AbstractObjectiveAnticitrullinating autoantibodies are specific markers for rheumatoid arthritis (RA). A functional haplotype of 4 exonic single‐nucleotide polymorphisms (SNPs) in a citrullinating enzyme, peptidylarginine deiminase 4 (PADI4), was shown to be associated with susceptibility to RA in a Japanese population and was shown to increase the stability ofPADI4messenger RNA. However, the association was not confirmed in 4 subsequent studies involving Caucasian RA patients living in the UK, a French Caucasian population, and a Spanish population. The aim of the current study was to investigate the association of SNPs in thePADI4gene with RA in a Korean population.MethodsFour exonic SNPs of thePADI4gene (padi4_89, padi4_90, padi4_92, and padi4_104) were genotyped in 545 unrelated patients with RA and 392 controls, using the MassArray SNP genotyping system. Allelic, genotypic, and haplotypic associations of the SNPs with RA susceptibility were examined using the chi‐square test and multivariate logistic regression analyses.ResultsIncreased RA susceptibility was significantly associated with the minor alleles of padi4_89 (P= 2.3 × 10−5), padi4_90 (P= 2.3 × 10−5), padi4_92 (P= 2.1 × 10−5), and padi4_104 (P= 1.1 × 10−3) and the haplotype carrying the 4 minor alleles (P= 1.0 × 10−4). Genotypes carrying the minor alleles and HLA–DRB1 shared epitope (SE) alleles (P= 9.4 × 10−21) were also associated with increased RA susceptibility. The genotypic associations were sustained among individuals who did not carry any SE alleles, except in the case of padi4_104. Individuals carrying the risk SNPs and/or SE alleles were more susceptible to RA than were individuals carrying neither risk SNPs nor SE alleles.ConclusionThePADI4SNPs and haplotypes are associated with RA susceptibility in Koreans. Thus, the association ofPADI4with RA may depend on genetic heterogeneity between Asians and Europeans.