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Open Access Research article

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

Chun Lai Too12*, Shahnaz Murad2, Jasbir Singh Dhaliwal2, Per Larsson3, Xia Jiang4, Bo Ding4, Lars Alfredsson4, Lars Klareskog1 and Leonid Padyukov1

Author affiliations

1 Rheumatology Unit, Department of Medicine, Karolinska University Hospital, CMM L8:04, S-171 76 Stockholm, Sweden

2 Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia

3 Department of Rheumatology, R 92, Karolinska University Hospital Huddinge, S-171 76 Stockholm, Sweden

4 Institute of Environmental Medicine, Karolinska Institutet, Nobel väg 13, Box 210, S-171 77 Stockholm, Sweden

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Citation and License

Arthritis Research & Therapy 2012, 14:R250  doi:10.1186/ar4093

Published: 19 November 2012

Abstract

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.