IL2RA is associated with persistence of rheumatoid arthritis.
BACKGROUND
Although rheumatoid arthritis (RA) is generally a chronic disease, a proportion of RA-patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission, reflecting loss of disease-persistence. To explore mechanisms underlying RA-persistence, we performed a candidate gene study. We hypothesized that variants associating with lack of radiographic progression also associate with DMARD-free sustained remission.


METHODS
645 Dutch RA-patients were studied on DMARD-free sustained remission during a maximal follow-up duration of 10-years. Variants associated with radiographic progression under an additive model in the total RA-population (Human Leukocyte Antigens (HLA)-DRB1-shared epitope (SE), Dickkopf-1 (DKK1)-rs1896368, DKK1-rs1896367, DKK1-rs1528873, C5Orf30-rs26232, Interleukin-2 receptor-α (IL2RA)-rs2104286, Matrix metalloproteinase-9 (MMP-9)-rs11908352, rs451066 and Osteoprotegerin (OPG)-rs1485305) were studied. Cox-regression analyses were performed and Bonferroni correction applied. Soluble IL2Rα (sIL2Rα)-levels were studied. For replication, 622 RA-patients included in the French Evaluation et Suivi de POlyarthrites Indifférenciées Récentes cohort (ESPOIR)-cohort were investigated. Results were combined in inverse-variance weighted meta-analysis.


RESULTS
Similar as previously reported, the SE-alleles associated with less remission (hazard ratio (HR) = 0.57, 95 % confidence interval (95 % CI) = 0.42-0.77, p = 2.72×10(-4)). Variants in DKK-1, C5orf30, MMP-9 and OPG were not associated with remission. The IL2RA-rs2104286 minor allele associated with a higher chance on remission (HR = 1.52, 95 % CI = 1.16-1.99, p = 2.44×10(-3)). The rs2104286 minor allele associated with lower sIL2Rα-levels (p = 1.44×10(-3)); lower sIL2Rα-levels associated with a higher chance on remission (HR per 100 pg/L = 0.81, 95 % CI = 0.68-0.95, p = 0.012). When including rs2104286 and sIL2Rα-levels in one analysis, the HR for rs2104286 was 2.27 (95 % CI = 1.06-4.84, p = 0.034) and for sIL2Rα 0.83 (95 % CI = 0.70-0.98, p = 0.026). Within ESPOIR, the HR of rs2104286 was 1.31 (95 % CI = 0.90-1.90). The meta-analysis revealed a p-value of 1.01×10(-3).


CONCLUSIONS
IL2RA-rs2104286 and sIL2Rα-level associated with RA-persistence. IL2RA variants are known to protect against multiple sclerosis, diabetes mellitus and RA. Besides HLA-SE, IL2RA-rs2104286 is thus far the only known genetic variant associated with both joint destruction and RA-persistence. This underlines the relevance of IL2RA for RA.
Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300, RC, Leiden, The Netherlands. h.w.van_steenbergen@lumc.nl.
H W
HW
van Steenbergen
Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300, RC, Leiden, The Netherlands. j.a.b.van_nies@lumc.nl.
J A B
JA
van Nies
Department of Rheumatology, Toulouse University Hospital, Toulouse, 31059 Toulouse cedex 9, France. adruyssen@hotmail.com.
A
A
Ruyssen-Witrand
Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300, RC, Leiden, The Netherlands. t.w.j.huizinga@lumc.nl.
T W J
TW
Huizinga
Department of Rheumatology, Toulouse University Hospital, Toulouse, 31059 Toulouse cedex 9, France. cantagrel.a@chu-toulouse.fr.
Al
A
Cantagrel
University of Paris 06 UPMC, UMR_S-938, 75005 Paris France, Department of Rheumatology, AP-HP, Saint-Antoine Hospital, 184, rue du Faubourg-Saint-Antoine, 75012, Paris, France. francis.berenbaum@sat.aphp.fr.
F
F
Berenbaum
Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300, RC, Leiden, The Netherlands. a.h.m.van_der_helm@lumc.nl.
A H M
AH
van der Helm-van Mil
D000328:Adult; D000368:Aged; D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012075:Remission, Spontaneous; D012307:Risk Factors; D028761:Withholding Treatment / Q000706:statistics & numerical data
D018501:Antirheumatic Agents; D053645:Interleukin-2 Receptor alpha Subunit