PADI4 and HLA-DRB1 Are Genetic Risks for Radiographic Progression in RA Patients, Independent of ACPA Status: Results from the IORRA Cohort Study

Abstract

IntroductionRheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment. Recently, a large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified. However, it is not clear whether these loci have significant impact on joint destruction or not. This is the first study focused on the 13 loci to investigate independent genetic risk factors for radiographic progression in the first five years from onset of RA.MethodsSharp/van der Heijde score of hands at 5-year disease duration, which represents joint damage, were measured retrospectively and used as an outcome variable in 865 Japanese RA patients. Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese GWAS meta-analysis, including HLA-DRB1 (shared epitope, SE), rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2). These putative genetic risk factors were assessed by a stepwise multiple regression analysis adjusted for possible non-genetic risk factors: autoantibody positivity (anti-citrullinated peptide antibody [ACPA] and rheumatoid factor), history of smoking, gender and age at disease onset.ResultsThe number of SE alleles (P = 0.002) and risk alleles of peptidyl arginine deiminase type IV gene (PADI4, P = 0.04) had significant impact on progressive joint destruction, as well as following non-genetic factors: ACPA positive (P = 0.0006), female sex (P = 0.006) and younger age of onset (P = 0.02).ConclusionsIn the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients. The results of this study give important knowledge of the risks on progressive joint damage in RA patients.

HLA-DRB1 shared epitope allele polymorphisms and rheumatoid arthritis: a systemic review and meta-analysis

“…In a study of RA patients in Western India, Prasannavar et al [19] reported that while HLA-DRB1*04 was strongly associated with RA, *03 and *14 appeared to confer a protective effect. Other study has also suggested that some HLA-DRB1 haplotypes may confer a protective effect [62].…”

“…Patients with RA had significantly higher frequencies of HLA-DRB1*04, *0401, *0404, *0405 and *0410 than controls (OR = 2.28-4.19). A study of Japanese patients with RA showed that the number of SE alleles was significantly associated with progressive joint destruction as well as anticitrullinated peptide antibody positivity and younger age of disease onset [62].…”

Associations Between PADI4 Gene Polymorphisms and Rheumatoid Arthritis: An Updated Meta-analysis

“…PADI4 has been implicated in the pathogenesis, activity and severity of RA (45,48). Recently, investigations on the relationship between PADI4 gene polymorphisms and RA have been extensively performed in different populations.…”

Association of IL-18 polymorphisms with rheumatoid arthritis: a meta-analysis

“…Human leukocyte antigen (HLA) alleles, such as HLA-DRB1*01, HLA-DRB1*13, and HLA-DRB1*15, have been reported to be implicated in the pathogenesis of RA (Kurko et al, 2013). Non-HLA genes, such as peptidylarginine deiminase type 4, protein tyrosine phosphatase nonreceptor 22, interleukin-23 receptor, interleukin-1β (IL-1β), macrophage migration inhibitory factor, tumor necrosis factor alpha (TNF-α), and CD40, have also been shown to be involved in the pathogenesis of RA (Suzuki et al, 2013).…”