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 1.13, p=0.12). Conclusion In the largest study performed to date, the genotype was not a significant risk factor for RA in people of European ancestry, in contrast to Asian populations. Introduction Rheumatoid arthritis (RA) is a complex autoimmune disease in which genetic and environmental factors contribute to the pathogenesis. 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 1.01 (95% CI 0.96 to 1 1.05, p=0.72). No association with anti-CCP antibodies and no interaction with either shared epitope or was detected. No evidence for association with RA was identified for any of the 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 1.13, p=0.12). Conclusion In the largest study performed to date, the genotype was not a significant risk factor for RA in people of European ancestry, in contrast to Asian populations. Introduction Rheumatoid arthritis (RA) is a complex autoimmune disease in which Mephenytoin genetic and environmental factors contribute to the pathogenesis. Around 60% of the risk of RA is genetic, a third of which is accounted for by gene encodes the type 4 peptidylarginine deiminase enzyme which catalyses the post-translational modification of arginine to citrulline, generating citrullinated proteins. Antibodies to these peptides are highly specific for RA and often predate the development of disease, suggesting a critical role in the pathogenesis of RA. therefore represents an attractive RA candidate gene and was first reported to be associated with RA in a Japanese population in 2003.5 This association has been consistently replicated in East Asian populations6 11 12; however findings in cohorts of European ancestry have been inconsistent. Studies in Spanish, Swedish and UK populations reported no evidence for association of with RA.7 9 10 Conversely, was found to be associated with RA in North American and German populations and two published meta-analyses suggested that polymorphisms do confer susceptibility to RA in those of European descent, albeit to a lesser degree than in Asian subjects.10 13C15 Consequently, it was hypothesised that these European studies were underpowered to detect a true but modest genetic effect. The present study was designed to address this issue by exploring the association between the genotype and RA in a large UK population. Materials and methods Study design The PADI4_94 Mephenytoin single nucleotide polymorphism (SNP) (rs2240340) was selected for investigation as it has the strongest evidence for association with RA in Asians and Caucasians.5 12 14 15 It was genotyped in an independent UK Caucasian population of 3732 patients with RA and 3039 controls Epha1 (see online supplement). In addition, imputed genotypes for the PADI4_94 SNP were compared between 1859 patients with RA and 2935 controls from the Wellcome Trust Case Control Consortium (WTCCC) study.16 Where linkage disequilibrium (LD) is high and confidence scores for imputed genotypes exceed 95%, the accuracy of imputation in predicting actual genotype counts exceeds 98.4%.17 An expanded reference group of 10 599 subjects was created by using imputed Mephenytoin genotype data for PADI4_94 from the four non-autoimmune disease case subjects (hypertension, coronary artery disease, type 2 diabetes Mephenytoin and bipolar disorder) genotyped as part of the WTCCC study Mephenytoin and combining this with the genotype data from the healthy controls. The data from the present cohort and the WTCCC study were combined to provide a robust estimate of effect size for this SNP in the UK population, giving a combined sample size of 5591 cases of RA and 13 638 controls. In addition, imputed genotype data for the original WTCCC cohort (1860 cases of RA, 2938 controls) were used to investigate other SNPs spanning the gene for evidence of association with RA. Analysis of data Allele and genotype frequencies were compared between patients with RA and controls using the 2 2 test for trend implemented in PLINK. The threshold for significance was defined at p 0.05. Meta-analysis Meta-analysis of the results together with previous studies investigating association of PADI4_94 with RA in populations of European ancestry was performed (see online supplement). A random effects model was used and between-study heterogeneity assessed using the Cochran Q-statistic (p 0.1 considered significant). Interaction analysis Data were available for shared epitope (SE) and the R620W SNP (rs2476601) in the current cohort. The risk of RA associated.