Chun Lai Too

Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: evidence from MyEIRA study and meta-analysis

IntroductionThe 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.MethodsA 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.ResultsThe 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)).ConclusionOur 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.

Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case–control study

Objectives Lung exposures including cigarette smoking and silica exposure are associated with the risk of rheumatoid arthritis (RA). We investigated the association between textile dust exposure and the risk of RA in the Malaysian population, with a focus on women who rarely smoke. Methods Data from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis population-based case–control study involving 910 female early RA cases and 910 female age-matched controls were analysed. Self-reported information on ever/never occupationally exposed to textile dust was used to estimate the risk of developing anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA. Interaction between textile dust and the human leucocyte antigen DR β-1 (HLA-DRB1) shared epitope (SE) was evaluated by calculating the attributable proportion due to interaction (AP), with 95% CI. Results Occupational exposure to textile dust was significantly associated with an increased risk of developing RA in the Malaysian female population (OR 2.8, 95% CI 1.6 to 5.2). The association between occupational exposure to textile dust and risk of RA was uniformly observed for the ACPA-positive RA (OR 2.5, 95% CI 1.3 to 4.8) and ACPA-negative RA (OR 3.5, 95% CI 1.7 to 7.0) subsets, respectively. We observed a significant interaction between exposure to occupational textile dust and HLA-DRB1 SE alleles regarding the risk of ACPA-positive RA (OR for double exposed: 39.1, 95% CI 5.1 to 297.5; AP: 0.8, 95% CI 0.5 to 1.2). Conclusions This is the first study demonstrating that textile dust exposure is associated with an increased risk for RA. In addition, a gene–environment interaction between HLA-DRB1 SE and textile dust exposure provides a high risk for ACPA-positive RA.

DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis

BackgroundMultiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA.MethodsWe investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA). Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA.ResultsWe identified and replicated one significant gene-environment interaction between rs6933349 and smoking in DNA methylation of cg21325723. This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicative P value = 0.056; additive P value = 0.016) and Asian populations (multiplicative P value = 0.035; additive P value = 0.00027), and it is mediated through DNA methylation of cg21325723.ConclusionsWe showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors.

Differences in the Spectrum of Anti-Citrullinated Protein Antibody Fine Specificities Between Malaysian and Swedish Patients With Rheumatoid Arthritis: Implications for Disease Pathogenesis.

Objective: Antibodies to the citrullinated protein antigens (ACPA) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different specificities in different populations is unclear. We report the fine specificity of the antibody responses towards citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in the more frequently studied Caucasians. Methods: A multiplex analytic microarray system was used to analyze the occurrence of antibodies to 10 different citrullinated peptides [filaggrin (fil307-324), vimentin (Vim2-17, Vim60-75), fibrinogen (Fibα563-583, Fibα580-600, Fibβ36-52, Fibβ62-81a, Fibβ62-81b), enolase (Eno5-21) and collagen type II (citCII355-378)] in 4,089 RA serum samples (1,231 Malaysian and 2,858 Swedish) and 827 normal controls samples (249 Malaysian and 578 Swedish). The positive reaction threshold was set for each population with each peptide separately based on 98% specificity. Results: Distinct differences in five ACPA fine specificities (Vim60-75, Vim2-17, Fibβ62-81b, Eno5-21 and CitCII355-378) were found between the Malaysian and Swedish RA populations despite identical frequency of anti-CCP2-positive individuals. In comparison with the Swedish RA patients, the Malaysian RA patients had significantly higher frequencies for antibodies towards Vim60-75 (54% vs 44%, Pcorrected=1.06x10−08), CitCII355-378(17% vs 13%, Pcorrected =0.02) and significantly lower frequencies towards Vim2-17 (25% vs 32%, Pcorrected=1.91x10−04), Fibβ62-81b (15% vs 30%, Pcorrected=2.47x10−22) and Eno5-21(23% vs 50%, Pcorrected=3.64x10−57). Conclusion: RA patients in different populations are different concerning ACPA fine specificities and similar concerning total frequencies of ACPAs, which could be due to variant genetic and/or environmental factors. This article is protected by copyright. All rights reserved.Antibodies to the citrullinated protein antigens (ACPAs) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different fine specificities in different populations is unclear. This study sought to examine the fine specificity of the antibody responses toward citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in more frequently studied cohorts of Caucasian subjects.

