbiota in a large population who do not have rheumatoid arthritis. METHODS: In this cross-sectional study done in the UK and Switzerland, we used genotyping and microbiota data from previous studies of the TwinsUK cohort, excluding participants who had ever had a diagnosis of rheumatoid arthritis, as well as their unaffected co-twins. We used blood samples for genotyping and stool samples for the assessment of the gut microbiota. We generated a polygenic risk score (PRS) for rheumatoid arthritis in 1650 TwinsUK participants without the disease, based on 233 GWAS-identified single nucleotide polymorphisms associated with rheumatoid arthritis. We validated the PRS using logistic regression against rheumatoid arthritis diagnosis in 2686 UK Biobank individuals with a confirmed diagnosis of rheumatoid arthritis. Amplicon sequence variants (ASVs) were generated from 16S rRNA gene sequencing of stool samples and assessed for association with the PRS for rheumatoid arthritis. We validated the findings in an independent sample comprised of first-degree relatives of patients with rheumatoid arthritis from the SCREEN-RA cohort. Differential abundance of ASVs present in more than 5% of samples, grouped by ASV taxon annotation, against the rheumatoid arthritis PRS as a continuous variable was assessed using fixed-effects covariates. To account for multiple testing, the false discovery rate calculation was applied to all p values to generate q values, with a significance threshold of 0·05 determined a priori. FINDINGS: spp and presence of preclinical rheumatoid arthritis phases (q=0·021). INTERPRETATION: spp in the gut microbiota are associated with the rheumatoid arthritis genotype in the absence of rheumatoid arthritis, including in individuals at high risk of developing rheumatoid arthritis. Our findings suggest that host genotype is associated with microbiota profile before disease onset. FUNDING: Versus Arthritis.
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Prevotella species associated with detrimental impacts on intestinal barrier integrity are enriched in IBS patients and in models of intestinal inflammation and may promote inflammatory arthritis.
“Prevotella species associated with detrimental impacts on intestinal barrier integrity are enriched in IBS patients and in models of intestinal inflammation [52, 113] and may promote inflammatory arthritis [3, 104, 126].”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [126]
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- Authors
- Wells, P. M., Adebayo, A. S., Bowyer, R. C. E., Freidin, M. B., Finckh, A., Strowig, T., Lesker, T. R., Alpizar-Rodriguez, D., Gilbert, B., Kirkham, B., Cope, A. P., Steves, C. J., & Williams, F. M. K.
- Affiliations
- King's College London (GB)
- University Hospital of Geneva (CH)
- Medizinische Hochschule Hannover (DE)
- Helmholtz Centre for Infection Research (DE)
- Guy's Hospital (GB)
- St Thomas' Hospital (GB)
- Corresponding author
- Williams, Frances M K
- ORCID
- Venue
- The Lancet Rheumatology
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 2
- Issue
- 7
- Pages
- e418-e427
- ISSN
- 2665-9913 (ISSN-L)
- PMC
- PMC7729822
- OpenAlex
- W3037169575
- Cited by
- 192
- References
- 32
- Citations by year
- 2026: 30 · 2025: 34 · 2024: 44 · 2023: 26 · 2022: 23 · 2021: 28 · 2020: 7
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Update notices
- erratum (2025-05-01)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Rheumatology (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- King's College London
- Manchester Biomedical Research Centre
- Guy's and St Thomas' NHS Foundation Trust
- Medical Research Council
- National Institute for Health Research
- Wellcome Trust (WT081878MA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- rheumatoid arthritis, gut microbiota, genetic risk, polygenic risk score, single nucleotide polymorphisms, preclinical rheumatoid arthritis, host-microbe interactions, first-degree relatives, Bacteroides, 16S rRNA gene sequencing, TwinsUK
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