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Open Access Highly Accessed Research article

Epistasis with HLA DR3 implicates the P2X7 receptor in the pathogenesis of primary Sjögren's syndrome

Susan Lester1, Leanne Stokes23, Kristen K Skarratt2, Ben J Gu24, Kathy L Sivils5, Christopher J Lessard5, James S Wiley24 and Maureen Rischmueller16*

Author Affiliations

1 Department of Rheumatology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia

2 Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Penrith, NSW, Australia

3 Health Innovations Research Institute, School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia

4 Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia

5 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

6 Discipline of Medicine, University of Adelaide, South Australia, Australia

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Arthritis Research & Therapy 2013, 15:R71  doi:10.1186/ar4248

Published: 2 June 2013

Abstract

Introduction

The aim of this study was to examine the association between functional polymorphisms in the pro-inflammatory P2X7 receptor and the Ro/La autoantibody response in primary Sjögren's syndrome (pSS).

Methods

Twelve functional P2RX7 polymorphisms were genotyped in 114 pSS patients fulfilling the Revised American-European Consensus Criteria for pSS, and 136 controls. Genotyping of the A1405G (rs2230912) polymorphism was performed on a replication cohort consisting of 281 pSS patients and 534 controls. P2X7 receptor function in lymphocytes and monocytes was assessed by measurement of ATP-induced ethidium+ uptake. Serum IL-18 levels were determined by ELISA.

Results

The minor allele of P2RX7 A1405G is a tag for a common haplotype associated with gain in receptor function, as assessed by ATP-induced ethidium+ uptake. A positive association between 1405G and anti-Ro±La seropositive pSS patients was observed in Cohort 1. Although not replicated in Cohort 2, there was a consistent, significant, negative epistatic interaction effect with HLA-DR3 in seropositive pSS patients from both cohorts, thereby implicating this gain of function variant in the pathogenesis of pSS. Serum IL-18 was elevated in seropositive pSS patients, but was not influenced by P2RX7 A1405G.

Conclusions

The P2RX7 1405G gain-of-function haplotype may be a risk factor for seropositive pSS in a subset of subjects who do not carry HLA risk alleles, but has no effect in subjects who do (epistasis). Potential mechanisms relate to autoantigen exposure and inflammatory cytokine expression. The observed elevation of IL-18 levels is consistent with P2X7 receptor activation in seropositive pSS patients. Collectively these findings implicate P2X7 receptor function in the pathogenesis of pSS.