A polygenic risk score for rheumatoid arthritis sheds light on the Prevotella association

Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with reduced life expectancy. It is heritable and an extensive repertoire of genetic variants have been identified. The gut microbiota may represent an environmental risk factor for RA. Indeed, Prevotella copri is a candidate keystone species, but whether it lies on the causal pathway for disease or is simply a bystander reflecting host-genetic predisposition to RA, remains to be determined. The study of disease-microbiota associations may be confounded by the presence of the disease of interest or by its treatment. To circumvent this issue, we assessed whether known RA risk alleles were associated with the gut microbiota, in a large who do not have RA. Methods Blood and stool acquired from volunteers from TwinsUK were used for genotyping and assessment of the gut microbiota, respectively. A weighted polygenic risk score (PRS) for RA was calculated in 1650 unaffected twins from the TwinsUK cohort, based on 233 published GWAS-identified published RA associated single nucleotide polymorphisms (SNPs). Amplicon sequence variants (ASVs) were generated from 16S rRNA sequencing of stool samples and assessed for association with RA PRS. Confirmation of findings was performed using an independent sample comprised of first-degree relatives of RA patients from the SCREEN-RA cohort (n=133). Findings We found that Prevotella spp was positively associated with RA PRS in TwinsUK participants (p.adj<1e-7). This finding was validated in SCREEN-RA participants carrying the shared epitope risk alleles (p.adj=1.12e-3). An association of Prevotella spp . with pre-clinical RA phases was also demonstrated (p.adj=0.021). Interpretation Prevotella in the gut microbiota is associated with RA genotype in the absence of RA, as well as in subjects at high risk of developing RA. This work suggests that host genotype is associated with microbiota profile prior to disease onset. Evidence before this study? Prevotella copri is increased within the gut microbiota in rheumatoid arthritis (RA) patients, predominantly those with early disease, before treatment is initiated. Prevotellaceae (family) has been demonstrated to be increased in pre-clinical RA cases compared to controls. Prevotella copri is posited to be an inflammatory driver, contributing to RA pathology by promoting a pro-inflammatory cytokine milieu. What does this study add? This study is the first to demonstrate that, in a large human cohort, carrying genetic risk factors for RA is associated with a higher abundance of Prevotella spp . in the absence of RA. How might this impact on clinical practice or future developments This work suggests that any potential causal role of Prevotella spp . occurs very early in disease development. Strategies to intervene should target early or asymptomatic at-risk groups ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by Arthritis Research UK Special Strategic Award (grant 21227). Twins UK receives funding from the Wellcome Trust; the National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St Thomas' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Claire J. Steves is funded by the Wellcome Trust (grant WT081878MA). Philippa Wells is supported by a joint PhD studentship from the Medical Research Council (MRC) and Clinical Disease Reasearch Foundation (CDRF). ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is available from TwinsUK.