Functional Haplotypes of Padi4 Gene are Associated with Rheumatoid Arthritis in Ethnic-Dependent Manner

Abstract

PURPOSE. Four exonic single-nucleotide polymorphisms (SNPs) and their haplotypes of PAID4 (peptidylarginine deiminase, type IV) gene were reported to be associated with RA susceptibility in a Japanese population but the association was not replicated in a UK Caucasian population. In this study, we aimed to validate this association in a Korean population. METHODS. Four exonic SNPs of the PADI4 gene, called padi4_89, padi4_90, padi4_92, and padi4_104, were genotyped for 545 RA patients (classified into 4 severity stages) and 392 controls (matched in sex and age) using the MassARRAY SNP genotyping system. Allelic, genotypic and haplotypic associations of the SNPs with RA susceptibility and radiographic severity were analyzed using chi-square statistics. RESULTS. All the 4 SNPs, 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 two of their haplotypes (P = 1.7×10-5 and 7.8×10-4) are significantly associated with RA susceptibility but not with radiographic severity in a Korean population. This association is sustained when the samples are stratified by carriage of HLA-DRB1 SE alleles. Moreover, individuals carrying both SNP risk allele(s) and SE allele(s) have higher susceptibility than those carrying only either of them, who have higher susceptibility than those carrying neither of them. CONCLUSIONS. Thus, the association of the PADI4 gene SNPs and haplotypes with RA susceptibility is validated with Koreans, and carriage of SNP risk allele(s) increases the susceptibility independently of the carriage of HLA-DRB1 SE alleles.