Association of Variants in IL2RA With Progression of Joint Destruction in Rheumatoid Arthritis. Issue 7 (2nd July 2013)

• Record Type: Journal Article
• Authors: Knevel, R.; de Rooy, D. P. C.; Zhernakova, A.; Gröndal, G.; Krabben, A.; Steinsson, K.; Wijmenga, C.; Cavet, G.; Toes, R. E. M.; Huizinga, T. W. J.; Gregersen, P. K.; van der Helm‐van Mil, A. H. M.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 7(2013:Jul.)
• Page Start: 1684
• Page End: 1693
• Publication Date: 2013-07-02
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.37938
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art37938-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="art37938-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="art37938-sec-0003" sec-type="section"> <title>Results</title> <p>In stage 1, 3 loci (<italic>AFF3</italic>, <italic>IL2RA</italic>, and <italic>BLK</italic>) 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 <italic>IL2RA</italic> (rs2104286) was associated with less progression of joint destruction (<italic>P</italic> = 7.2 × 10<sup>−4</sup>). Furthermore, the <italic>IL2RA</italic> (rs2104286) protective genotype was associated with lower (0.85‐fold [95% confidence interval 0.77–0.93], <italic>P</italic> = 1.4 × 10<sup>−3</sup>) circulating levels of soluble interleukin‐2 receptor α (sIL‐2Rα). Additionally, lower sIL‐2Rα levels were associated with a lower rate of joint destruction (<italic>P</italic> = 3.4 × 10<sup>−3</sup>). The association of <italic>IL2RA</italic> with the rate of joint destruction was further localized to a 40‐kb region encompassing the <italic>IL2RA</italic> intron 1 and the 5′ region of <italic>IL2RA</italic> and <italic>RBM17</italic>.</p> </sec> <sec id="art37938-sec-0004" sec-type="section"> <title>Conclusion</title> <p>The present genetic and serologic data suggest that inherited altered genetic constitution at the <italic>IL2RA</italic> locus may predispose to a less destructive course of RA.</p> </sec> </abstract>