OBJECTIVE: Heritability studies have suggested an important role of genetic predisposition in the progression of joint destruction in rheumatoid arthritis (RA); the heritability is estimated at 45-58%. Several single-nucleotide polymorphisms (SNPs) have been identified as being associated with RA susceptibility. Our objective was to study the association of several of these loci with progression of joint destruction. METHODS: We studied 1,750 RA patients in 4 independent data sets with 4,732 radiographs scored using the modified Sharp/van der Heijde method. Thirteen susceptibility SNPs that were not previously associated with joint destruction were tested in 596 Dutch RA patients. Subsequently, significant SNPs were studied in data sets of RA patients from North America and Iceland. Data were summarized in inverse-weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped. RESULTS: In stage 1, 3 loci (AFF3, IL2RA, and BLK) were significantly associated with the rate of joint destruction and were further analyzed in the additional data sets. In the combined meta-analyses, the minor (C) allele of IL2RA (rs2104286) was associated with less progression of joint destruction (P = 7.2 × 10(-4) ). Furthermore, the IL2RA (rs2104286) protective genotype was associated with lower (0.85-fold [95% confidence interval 0.77-0.93], P = 1.4 × 10(-3) ) circulating levels of soluble interleukin-2 receptor α (sIL-2Rα). Additionally, lower sIL-2Rα levels were associated with a lower rate of joint destruction (P = 3.4 × 10(-3) ). The association of IL2RA with the rate of joint destruction was further localized to a 40-kb region encompassing the IL2RA intron 1 and the 5' region of IL2RA and RBM17. CONCLUSION: The present genetic and serologic data suggest that inherited altered genetic constitution at the IL2RA locus may predispose to a less destructive course of RA.
OBJECTIVE: Heritability studies have suggested an important role of genetic predisposition in the progression of joint destruction in rheumatoid arthritis (RA); the heritability is estimated at 45-58%. Several single-nucleotide polymorphisms (SNPs) have been identified as being associated with RA susceptibility. Our objective was to study the association of several of these loci with progression of joint destruction. METHODS: We studied 1,750 RApatients in 4 independent data sets with 4,732 radiographs scored using the modified Sharp/van der Heijde method. Thirteen susceptibility SNPs that were not previously associated with joint destruction were tested in 596 Dutch RApatients. Subsequently, significant SNPs were studied in data sets of RApatients from North America and Iceland. Data were summarized in inverse-weighted variance meta-analyses. Further, the association with circulating protein levels was studied and the associated region was fine-mapped. RESULTS: In stage 1, 3 loci (AFF3, IL2RA, and BLK) were significantly associated with the rate of joint destruction and were further analyzed in the additional data sets. In the combined meta-analyses, the minor (C) allele of IL2RA (rs2104286) was associated with less progression of joint destruction (P = 7.2 × 10(-4) ). Furthermore, the IL2RA (rs2104286) protective genotype was associated with lower (0.85-fold [95% confidence interval 0.77-0.93], P = 1.4 × 10(-3) ) circulating levels of soluble interleukin-2 receptor α (sIL-2Rα). Additionally, lower sIL-2Rα levels were associated with a lower rate of joint destruction (P = 3.4 × 10(-3) ). The association of IL2RA with the rate of joint destruction was further localized to a 40-kb region encompassing the IL2RA intron 1 and the 5' region of IL2RA and RBM17. CONCLUSION: The present genetic and serologic data suggest that inherited altered genetic constitution at the IL2RA locus may predispose to a less destructive course of RA.
Authors: Ian C Scott; Frühling Rijsdijk; Jemma Walker; Jelmar Quist; Sarah L Spain; Rachael Tan; Sophia Steer; Yukinori Okada; Soumya Raychaudhuri; Andrew P Cope; Cathryn M Lewis Journal: J Rheumatol Date: 2015-05-15 Impact factor: 4.666
Authors: H W van Steenbergen; S Raychaudhuri; L Rodríguez-Rodríguez; S Rantapää-Dahlqvist; E Berglin; R E M Toes; T W J Huizinga; B Fernández-Gutiérrez; P K Gregersen; A H M van der Helm-van Mil Journal: Arthritis Rheumatol Date: 2015-04 Impact factor: 10.995
Authors: Maria I Danila; Vincent Albert Laufer; Richard J Reynolds; Qi Yan; Nianjun Liu; Peter K Gregersen; Annette Lee; Marlena Kern; Carl D Langefeld; Donna K Arnett; S Louis Bridges Journal: Mol Med Date: 2017-06-29 Impact factor: 6.354
Authors: Lukas Mangnus; Hanna W van Steenbergen; Elisabet Lindqvist; Elisabeth Brouwer; Monique Reijnierse; Tom W J Huizinga; Peter K Gregersen; Ewa Berglin; Solbritt Rantapää-Dahlqvist; Désirée van der Heijde; Annette H M van der Helm-van Mil Journal: Arthritis Res Ther Date: 2015-08-24 Impact factor: 5.156
Authors: H W van Steenbergen; J A B van Nies; A Ruyssen-Witrand; T W J Huizinga; Al Cantagrel; F Berenbaum; A H M van der Helm-van Mil Journal: Arthritis Res Ther Date: 2015-09-08 Impact factor: 5.156