Objective: The peptidylarginine deiminase type 4 gene (PADI4) was recently reported to be associated with rheumatoid arthritis (RA) in a Japanese population. The presence of a single-nucleotide polymorphism (SNP) located in intron 3 of PADI4 provided the strongest evidence of this association. Moreover, functional haplotypes that affect stability of transcripts were identified. However, subsequent research failed to confirm the observed association in a UK population. The present study was undertaken to further investigate the association of PADI4 with RA, using a series of population-based samples from subjects with the same ethnic background as the subjects in the original study.
Methods: DNA samples were obtained from 1,230 Japanese RA patients and 948 ethnically matched controls. Genotyping was performed using 5' allele discrimination assays. All samples were genotyped for 3 SNPs on PADI4 (padi4_94, padi4_104, and padi4_102), which comprised the reported haplotypes. Chi-square testing was performed for a case-control study and the PENHAPLO program was used for haplotype estimation.
Results: All tested SNPs were found to show significant differences in frequency between cases and controls (P = 0.010-0.0008), which confirmed the association observed in the original study. Odds ratios calculated for allele frequencies were 1.23, 1.21, and 1.36 in padi4_94, padi4_104, and padi4_102 respectively.
Conclusion: Replication of association in individual samples strongly suggests that PADI4 is a true susceptibility gene for RA.