PADI4 and HLA-DRB1 Are Genetic Risks for Radiographic Progression in RA Patients, Independent of ACPA Status: Results from the IORRA Cohort Study

Taku Suzuki,Shigeki Momohara,Yoshiaki Toyama,Eisuke Inoue,Hisashi Yamanaka,Koichiro Yano,Katsunori Ikari,Atsuo Taniguchi,Sunil K Ahuja

doi:10.1371/journal.pone.0061045

Taku Suzuki, Shigeki Momohara + Show 7 more

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https://doi.org/10.1371/journal.pone.0061045

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Journal: PloS one	Publication Date: Apr 8, 2013
Citations: 48	License type: CC BY 4.0

Affiliation: Tokyo Women's Medical University, Keio University

Abstract

IntroductionRheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment. Recently, a large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified. However, it is not clear whether these loci have significant impact on joint destruction or not. This is the first study focused on the 13 loci to investigate independent genetic risk factors for radiographic progression in the first five years from onset of RA.MethodsSharp/van der Heijde score of hands at 5-year disease duration, which represents joint damage, were measured retrospectively and used as an outcome variable in 865 Japanese RA patients. Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese GWAS meta-analysis, including HLA-DRB1 (shared epitope, SE), rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2). These putative genetic risk factors were assessed by a stepwise multiple regression analysis adjusted for possible non-genetic risk factors: autoantibody positivity (anti-citrullinated peptide antibody [ACPA] and rheumatoid factor), history of smoking, gender and age at disease onset.ResultsThe number of SE alleles (P = 0.002) and risk alleles of peptidyl arginine deiminase type IV gene (PADI4, P = 0.04) had significant impact on progressive joint destruction, as well as following non-genetic factors: ACPA positive (P = 0.0006), female sex (P = 0.006) and younger age of onset (P = 0.02).ConclusionsIn the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients. The results of this study give important knowledge of the risks on progressive joint damage in RA patients.

Highlights

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment
Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese genomewide association studies (GWAS) meta-analysis, including HLA-DRB1, rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2)
In the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment. A large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified. It is not clear whether these loci have significant impact on joint destruction or not. Since RA is a complex disease influenced by both genetic and environmental factors, susceptibility genes to the disease have been widely investigated and identified, especially in the era of genomewide association studies (GWAS) and GWAS meta-analyses.[16,17,18] Recently, a large-scaled GWAS meta-analysis was conducted using samples from more than 9,000 Japanese RA patients and 38,000 controls. Nine novel RA susceptibility loci were identified; B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2. [16] The study showed that some previously reported RA susceptibility genes satisfied the genome-wide significance threshold (P,5.0 61028); HLA-DRB1, PADI4, TNFAIP3 and CCR6. [16] Of these 13 RA-susceptible loci, HLA-DRB1 shared epitope (SE) have been reported to have impact on disease severity.[19,20,21] the question remains whether if the other RA-susceptible genes have significant impact on joint destruction

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