Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable... Show moreMulti-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 x 10(-8)), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA. Show less
Spiliopoulou, A.; Colombo, M.; Plant, D.; Nair, N.; Cui, J.; Coenen, M.J.H.; ... ; McKeigue, P. 2019
Introduction: To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA)... Show moreIntroduction: To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans. Methods: Two IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors. Results: Of the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score >0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)(adj) = 8.08 (95% confidence interval (CI): 1.60-40.89), P = 0.01 and ORadj = 2.97 (95% CI, 1.08 to 8.17), P = 0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj = 8.45 (95% CI, 1.57 to 45.44), P = 0.01, and ORadj = 3.57 (95% CI, 1.18 to 10.76), P = 0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj = 4.52 (95% CI, 1.20 to 17.03), P = 0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls. Conclusions: We found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations. Show less
Objective. To examine the association between baseline bone mineral density (BMD) and radiographic damage at 3 years of disease duration in a longitudinal cohort of African Americans with recent... Show moreObjective. To examine the association between baseline bone mineral density (BMD) and radiographic damage at 3 years of disease duration in a longitudinal cohort of African Americans with recent-onset rheumatoid arthritis (RA). Methods. African American RA patients with a disease duration of <2 years (n = 141) were included in the study. All patients underwent baseline BMD measurements (femoral neck and/or lumbar spine) using dual x-ray absorptiometry. T scores were calculated using normative data from the general population of African Americans. Patients were categorized as having osteopenia/osteoporosis (T score less than or equal to -1) or as being healthy. Hand and wrist radiographs, obtained at baseline and at 3 years of disease duration, were scored using the modified Sharp/van der Heijde method. The association between baseline BMD and total radiographic score at 3 years of disease was examined using multivariable negative binomial regression. Results. At baseline, the mean age and the mean disease duration were 52.4 years and 14.8 months, respectively; 85.1% of the patients were women. The average total radiographic scores at baseline and at 3 years of disease were 2.4 and 5.7, respectively. In the final reduced multivariable model, adjusting for age, sex, anti-cyclic citrullinated peptide antibody positivity, and the presence of radiographic damage at baseline, the total radiographic score at 3 years disease in patients with osteopenia/osteoporosis of the femoral neck was twice that in patients with normal bone density, and the difference was statistically significant (P = 0.0084). No association between lumbar spine osteopenia/osteoporosis and radiographic score was found. Conclusion. Our findings suggest that reduced generalized BMD may be a predictor of future radiographic damage and support the hypothesis that radiographic damage and reduced generalized BMD in RA patients may share a common pathogenic mechanism. Show less
Cui, J.; Saevarsdottir, S.; Thomson, B.; Padyukov, L.; Helm-van Mil, A.H.M. van der; Nititham, J.; ... ; Ge 2010
Objective. Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors... Show moreObjective. Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods. A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (Delta DAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results. Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the Delta DAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99). Conclusion. Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections. Show less
Bridges, S.L.; Causey, Z.L.; Burgos, P.I.; Huynh, B.Q.N.; Hughes, L.B.; Danila, M.I.; ... ; Heijde, D.M. van der 2010
Objective. To describe radiographic changes in African Americans with rheumatoid arthritis (RA) from the Consortium for the Longitudinal Evaluations of African Americans with Early Rheumatoid... Show moreObjective. To describe radiographic changes in African Americans with rheumatoid arthritis (RA) from the Consortium for the Longitudinal Evaluations of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry, a multicenter observational study. Methods. Self-declared African American patients were enrolled in CLEAR I, a longitudinal cohort of early RA (disease duration of <2 years) from 2000 to 2005, or in CLEAR II, a cross-sectional cohort (any disease duration) from 2006 to the present. Demographic and clinical data were obtained, and sets of hand/wrist and foot radiographs were scored using the modified Sharp/van der Heijde scoring system. Results. A total of 357 and 418 patients were enrolled in CLEAR I and CLEAR II, respectively. We report here an interim analysis of radiographic severity in these patients. For the CLEAR I cohort, 294 patients had a mean radiographic score of 2.89 at the baseline visit; 32.0% showed either erosions (25.9%) or joint space narrowing (JSN; 19.4%). At the 36-month visit, the mean score was 5.65; 44.2% had erosions, 41.5% had JSN, and 54.4% had either. Among those patients without radiographic damage at baseline, 18.9% had progressed at the 36-month visit, compared with 57.1% of those with baseline damage (P < 0.0001). For the CLEAR II cohort, of 167 patients with RA of any duration, 65.3% exhibited joint erosions, 65.3% exhibited JSN, and 74.8% exhibited either. The mean radiographic score was 33.42. Conclusion. To our knowledge, this is the largest radiographic study of African American RA patients. Damage occurs early in the disease and is associated with radiographic progression at 3 years of disease duration. The CLEAR Registry will provide a valuable resource for future analyses of genetic, clinical, and environmental factors associated with radiographic severity of RA in African Americans. Show less
