Shared Epitope Alleles Remain A Risk Factor for Anti-Citrullinated Proteins Antibody (ACPA) – Positive Rheumatoid Arthritis in Three Asian Ethnic Groups

Too Chun-Lai,Lars Alfredsson,Abqariyah Yahya,Jasbir Singh Dhaliwal,Lars Klareskog,Shahnaz Murad,Leonid Padyukov,Per Tobias Larsson,Nor Asiah Muhamad,Emeli Lundström,

doi:10.1371/journal.pone.0021069

Abstract

BackgroundTo investigate the associations between HLA-DRB1 shared epitope (SE) alleles and rheumatoid arthritis in subsets of rheumatoid arthritis defined by autoantibodies in three Asian populations from Malaysia.Methods1,079 rheumatoid arthritis patients and 1,470 healthy controls were included in the study. Levels of antibodies to citrullinated proteins (ACPA) and rheumatoid factors were assessed and the PCR-SSO method was used for HLA-DRB1 genotyping.ResultsThe proportion of ACPA positivity among Malay, Chinese and Indian rheumatoid arthritis patients were 62.9%, 65.2% and 68.6%, respectively. An increased frequency of SE alleles was observed in ACPA-positive rheumatoid arthritis among the three Asian ethnic groups. HLA-DRB1*10 was highly associated with rheumatoid arthritis susceptibility in these Asian populations. HLA-DRB1*0405 was significantly associated with susceptibility to rheumatoid arthritis in Malays and Chinese, but not in Indians. HLA-DRB1*01 did not show any independent effect as a risk factor for rheumatoid arthritis in this study and HLA-DRB1*1202 was protective in Malays and Chinese. There was no association between SE alleles and ACPA- negative rheumatoid arthritis in any of the three Asian ethnic groups.ConclusionThe HLA-DRB1 SE alleles increase the risk of ACPA-positive rheumatoid arthritis in all three Asian populations from Malaysia.

Highlights

Our knowledge on disease pathology and risk assignment in rheumatoid arthritis is mainly based on studies of Caucasian populations [1]
Detailed studies on interactions between genetic and environmental risk factors for rheumatoid arthritis (RA) so far mainly been reported from Europe and the USA, and have demonstrated that the major genetic risk factor for RA, i.e. presence of certain Human leukocyte antigens (HLA)-DRB1 (MIM ID*142857) alleles exert their effects only in the subset of RA that is defined by the presence of Anti-Citrullinated Proteins Antibody (ACPA) [3,4]
The shared epitope (SE)-positivity was noted to be significantly associated with RA in all the three ethnic groups (Malay odds ratio (OR) = 3.98, 95%CI 2.94–5.40, p = 2.74610220; Chinese OR = 4.52, 95%CI 2.53–8.06, p = 7.6961028 and Indian OR = 2.16, 95% confidence interval (95% CI) 1.49–3.12, p = 4.0961025) (Table 1)

Summary

Introduction

Our knowledge on disease pathology and risk assignment in rheumatoid arthritis is mainly based on studies of Caucasian populations [1]. Investigations on different ethnic groups are, relatively rare and have not followed the rapidly increasing understanding of the genetic heterogeneity of rheumatoid arthritis (RA). Detailed studies on interactions between genetic and environmental risk factors for RA so far mainly been reported from Europe and the USA, and have demonstrated that the major genetic risk factor for RA, i.e. presence of certain HLA-DRB1 (MIM ID*142857) alleles exert their effects only in the subset of RA that is defined by the presence of ACPA [3,4]. To investigate the associations between HLA-DRB1 shared epitope (SE) alleles and rheumatoid arthritis in subsets of rheumatoid arthritis defined by autoantibodies in three Asian populations from Malaysia

Methods

Results

Conclusion