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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.|Department of infectious disease and immunology, Kanagawa Children's Medical Center, Yokohama, Japan.
Kaori
K
Hisa
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.|Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
Masakatsu D
MD
Yanagimachi
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.
Takuya
T
Naruto
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.
Takako
T
Miyamae
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.
Masako
M
Kikuchi
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.
Rhoki
R
Hara
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.|Department of infectious disease and immunology, Kanagawa Children's Medical Center, Yokohama, Japan.
Tomoyuki
T
Imagawa
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.
Shumpei
S
Yokota
Department of pediatrics, Yokohama City Graduate School of Medicine, Yokohama, Japan.|Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Masaaki
M
Mori
D001171:Arthritis, Juvenile / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D000939:Epitopes / Q000235:genetics; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
D000939:Epitopes; D059811:HLA-DRB1 Chains; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases