To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles.
Objective. There is substantial uncertainty regarding the prevalence of depression in RA. We conducted a systematic review aiming to describe the prevalence of depression in RA.Methods. Web of Science, PsycINFO, CINAHL, Embase, Medline and PubMed were searched for cross-sectional studies reporting a prevalence estimate for depression in adult RA patients. Studies were reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and a meta-analysis was performed.Results. A total of 72 studies, including 13 189 patients, were eligible for inclusion in the review. Forty-three methods of defining depression were reported. Meta-analyses revealed the prevalence of major depressive disorder to be 16.8% (95% CI 10%, 24%). According to the PHQ-9, the prevalence of depression was 38.8% (95% CI 34%, 43%), and prevalence levels according to the HADS with thresholds of 8 and 11 were 34.2% (95% CI 25%, 44%) and 14.8% (95% CI 12%, 18%), respectively. The main influence on depression prevalence was the mean age of the sample.Conclusion. Depression is highly prevalent in RA and associated with poorer RA outcomes. This suggests that optimal care of RA patients may include the detection and management of depression.
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to play an important role in genetic susceptibility to common disease. To address this we undertook a large direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed ~19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated ~50% of all common CNVs larger than 500bp. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell-lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease, IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis, and type 1 diabetes, and TSPAN8 for type 2 diabetes, though in each case the locus had previously been identified in SNP-based studies, reflecting our observation that the majority of common CNVs which are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs which can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 × 10 -5 -5 × 10 -7 in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 × 10 -8 ) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-α-induced protein 3 (TNFAIP3).The WTCCC genome-wide association screen (GWA) of 1,860 rheumatoid arthritis cases and 2,938 healthy controls confirmed association with SNPs within the HLA region and the PTPN22 gene (P < 1 × 10 -7 ; ref. 1). Nine other loci showed strong evidence for association (P = 1 × 10 -5 -5 × 10 -7 ). SNPs at these loci were genotyped in an independent cohort of 5,063 rheumatoid arthritis cases and 3,849 healthy controls (Supplementary Methods and Supplementary Table 1 Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts www.sequenom.com), to establish whether they are genuinely associated with the disease. In this cohort, we had 80% power to detect most of the effect sizes reported in the initial study at P < 0.05 (Supplementary Table 2 online). We selected ten SNPs for genotyping; these included the known rheumatoid arthritis susceptibility variant rs2476601, mapping to the PTPN22 gene, and nine previously unknown SNPs identified by the WTCCC study1. A Bonferroni correction of 9 was applied to account for the previously unknown loci investigated, resulting in a P value threshold of P < 0.006 for claims of significance in this validation study. We regarded SNPs validated at P values between 0.05 and 0.006 as suggestive evidence.We detected strong association with the rheumatoid arthritis-causing SNP in the PTPN22 gene (rs2476601), as expected (odds ratio (OR) = 1.53, 95% CI = 1.39-1.68, trend P = 2.0 × 10 -18 ). This was not a completely independent replication, as association of rheumatoid arthritis with this locus has been reported in previous studies using some of the same samples included in the current study2-4. However, it confirmed the suitability of this cohort for validation studies. Of the nine newly identified SNPs tested, rs6920220 (G > A) showed association with rheumatoid arthritis in this cohort (OR for minor allele = 1.23, 95% CI = 1.15-1.33, trend P = 1.1 × 10 -8 ) (Table 1). For this SNP, the allele frequencies were similar across control groups tested in the WTCCC study and the healthy controls tested here (minor allele frequency (MAF) 0.22 and 0.21, respectively). We therefore undertook a combined analysis of the WTCCC data and the validation data, and we obtained strong statistical evidence for association between this SNP and rheumatoid arthritis (OR = 1.22, 95% CI = 1.15-1.29, trend P = 3.6 × 10 -12
RA has a substantial impact on HRQoL. This supports recent NICE guidelines stipulating that RA patients should be regularly assessed for the impact their disease has on HRQoL and appropriate management provided.