Spectrum of Anti Citrullinated Peptide Antibodies (ACPA) fine specificities is different between Malaysian and Swedish rheumatoid arthritis patients: Implications for pathogenesis of RA

Objective: Antibodies to the citrullinated protein antigens (ACPA) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different specificities in different populations is unclear. We report the fine specificity of the antibody responses towards citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in the more frequently studied Caucasians. Methods: A multiplex analytic microarray system was used to analyze the occurrence of antibodies to 10 different citrullinated peptides [filaggrin (fil307-324), vimentin (Vim2-17, Vim60-75), fibrinogen (Fibα563-583, Fibα580-600, Fibβ36-52, Fibβ62-81a, Fibβ62-81b), enolase (Eno5-21) and collagen type II (citCII355-378)] in 4,089 RA serum samples (1,231 Malaysian and 2,858 Swedish) and 827 normal controls samples (249 Malaysian and 578 Swedish). The positive reaction threshold was set for each population with each peptide separately based on 98% specificity. Results: Distinct differences in five ACPA fine specificities (Vim60-75, Vim2-17, Fibβ62-81b, Eno5-21 and CitCII355-378) were found between the Malaysian and Swedish RA populations despite identical frequency of anti-CCP2-positive individuals. In comparison with the Swedish RA patients, the Malaysian RA patients had significantly higher frequencies for antibodies towards Vim60-75 (54% vs 44%, Pcorrected=1.06x10−08), CitCII355-378(17% vs 13%, Pcorrected =0.02) and significantly lower frequencies towards Vim2-17 (25% vs 32%, Pcorrected=1.91x10−04), Fibβ62-81b (15% vs 30%, Pcorrected=2.47x10−22) and Eno5-21(23% vs 50%, Pcorrected=3.64x10−57). Conclusion: RA patients in different populations are different concerning ACPA fine specificities and similar concerning total frequencies of ACPAs, which could be due to variant genetic and/or environmental factors. This article is protected by copyright. All rights reserved.Antibodies to the citrullinated protein antigens (ACPAs) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different fine specificities in different populations is unclear. This study sought to examine the fine specificity of the antibody responses toward citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in more frequently studied cohorts of Caucasian subjects.

SAT0739-HPR Occupational exposure to pesticides increases the risk of rheumatoid arthritis: results from the malaysian population-based case-control study

Background Several studies have suggested farming occupation with exposure to pesticides as risk factor for rheumatoid arthritis (RA). Objectives We investigated the association between pesticides exposure and risk of RA subsets in the Malaysian population. Methods Data from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study involving 1055 early RA cases and 1057 age, sex and residential area matched controls were analysed. All study subjects answered a structured questionnaire on a broad range of issues including occupational exposures to pesticides. The self-reported information on ever/never occupationally exposed to pesticides was used to estimate the risk of developing ACPA-positive and ACPA-negative RA. Association between pesticides exposure and the HLA-DRB1 shared epitope (SE) was evaluated. Results The proportion of ACPA positivity in the RA patients was 64.4% and 1.9% in the normal controls. The presence of HLA-DRB1 SE alleles in RA patients was 40.2% and 15.8% in the normal controls. Our data demonstrated that occupational exposure to pesticides was significantly associated with an increased risk of developing RA in the Malaysian population (OR 2.31, 95% CI 1.12–4.73, p=0.03). The association between occupational exposure to pesticides and risk of RA was observed with ACPA-positive RA (OR 3.10 95% CI 1.49–6.47, p=0.003), but not with ACPA-negative RA. A dramatically increased risk for ACPA-positive RA was seen in individuals who both exposed to pesticides occupationally and carried SE alleles (OR 28.06, 95% CI 3.58–220.09, p<0.0001). Conclusions This study demonstrates that occupational exposure to pesticides is associated with an increased risk of ACPA-positive RA in Malaysian population. References [1] Sverdrup B, Källberg H, Bengtsson C, Lundberg I, Padyukov L, Alfredsson L, Klareskog L and the Epidemiological Investigation of Rheumatoid Arthritis study group. Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case–control study-Arthritis Research & Therapy2005;7:R1296-R1303. [2] Meyer A, Sandler DP, Beane Freeman LE, Hofmann JN, Parks CG. Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study. Environ Health Perspect2017;14;125(7):077010. Disclosure of Interest None declared

