1509 Seddighzadeh, et al: STAT variants in RA Personal non-commercial use only. The Journal of Rheumatology Copyright © 2012. All rights reserved. Variants Within STAT Genes Reveal Association with Anticitrullinated Protein Antibody-negative Rheumatoid Arthritis in 2 European Populations MARIA SEDDIGHZADEH, ANTONIO GONZALEZ, BO DING, AIDA FERREIRO-IGLESIAS, JUAN J. GOMEZ- REINO, Rheumatoid Arthritis Network and Coordinated Project, LARS KLARESKOG, LARS ALFREDSSON, KYRI DUNUSSI-JOANNOPOULOS, JAMES D. CLARK, and LEONID PADYUKOV ABSTRACT. Objective. STAT3 and 4 are, among other factors, critical for the interleukin 12 (IL-12)-mediated Th1 response, for transfer of IL-23 signals, and for survival and expansion of Th17 cells. We investigated the association of STAT3 and STAT4 polymorphisms with serologically distinct subgroups of rheuma- toid arthritis (RA). Methods. A total of 41 single-nucleotide polymorphisms (SNP) within STAT3 and STAT1-STAT4 loci were investigated in a Swedish cohort of 2043 RA cases and 1115 controls. Nine of the associated SNP were tested in a Spanish cohort of 1223 RA cases and 1090 controls. Results. Fourteen SNP in the STAT3 and STAT1-STAT4 loci were associated with anticitrullinated pro- tein antibody (ACPA)-negative RA in the Swedish cohort. Three of the SNP in STAT4 and 2 SNP in STAT3 remained associated with ACPA-negative RA after considering the Spanish results. In addition, rs7574865 and rs10181656, in STAT4, were associated with ACPA-positive RA in the Swedish study. One of these SNP, rs7574865, showed a similar pattern of the association in serologically distinct sub- groups of RA in a metaanalysis of all 7 published studies. Conclusion. Our findings suggest that variants in STAT genes may contribute differentially to suscep- tibility to RA in seropositive and in seronegative patients. (First Release July 1 2012; J Rheumatol 2012;39:1509–16; doi:10.3899/jrheum.111284) Key Indexing Terms: STAT ANTICITRULLINATED PROTEIN ANTIBODY RHEUMATOID ARTHRITIS SINGLE-NUCLEOTIDE POLYMORPHISM From the Rheumatology Unit, Department of Medicine, and the Institute for Environmental Medicine, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden; the Laboratorio Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria – Hospital Clinico Universitario de Santiago, Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain; and Inflammation and Immunology, Pfizer Research, Cambridge, Massachusetts, USA. Supported by the Combine project from Swedish Vinnova. The Rheumatoid Arthritis Network and Coordinated Project was established with support from the Instituto de Salud Carlos III (ISCIII, Spain) grants G03/152 and PI041513. Genotyping of the Network samples was funded by grant PI080744 from the ISCIII to Dr. Gonzalez. M. Seddighzadeh, PhD, Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital; A. Gonzalez, MD, PhD, Laboratorio Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria – Hospital Clinico Universitario de Santiago; B. Ding, PhD, Institute for Environmental Medicine, Karolinska Institutet; A. Ferreiro-Iglesias, MSc, Laboratorio Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria – Hospital Clinico Universitario de Santiago; J.J. Gomez-Reino, MD, PhD, Laboratorio Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria – Hospital Clinico Universitario de Santiago, Department of Medicine, University of Santiago de Compostela; L. Klareskog, MD, PhD, Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital; L. Alfredsson, PhD, Institute for Environmental Medicine, Karolinska Institutet; K. Dunussi-Joannopoulos, MD, PhD; J.D. Clark, PhD, Inflammation and Immunology, Pfizer Research; L. Padyukov, MD, PhD, Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital. Address correspondence to Dr. M. Seddighzadeh, Department of Medicine, Rheumatology Unit, CMM L8:04, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden. E-mail: maria.seddighzadeh@ki.se Accepted for publication May 7, 2012. Rheumatoid arthritis (RA) is an autoimmune disease in which genetic and environmental factors are involved 1 . It can be divided into 2 clinically relevant subgroups by the presence of autoantibodies to citrullinated proteins/peptides (ACPA). ACPA-positive and ACPA-negative RA are different in sever- ity, with ACPA-negative RA generally being a milder disease. Most of the genetic variants associated with RA are specific to ACPA-positive RA [e.g., HLA-DRB1 shared epitope (SE) alle- les, PTPN22, C5/TRAF-1] and only a few have no such dis- crimination or are restricted to ACPA-negative RA 2,3,4 . Especially striking is the case of HLA-DRB1 SE alleles, which notably increase the risk for autoantibody-positive RA in most European white populations 5 , but have no effect or a very modest one for autoantibody-negative RA. This finding is consistent with the idea that development of autoantibod- ies, in RA and in other autoimmune diseases, results from a loss of tolerance, which is tightly connected to T cell function and MHC class II specificity. However, the details of these www.jrheum.org Downloaded on October 24, 2021 from