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.