Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/50843
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Type: Journal article
Title: Epistasis between the MHC and the RCAα block in primary Sjögren syndrome
Other Titles: Epistasis between the MHC and the RCA alpha block in primary Sjogren syndrome
Author: Lester, S.
McLure, C.
Williamson, J.
Bardy, P.
Rischmueller, M.
Dawkins, R.
Citation: Annals of the Rheumatic Diseases, 2008; 67(6):849-854
Publisher: British Med Journal Publ Group
Issue Date: 2008
ISSN: 0003-4967
1468-2060
Statement of
Responsibility: 
S. Lester, C. McLure, J. Williamson, P. Bardy, M. Rischmueller, R. L. Dawkins
Abstract: OBJECTIVE: The RCA alpha block (Regulators of Complement Activation, 1q32) contains critical complement regulatory genes such as CR1 and MCP. This study examined RCA alpha block haplotype associations with both disease susceptibility and diversification of the anti-Ro/La autoantibody response in primary Sjögren syndrome (pSS). METHODS: 115 patients with pSS and 98 controls were included in the study. 93 of 109 (85%) of the patients with pSS were seropositive for Ro/La autoantibodies. The Genomic Matching Technique (GMT) was used to define RCA alpha block ancestral haplotypes (AH). RESULTS: RCA alpha block haplotypes, AH1 and AH3, were both associated with autoantibody-positive pSS (p = 0.0003). Autoantibody associations with both HLA DR3 and DR15 have been previously defined. There was an epistatic interaction (p = 0.023) between RCA alpha AH1 and HLA DR3, and this genotypic combination was present in 48% of autoantibody-positive patients with pSS compared with 8% of controls. This epistasis is most simply attributable to an interaction between C4 and its receptor, CR1, encoded within the RCA alpha block. Both DR3 and a relative C4 deficiency are carried on the major histocompatibility complex 8.1 ancestral haplotype. Only four of 92 (4%) autoantibody-positive patients with pSS did not carry any risk RCA alpha or HLA haplotype, compared with 36 of 96 (38%) controls, and there were differences in haplotype frequencies within autoantibody subsets of pSS. CONCLUSIONS: Normal population variation in the RCA alpha block, in addition to the major histocompatibility complex, contributes genetic susceptibility to systemic autoimmune disease and the autoantibody response. This finding provides evidence for the role of regulation of complement activation in disease pathogenesis.
Keywords: Humans; Sjogren's Syndrome; Genetic Predisposition to Disease; Ribonucleoproteins; Receptors, Complement 3b; Autoantibodies; Autoantigens; Logistic Models; Case-Control Studies; Genes, MHC Class II; Epistasis, Genetic; Gene Frequency; Haplotypes; Complement C4
Rights: Copyright © 2008 BMJ Publishing Group Ltd & European League Against Rheumatism.
RMID: 0020080667
DOI: 10.1136/ard.2007.075044
Appears in Collections:Medicine publications

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