AB0125 Anti-dengue igg antibody positivity and risk of developing rheumatoid arthritis: evidence from the malaysian epidemiological investigation of rheumatoid arthritis (MYEIRA) case-control study

Background Arthralgia is one of the common symptoms seen in RA and in mosquito-borne viral diseases (dengue and chikungunya infections). Studies have reported that both dengue and chikungunya infections are associated with long-term persistent rheumatic symptoms including joints, muscle and bone pain. Objectives We investigated the association between anti-dengue IgG antibody positivity and risk of developing anti-citrullinated peptide antibody (ACPA)-positive and ACPA-negative RA in the multi-ethnic Malaysian population. Methods A total of 1147 early RA cases (515 Malay, 254 Chinese and 378 Indians) and 1519 age, sex and residential area matched population-based controls (1,023 Malay, 208 Chinese, and 288 Indians) were included in this study. Anti-dengue IgG antibody was determined by ELISA method. The presence of anti-dengue IgG antibody and risk of developing ACPA-positive/ACPA-negative RA were estimated by calculating the odds ratio (OR) with 95% confidence interval (95% CI). Results Our data demonstrated that 79.1% (n=1,003) and 77.1% (n=1,255) RA and control subjects were positive for anti-dengue IgG antibody, respectively. Data analysis revealed that the Chinese RA patients has highest frequency of anti-dengue IgG antibody (86.6%) followed by the Indian (80.4%) and Malay (74.4%) RA patients while 83.7%, 87.5% and 73% Chinese, Indian and Malay healthy controls were positive for this antibody, respectively. The anti-dengue IgG antibody positivity was significantly associated with decreased risk of RA in the Indian population (OR 0.59, 95% CI: 0.38–0.91, p=0.02) and particularly for the ACPA-positive subset of RA (OR 0.60, 95% CI 0.37–0.96, p=0.03). Interestingly, we observed a non-significant increased risk for ACPA-positive RA in the Chinese (OR 1.49, 95% CI 0.81–2.72) and Malay populations (OR 1.06, 95% CI: 0.79–1.41) with anti-dengue IgG antibody. No association was observed between ACPA-negative RA and the antibody positivity. Conclusions Our study describes the association between anti-dengue IgG antibody occurrence and ACPA-positive RA, but not ACPA-negative RA in an ethnicity-dependent manner. Future research is needed to explore the biological mechanisms behind these findings. References [1] Mohd Zim MA, et al. Chikungunya infection in Malaysia: Comparison with dengue infection in adults and predictors of persistent arthralgia. Journal of Clinical Virology2013;56(2013):141–145. [2] Gissel Garcı et al. Long-term persistence of clinical symptoms in dengue-infected persons and its association with immunological disorders. International Journal of Infectious Diseases2011;15(2011):e38–e43. Disclosure of Interest None declared

P11: NON-STEROIDAL ANTI-INFLAMMATORY DRUG INDUCED URTICARIA/ANGIOEDEMA ASSOCIATIONS WITH THE HUMAN LEUKOCYTE ANTIGEN (HLA) GENES IN A MALAY POPULATION

NON-STEROIDAL ANTI-INFLAMMATORY DRUG INDUCED URTICARIA/ANGIOEDEMA ASSOCIATIONS WITH THE HUMAN LEUKOCYTE ANTIGEN (HLA) GENES IN A MALAY POPULATION MF Bakhtiar, CL Too, LK Tan, S Sulaiman, MM Tang, N-AA Fauzi, AR Nagum, CT Joseph, FY Kwok and GC Rayappa Allergy Unit, Allergy and Immunology Research Center, Institute for Medical Research, Kuala Lumpur, Malaysia Immunogenetic Unit, Allergy and Immunology Research Center, Institute for Medical Research, Kuala Lumpur, Malaysia Department of Dermatology, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia Anaesthetic Allergy Clinic, Department of Anaesthesia and Intensive Care, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia Pharmacology Discipline Sub Unit, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, Malaysia

