Background Rheumatoid arthritis (RA) is characterized by chronic inflammation and joint destruction, resulting in deteriorated physical function. Genetic predisposition factors associated with the susceptibility to RA and the severity of joint destruction have been reported so far.1,2 However, risk loci for progression of functional disability remain poorly understood. The Health Assessment Questionnaire (HAQ) score is considered as the main and good functional outcome measure in RA. We used the Japanese version of HAQ (J-HAQ) score change in five years and investigated whether 22 established susceptibility genes for RA1 were associated with progression of functional disability in Japanese patients with RA.
Objectives The purpose of this study was to find the genetic factors associated with progression of functional disability in Japanese patients with RA.
Methods This study included 1384 Japanese patients with RA, who participated in the Institute of Rheumatology Rheumatoid Arthritis cohort study (IORRA) from 2000 to 2004, and from whom the J-HAQ score was obtained at the enrollment in IORRA and five years later. The J-HAQ score change was calculated as the value in 5 years minus the one at the enrollment. HLA-DRB1 shared epitope (SE) and 21 single nucleotide polymorphisms (SNPs) reported in the recent genome-wide association study meta-analysis1 were selected and genotyped in the DNA samples: rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4), rs2847297 (PTPN2), rs2075876 (AIRE), rs3890745 (TNFRSF14), rs7528684 (FCRL3), rs934734 (SPRED2), rs1160542 (AFF3), rs7574865 (STAT4), rs231775 (CTLA4), rs729302 (IRF5) and rs13277113 (BLK). Multivariate linear regression analyses were performed in order to examine the association of HLA-DRB1 SE and each SNP with the J-HAQ score change. Adjustments were made for non-genetic factors associated with the J-HAQ score change. They had been determined by univariate linear regression analyses.
Results Univariate linear regression analyses showed that gender, age at the enrollment, disease duration, year of the enrollment, anti-citrullinated peptide antibody status and the J-HAQ score at the enrollment were significantly associated with the J-HAQ score change. Multivariate linear regression analyses revealed that the minor allele of rs7574865 (STAT4) was associated with an increase of the J-HAQ score in five years (P=0.046). However, the association was not significant after Bonferroni correction for multiple comparisons. The other genes showed no association.
Conclusions Our results indicated that rs7574865 (STAT4) might be a risk factor for progression of functional disability, but the association could not reach the level of the significance. Further studies would be required to confirm the association.
Okada Y, et al. Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat genet. 2012 Mar 25;44(5):511-6.
Suzuki T, et al. PADI4 and HLA-DRB1 are genetic risks for radiographic progression in RA patients, independent of ACPA status: results from IORRA cohort study. PLoS One. 2013;8(4):e61045. doi: 10.1371/journal.pone.0061045. Epub 2013 Apr 8.
Acknowledgements We thank all DNA donors for making this study possible. We appreciate all the members of Institute of Rheumatology, Tokyo Women's Medical University for their effort on the IORRA cohort. We are also grateful to Ms Kaori Arai for her technical assistance.
Disclosure of Interest : A. Mizuno: None declared, S. Yoshida: None declared, K. Ikari Grant/research support: Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Speakers bureau: Abbvie Japan Co.,Ltd., Asahikasei Pharma Corporation, Astellas Pharma Inc., Eisai Co.,Ltd., Kaken Pharmaceutical Co.,Ltd., Mitsubishi Tanabe Pharma Corporation, Taishotoyama Pharmaceutical Co.,Ltd., Y. Toyama: None declared, A. Taniguchi: None declared, H. Yamanaka Grant/research support: Abbott, AbbVie, Asahikasei, Astellas, AstraZeneca, Bristol-Myers Squib, Chugai, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, MSD, Nippon Kayaku, Pfizer, Santen, Taishotoyama, Takeda, Teijin, Consultant for: Abbott, AbbVie, Astellas, AstraZeneca, Bristol-Myers Squib, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin., Speakers bureau: Abbott, AbbVie, Astellas, Bristol-Myers Squib, Chugai, Eisai, Mitsubishi Tanabe, Pfizer, Takeda, Teijin., S. Momohara: None declared