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PLoS One. 2017 Feb 9;12(2):e0171961. doi: 10.1371/journal.pone.0171961. eCollection 2017.

PADI4 and the HLA-DRB1 shared epitope in juvenile idiopathic arthritis.

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Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.
Department of infectious disease and immunology, Kanagawa Children's Medical Center, Yokohama, Japan.
Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.



Both genetic and environmental factors are associated with susceptibility to juvenile idiopathic arthritis (JIA). Many studies have reported that both a 'shared epitope' (SE) encoded by several HLA-DRB1 alleles and the peptidyl arginine deiminase type 4 (PADI4) gene polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). However, it is uncertain whether JIA and RA share the latter genetic risk factor. Therefore, here we investigated relationships between HLA-SE and PADI4 polymorphisms with clinical subtypes of JIA.


JIA patients (39 oligoarthritis, 48 RF-positive polyarthritis, 19 RF-negative polyarthritis and 82 systemic) and 188 healthy controls were genotyped for HLA-DRB1 by PCR-sequence-specific oligonucleotide probe methodology. Three PADI4 gene single nucleotide polymorphisms (SNPs), rs2240340, rs2240337 and rs1748033, were genotyped using TaqMan SNP Genotyping Assays.


Frequencies of the HLA-SE were higher in RF-positive polyarticular JIA than in healthy controls. RF-positive polyarticular JIA was associated with HLA-SE (OR = 5.3, 95% CI = 2.5-11.9, pc < 0.001). No associations were found between clinical subtypes of JIA and PADI4 allele frequency. Nonetheless, rs2240337 in the PADI4 gene was significantly associated with anti-cyclic citrullinated peptide antibody (ACPA)-positivity in JIA. The A allele at rs2240337 was a significant risk factor for ACPA positivity in JIA (OR = 5.6, 95% CI = 1.71-23.7 pc = 0.03).


PADI4 gene polymorphism is associated with ACPA-positivity in JIA. The association of HLA-SE with RF-positive polyarticular JIA as well as RA is confirmed in Japanese. Thus, HLA-SE and PADI4 status both influence JIA clinical manifestations.

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Conflict of interest statement

Apart from the submitted work, Masaaki Mori has received grants from Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, AbbVie LLC, UCB Japan Co. Ltd., Astellas Pharma Inc., and Eisai Co., Ltd. Dr. Mori has also received lecture fees from MSD K.K and AbbVie LLC, and consulting fees from Daiichi Sankyo Co., Ltd. and Taisho Pharmaceutical Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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