To discover novel RA risk loci, we systematically examined 370 SNPs from 179 independent loci with p<0.001 in a published meta-analysis of RA GWAS of 3,393 cases and 12,462 controls1. We used GRAIL2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3-11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three validate convincingly: CD2/CD58 (rs11586238, p=1×10−6 replication, p=1×10−9 overall), and CD28 (rs1980422, p=5×10−6 replication, p=1×10−9 overall), PRDM1 (rs548234, p=1×10−5 replication, p=2×10−8 overall). An additional four replicate (p<0.0023): TAGAP (rs394581, p=0.0002 replication, p=4×10−7 overall), PTPRC (rs10919563, p=0.0003 replication, p=7×10−7 overall), TRAF6/RAG1 (rs540386, p=0.0008 replication, p=4×10−6 overall), and FCGR2A (rs12746613, p=0.0022 replication, p=2×10−5 overall). Many of these loci are also associated to other immunologic diseases.
Rationale Health status is impaired in patients with interstitial lung disease (ILD). There is a paucity of tools that assess health status in ILD. The objective of this study was to develop and validate the King's Brief Interstitial Lung Disease questionnaire (K-BILD), a new health status measure for patients with ILD. Methods Patients with ILD were recruited from outpatient clinics. The development of the questionnaire consisted of three phases: item generation; item reduction, allocation to domains by factor analysis, Rasch analysis to create unidimensional scales and validation; and repeatability testing. Results 173 patients with ILD (49 with idiopathic pulmonary fibrosis) completed a preliminary 71-item questionnaire. 56 items were removed due to redundancy, low factor loadings or poor fit to the Rasch model. The final version of the K-BILD questionnaire consisted of 15 items and three domains (breathlessness and activities, chest symptoms and psychological). Internal consistency assessed with Cronbach's a coefficient was 0.94 for the K-BILD total score. Concurrent validity of the K-BILD questionnaire was high compared with St George's Respiratory Questionnaire (r¼0.90) and moderate with lung function (vital capacity, r¼0.50). The K-BILD questionnaire was repeatable over 2 weeks (n¼44), with intraclass correlation coefficients for domains and total score 0.86e0.94. The K-BILD construct validity for patients with idiopathic pulmonary fibrosis was similar to that of other ILDs. Conclusion The K-BILD questionnaire is a brief, valid, self-completed health status measure for ILD. It could be used in the clinic to assess ILD from the patients' perspective.
Objective. The aim of this analysis is to examine the longitudinal impact of symptoms of depression/anxiety on treatment response, long-term disease activity and physical disability in RA.Methods. Secondary analysis of clinical trial data was performed. Data were collected at baseline and at 6-monthly intervals for 2 years. The EuroQoL (EQ-5DTM) indicated depression/anxiety symptom severity. Our primary outcomes of interest were (i) DAS-28 and (ii) physical disability measured via the HAQ. Secondary outcomes were: tender and swollen joint counts, patient global assessment, ESR and odds of reaching clinical remission. Multilevel models were used to assess the impact of baseline and persistent depression/anxiety on outcomes over 2 years.Results. Data from 379 patients were included. After adjusting for covariates, baseline depression/anxiety symptoms were associated with increased DAS-28 outcomes and increased tender joint counts. Persistent depression/anxiety symptoms were associated with increased DAS-28 scores, HAQ scores, tender joint counts and patient global assessment of disease activity, and reduced odds of reaching clinical remission. Patients with symptoms of depression/anxiety at baseline also showed a 50% reduction in prednisolone treatment effect, in comparison with patients with no symptoms of depression/anxiety at baseline.Conclusion. Baseline and persistent symptoms of depression/anxiety are associated with poorer health outcomes over time, as well as reduced treatment response. Mental health should be routinely measured both in clinical practice and in research, and managed alongside rheumatological disease to optimize health outcomes. Further research is required to examine whether treatment of mental disorders can improve rheumatological outcomes.
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