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

¹ C Y O’Connor ERADE Village, Canning Vale, Western Australia, Australia
² Arthritis Research Laboratory, Hanson Institute, The Royal Adelaide Hospital, Adelaide, South Australia, Australia
³ Rheumatology Department, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
⁴ Transplant Services, Australian Red Cross Blood Service, Adelaide, South Australia

Correspondence to:
Professor Roger Dawkins, C Y O’Connor ERADE Village, PO Box 5100, Canning Vale South, Western Australia, 6155, Australia; cyoadmin{at}biosciencewa.com

Objective: The RCA block (Regulators of Complement Activation, 1q32) contains critical complement regulatory genes such as CR1 and MCP. This study examined RCA 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 block ancestral haplotypes (AH).

Results: RCA 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 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 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 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 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.