RESEARCH - Epistasis between the MHC and the RCA alpha block in primary Sjögren syndrome

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Ann Rheum Dis. 2008 Jun;67(6):849-54. Epub 2007 Sep 18.

Epistasis between the MHC and the RCA alpha block in primary Sjögren syndrome.

Lester S, McLure C, on J, Bardy P, Rischmueller M, Dawkins RL.

C Y O'Connor ERADE Village, Canning Vale, Western Australia, Australia.

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.

PMID: 17878210

http://www.ncbi.nlm.nih.gov/pubmed/17878210

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