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BackgroundThe identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk.ResultsAlthough the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells.ConclusionsOur results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1078-x) contains supplementary material, which is available to authorized users.

Disease activity in rheumatoid arthritis (RA) is assessed by a combination of objective and subjective tests, combined to produce a disease activity score in 28 joints (DAS28). There is some evidence that RA disease activity, as assessed by DAS28, can be influenced by vitamin D levels. It is difficult to know whether this is due to a true immunomodulatory effect of vitamin D or a more subjective effect of low vitamin D on pain perception. We addressed this issue by comparing vitamin D levels with disease activity, analysing each component of the DAS28 score separately. We measured 25-hydroxy vitamin D levels in 176 outpatients with RA at two different centres and recorded a DAS28 score using an ESR checked at the same time. We calculated DAS28 both with and without the patient's rating of their symptoms on the visual analogue score (VAS) to assess the effect of VAS on DAS28. The vitamin D results were expressed as nanomole per litre with 50 nmol/l taken as the lower limit of normal. We calculated mean levels of vitamin D and undertook a multivariate regression analysis to assess correlations between vitamin D levels and DAS28 (and its individual components), corrected for centre, age and gender. The overall mean DAS28 score was 3.66 (SE ± 0.11) using all four criteria and 3.43 (SE ± 0.10) using just three criteria (omitting VAS). The mean vitamin D level was 39.42 nmol/l (SE ± 1.55). There was no significant correlation between vitamin D and DAS28 scores with or without the inclusion of VAS. However, there was a significant inverse relationship between vitamin D and VAS itself (coefficient = 0.249, p = 0.013). The mean DAS28 score was greater in vitamin D-deficient patients and this was explained by their higher VAS scores. Our data confirms that vitamin D deficiency is common in RA. This paper provides evidence that the VAS component, assessing patient perception of symptoms, is inversely related to vitamin D, with lower levels producing higher VAS values. Although there was no overall correlation between vitamin D levels and DAS28, patients may perceive themselves or be perceived by assessors as having responded less well to disease modification in the presence of vitamin D deficiency. This could have major implications for subsequent management, and clinicians need to be aware of the potential confounding effect of vitamin D deficiency in assessing RA disease activity using the full DAS28 tool.

Background: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era. Objectives: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies.

ObjectivesAn interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.MethodsIn a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes.ResultsWe reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α).ConclusionsOur data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.