Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/81562
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Type: Journal article
Title: Epistasis with HLA DR3 implicates the P2X7 receptor in the pathogenesis of primary Sjögren's syndrome
Other Titles: Epistasis with HLA DR3 implicates the P2X7 receptor in the pathogenesis of primary Sjogren's syndrome
Author: Lester, S.
Stokes, L.
Skarratt, K.
Gu, B.
Sivils, K.
Lessard, C.
Wiley, J.
Rischmueller, M.
Citation: Arthritis Research & Therapy, 2013; 15(4):1-10
Publisher: BioMed Central Ltd.
Issue Date: 2013
ISSN: 1478-6354
1478-6362
Statement of
Responsibility: 
Susan Lester, Leanne Stokes, Kristen K Skarratt, Ben J Gu, Kathy L Sivils, Christopher J Lessard, James S Wiley and Maureen Rischmueller
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.
Keywords: Humans; Sjogren's Syndrome; Ribonucleoproteins; Interleukin-18; Autoantibodies; Antibodies, Antinuclear; HLA-DR3 Antigen; Autoantigens; Enzyme-Linked Immunosorbent Assay; Epistasis, Genetic; Genotype; Polymorphism, Single Nucleotide; Female; Male; Receptors, Purinergic P2X7
Rights: © 2013 Lester et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
RMID: 0020132524
DOI: 10.1186/ar4248
Appears in Collections:Medicine publications

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