SAT0722-HPR Familial risks of rheumatoid arthritis: evidence from the malaysian epidemiological investigation of rheumatoid arthritis case-control study

Background Family history of rheumatoid arthritis (RA) is a surrogate for an individuals genetic and partly environmental risk of developing RA. It is assessed daily in clinical practice and its magnitude and pattern of distribution may provide information on the RA etiology. Objectives We investigated the association between family history of RA and the risk of anti-citrullinated peptide antibody (ACPA)-positive and ACPA-negative RA in the Malaysian population. Methods Data from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study involving 1,055 early RA cases and 1,055 age, sex and residential area-matched controls were analyzed. Information from interview-reported family history of RA or rheumatic stiff back among first degree relatives was used to estimate the risk of developing ACPA-positive and ACPA negative RA. The odds ratio (OR) with 95% confidence interval (CI) was calculated. Results In this study, 64% of the RA patients were ACPA-positive and 40% of the overall RA carried HLA-DRB1 shared epitope (SE) alleles. Family history of RA was significantly associated with an increased risk of developing RA in the Malaysian population (RA versus controls, 17.0% vs. 7.7%, OR 2.4, 95% CI 1.8–3.2, p<0.0001). The association between positive family history and risk of RA was uniformly observed for the ACPA-positive RA (OR 2.5, 95% CI 1.8–3.3, p<0.0001) and ACPA-negative RA (OR 2.3, 95% CI 1.6–3.2, p<0.0001) subsets, respectively. A dramatically increased risk for ACPA-positive RA was seen in individuals who both were having positive family history of RA and carried HLA-DRB1 SE alleles (OR 14.7, 95% CI 7.7–27.8). We also observed a lesser risk magnitude in the ACPA-negative RA patients (OR 5.7, 95% CI 2.7–11.9). Conclusions Our data demonstrate that family history of RA remains an important clinical risk factor for RA. In addition, positive family history of RA was associated with an increased risk of developing both the ACPA-positive and ACPA-negative RA in the Malaysian population, suggesting that the two RA subsets are similar in genetic risk factors that overlap with these diseases. References Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid arthritis: an old concept with new developments. Nat Rev Rheumatol. 2016 Jun;12(6):335–43. Frisell T, Hellgren K, Alfredsson L, Raychaudhuri S, Klareskog L, Askling J. Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case-control study in Sweden. Ann Rheum Dis. 2016 Jan;75(1):183–9. Disclosure of Interest None declared

O18-6 Occupational exposure to textile dust increases the risk of RA: results from a malaysian population-based case-control study

Objectives Lung exposures including cigarette smoking and silica exposure are associated with the risk of rheumatoid arthritis (RA). We investigated the association between textile dust exposure and the risk of RA in the Malaysian population, with a focus on women who rarely smoke. Methods Data from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study involving 910 female early RA cases and 910 female age-matched controls were analysed. Self-reported information on ever/never occupationally exposed to textile dust was used to estimate the risk of developing anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA. Interaction between textile dust and the HLA-DRB1 shared epitope (SE) was evaluated by calculating the attributable proportion due to interaction (AP), with 95% CI. Results Occupational exposure to textile dust was significantly associated with an increased risk of developing RA in the Malaysian female population (OR 2.8, 95% CI: 1.6–5.2). The association between occupational exposure to textile dust and risk of RA was uniformly observed for the ACPA-positive RA (OR 2.5, 95% CI: 1.3–4.8) and ACPA-negative RA (OR 3.5, 95% CI: 1.7–7.0) subsets, respectively. We observed a significant interaction between exposure to occupational textile dust and HLA-DRB1 SE alleles regarding the risk of ACPA-positive RA (OR for double exposed: 39.1, 95% CI: 5.1–297.5; AP: 0.8, 95% CI: 0.5–1.2). Conclusions This is the first study demonstrating that textile dust exposure is associated with an increased risk for RA. In addition a gene-environment interaction between HLA-DRB1 SE and textile dust exposure provides a high risk for ACPA-positive RA.