PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population

Abstract

BackgroundPolymorphisms of the peptidylarginine deiminase type 4 (PADI4) gene confer susceptibility to rheumatoid arthritis (RA) in East Asian people. However, studies in European populations have produced conflicting results. This study explored the association of the PADI4 genotype with RA in a large UK Caucasian population.MethodsThe PADI4_94 (rs2240340) single nucleotide polymorphism (SNP) was directly genotyped in a cohort of unrelated UK Caucasian patients with RA (n=3732) and population controls (n=3039). Imputed data from the Wellcome Trust Case Control Consortium (WTCCC) was used to investigate the association of PADI4_94 with RA in an independent group of RA cases (n=1859) and controls (n=10 599). A further 56 SNPs spanning the PADI4 gene were investigated for association with RA using data from the WTCCC study.ResultsThe PADI4_94 genotype was not associated with RA in either the present cohort or the WTCCC cohort. Combined analysis of all the cases of RA (n=5591) and controls (n=13 638) gave an overall OR of 1.01 (95% CI 0.96 to 1.05, p=0.72). No association with anti-CCP antibodies and no interaction with either shared epitope or PTPN22 was detected. No evidence for association with RA was identified for any of the PADI4 SNPs investigated. Meta-analysis of previously published studies and our data confirmed no significant association between the PADI4_94 genotype and RA in people of European descent (OR 1.06, 95% CI 0.99 to 1.13, p=0.12).ConclusionIn the largest study performed to date, the PADI4 genotype was not a significant risk factor for RA in people of European ancestry, in contrast to Asian populations.

Pharmacogenetics of rheumatoid arthritis: Potential targets from susceptibility genes and present therapies

“…This result is supported by a recent meta-analysis which confirmed a lack of association between PADI4_94 genotype and RA in people of European descent (OR = 1.1, 95% CI: 1.0-1.1; P = 0.12). 71 This meta-analysis contrasted two earlier meta-analyses which suggested that the PADI4_94 polymorphism confers susceptibility to RA in those of European descent (OR = 1.1; 95% CI: 1.0-1.2; P = 0.0096), albeit to a lesser degree than in Asian subjects. 72,73 The discrepancy between studies of Caucasian descent can be explained, at least in part, by previous studies being underpowered to detect an OR of this level, thus producing false-positive results.…”

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

“…[15][16][17] Examples are a PTPN22-R620W polymorphism which is strongly associated with RA and other autoimmune diseases in Caucasian populations, but is absent in Orientals, and an association with PADI4 SNP found in Japanese populations which is not detected in most Caucasian populations, despite the presence of these gene polymorphisms. [15][16][17][18][19][20] Our own studies of the Cree/Ojibway population in Central Canada have suggested a 2-3% prevalence rate of diagnosed RA, and a 60-70% frequency of SE alleles in the background population. 7,8,21 We sought to determine additional non-HLA genes that may contribute to the high frequency of RA detected in this population.…”

Immunochip Identifies Novel, and Replicates Known, Genetic Risk Loci for Rheumatoid Arthritis in Black South Africans

“…The R620W variant of the PTPN22 gene is strongly and consistently associated with RA in Europeans (10,11) but not in Asians or black South Africans (12)(13)(14). In contrast, specific haplotypes of the PADI4 gene confer risk for RA in Asians (15)(16)(17)(18) and less or no risk in Europeans (9,(18)(19)(20)(21). However a haplotype in the STAT4 gene is associated with RA in both Europeans and Asians (22,23).…”