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Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis.

ABSTRACT: Epidemiologic studies have shown associations between periodontitis and rheumatoid arthritis (RA), but a causal relationship has not been established. Citrullination of gingival proteins by human peptidylarginine deiminases (PADs) or PAD from Porphyromonas gingivalis has been proposed to generate autoantigens in anti-CCP-positive RA. This study investigated whether the association between periodontitis and RA is influenced by single nucleotide polymorphisms (SNPs) in the genes encoding PAD2 and PAD4 that catalyze aberrant citrullination in RA and often are overexpressed in inflamed gingival connective tissue in subjects with periodontitis. The study included 137 RA patients and 161 controls with self-reported periodontitis. Periodontitis onset preceded RA onset by 13 years on average and was not associated with any of the SNPs investigated. In subjects with periodontitis, carriage of the minor alleles of rs2057094 and rs2235912 in PADI2 significantly increased the risk of RA (odds ratios 1.42 [p = 0.03] and 1.48 [p = 0.02], respectively), and this effect was driven by the anti-CCP-negative RA patients. The minor alleles of these SNPs only increased risk of anti-CCP-positive RA in individuals with periodontitis and a history of smoking. These data suggest that individuals with periodontitis carrying the minor alleles of SNPs rs2057094, rs2076616 and rs2235912 in PADI2 may be at increased risk of RA.

SUBMITTER: Massarenti L

PROVIDER: S-EPMC9455246 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis.

Massarenti Laura L Enevold Christian C Damgaard Dres D Hansen Peter Riis PR Frisch Morten M Ødum Niels N Jacobsen Søren S Nielsen Claus Henrik CH

International journal of molecular sciences 20220823 17

Epidemiologic studies have shown associations between periodontitis and rheumatoid arthritis (RA), but a causal relationship has not been established. Citrullination of gingival proteins by human peptidylarginine deiminases (PADs) or PAD from <i>Porphyromonas gingivalis</i> has been proposed to generate autoantigens in anti-CCP-positive RA. This study investigated whether the association between periodontitis and RA is influenced by single nucleotide polymorphisms (SNPs) in the genes encoding PA ...[more]

PMID: 36076933

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Project description:INTRODUCTION: The majority of our knowledge regarding disease-related mechanisms of uncontrolled citrullination and anti-citrullinated protein antibody development in rheumatoid arthritis (RA) was investigated in Caucasian populations. However, peptidylarginine deiminase (PADI) type 4 gene polymorphisms are associated with RA in East Asian populations and weak or no association was found in Caucasian populations. This study explores the association between the PADI4 polymorphisms and RA risk in a multiethnic population residing in South East Asia with the goal of elucidating generalizability of association in non-Caucasian populations. METHODS: A total of 320 SNPs from the PADI locus (including PADI1, PADI2, PADI3, PADI4 and PADI6 genes) were genotyped in 1,238 RA cases and 1,571 control subjects from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) case-control study. Additionally, we conducted meta-analysis of our data together with the previously published studies of RA from East Asian populations. RESULTS: The overall odds ratio (ORoverall) for the PADI4 (rs2240340) allelic model was 1.11 (95% confidence interval (CI) = 1.00 to 1.23, P = 0.04) and for the genotypic model was 1.20 (95% CI = 1.01 to 1.44, P = 0.04). Haplotype analysis for four selected PADI4 SNPs revealed a significant association of one with susceptibility (P = 0.001) and of another with a protective effect (P = 0.02). The RA susceptibility was further confirmed when combined meta-analysis was performed using these data together with data from five previously published studies from Asia comprising 5,192 RA cases and 4,317 control subjects (ORoverall = 1.23 (95% CI = 1.16 to 1.31, Pheterogeneity = 0.08) and 1.31 (95% CI = 1.20 to 1.44, Pheterogeneity = 0.32) in allele and genotype-based models, respectively). In addition, we also detected a novel association of PADI2 genetic variant rs1005753 with RA (ORoverall = 0.87 (95% CI = 0.77 to 0.99)). CONCLUSION: Our study demonstrates an association between PADI4 and RA in the multiethnic population from South East Asia and suggests additional association with a PADI2 gene. The study thus provides further support for the notion that polymorphisms in genes for enzymes responsible for citrullination contribute to RA development in multiple populations of Asian descent.

Project description:ObjectiveTo determine if the baseline presence of autoantibodies to peptidylarginine deiminase 4 (PAD4) predicts therapeutic response to biologic and conventional disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) in whom methotrexate (MTX) monotherapy was unsuccessful.MethodsBaseline serum from 282 RA patients in whom MTX monotherapy was unsuccessful was screened for the presence of anti-PAD4 antibodies by immunoprecipitation. Clinical response to either triple DMARD (MTX, sulfasalazine, and hydroxychloroquine) or MTX/etanercept combination therapy was determined at 24 and 48 weeks post-treatment initiation. Disease activity was measured using the Disease Activity Score 28-joint assessment (DAS28), and erosive disease was quantified using the Sharp/van der Heijde scoring method. Generalized estimating equations (GEEs) were used to model the clinical responses to treatment in patients with and those without baseline anti-PAD4 antibodies.ResultsAnti-PAD4 antibody positivity was associated with male sex, a history of never smoking, and anti-citrullinated protein antibodies. At baseline, patients with anti-PAD4 antibodies had longer disease duration and significantly more radiographic joint damage than anti-PAD4-negative patients, but did not differ in disease activity according to the DAS28. In unadjusted analyses and multivariable GEE models, patients with anti-PAD4 antibodies exhibited greater improvements in DAS28 (adjusted P = 0.02 and P = 0.008, respectively) and less radiographic progression (adjusted P = 0.01 and P = 0.002, respectively) compared to anti-PAD antibody-negative patients, independent of treatment received.ConclusionAlthough anti-PAD4 antibodies were associated with worse baseline radiographic joint damage, suggesting a history of active or undiagnosed disease, treatment escalation therapy was more effective in reducing disease activity and slowing the progression of joint damage in this patient subset.

Project description:BackgroundGiven that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti-PAD4 antibodies in patients with early and established RA.MethodsSera from patients with early (duration <2 years; n = 422) or established (duration ≥2 years; n = 359) RA from two randomized clinical trials of tofacitinib ± methotrexate compared with adalimumab + MTX or MTX alone were evaluated for the presence of anti-PAD4 and anti-PAD3/4 antibodies at baseline and posttreatment time points. Summary statistics were calculated for demographic, clinical, and serological characteristics, and generalized estimating equations were used to model clinical outcomes by disease duration according to anti-PAD4 status.ResultsAnti-PAD4 antibodies were present in 22% and 40% of patients with early and established RA, respectively, stable following treatment, and associated with baseline joint damage only in established RA. In early RA, baseline anti-PAD4 antibodies were associated with a greater improvement in disease activity score 28-joint count using C-reactive protein levels after treatment compared with individuals with negative anti-PAD4 (P = 0.049). Tofacitinib ± MTX was more broadly efficacious than MTX alone at improving clinical outcomes in early and established RA, irrespective of anti-PAD4 status (P < 0.05 for all), whereas adalimumab + MTX exhibited differential benefits in achieving disease activity score remission in early RA (P = 0.036) and American College of Rheumatology 20 responses in established RA (P = 0.002).ConclusionDifferences in prevalence, clinical associations, and treatment-response outcomes according to anti-PAD4 antibody status in early and established RA suggests the existence of a therapeutic window to prevent the accumulation of irreversible joint damage in early patients with RA with anti-PAD4 antibodies.

Dataset Information

Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis.

Publications

Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis.

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