Lester S, McLure C, Williamson J, Bardy P, Rischmueller M, Dawkins R L
C Y O'Connor ERADE Village, Canning Vale, Western Australia, Australia.
Ann Rheum Dis. 2008 Jun;67(6):849-54. doi: 10.1136/ard.2007.075044. Epub 2007 Sep 18.
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).
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).
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.
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.
补体激活调节因子α区域（Regulators of Complement Activation，1q32）包含关键的补体调节基因，如CR1和MCP。本研究检测了补体激活调节因子α区域单倍型与原发性干燥综合征（pSS）的疾病易感性及抗Ro/La自身抗体反应多样性之间的关联。
本研究纳入了115例pSS患者和98名对照。109例pSS患者中有93例（85%）Ro/La自身抗体呈血清阳性。采用基因组匹配技术（GMT）来定义补体激活调节因子α区域的祖先单倍型（AH）。
补体激活调节因子α区域单倍型AH1和AH3均与自身抗体阳性的pSS相关（p = 0.0003）。先前已确定自身抗体与HLA DR3和DR15均有关联。补体激活调节因子α区域AH1与HLA DR3之间存在上位性相互作用（p = 0.023），这种基因型组合在48%的自身抗体阳性pSS患者中出现，而在对照中仅为8%。这种上位性作用最简单的归因是补体激活调节因子α区域内编码的C4与其受体CR1之间的相互作用。DR3和相对的C4缺乏均存在于主要组织相容性复合体8.1祖先单倍型上。92例自身抗体阳性的pSS患者中只有4例（4%）未携带任何补体激活调节因子α区域或HLA风险单倍型，而96名对照中有36例（38%），并且pSS自身抗体亚组内的单倍型频率存在差异。
除主要组织相容性复合体外，补体激活调节因子α区域的正常人群变异也会导致对系统性自身免疫性疾病和自身抗体反应的遗传易感性。这一发现为补体激活调节在疾病发病机制中的作用提供了证据。
