Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23

BACKGROUND: The 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. RESULTS: Although 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. CONCLUSIONS: Our 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

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

The effect of vitamin D levels on the assessment of disease activity in rheumatoid arthritis

Abstract 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