Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
PLoS Genet. 2011 May;7(5):e1002079. doi: 10.1371/journal.pgen.1002079. Epub 2011 May 26.
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.
系统性红斑狼疮（SLE）是一种复杂的多基因自身免疫性疾病，与补体激活增加有关。染色体 1q32 位置上编码补体调节因子 H（CFH）和 5 个 CFH 相关蛋白（CFHR1-CFHR5）的基因变异与多种人类疾病相关，可能导致补体激活失调，从而导致 SLE 易感性。我们评估了 60 个覆盖 CFH-CFHRs 区域的单核苷酸多态性（SNP）与来自四个种族的 15864 例病例对照受试者的 SLE 相关性。在欧洲裔美国人（EA）和非裔美国人（AA）中检测到与 SLE 显著相关的等位基因关联，这可能归因于一个内含子 CFH SNP（rs6677604，位于内含子 11，P(meta) = 6.6×10(-8)，OR = 1.18）和 CFHR1 和 CFHR4 之间的一个基因间 SNP（rs16840639，P(meta) = 2.9×10(-7)，OR = 1.17），而不是先前确定的与疾病相关的 CFH 外显子 SNP，包括 I62V、Y402H、A474A 和 D936E。此外，rs6677604 与 SLE 的等位基因关联随后在亚洲人（AS）中得到确认。单倍型分析显示，由 rs6677604 和 rs16840639 标记的潜在因果变异位于从 CFH 的内含子 9 延伸到 CFHR1 下游的约 146 kb 块内。在这个块内，CFHR3 和 CFHR1 的缺失（CFHR3-1Δ），使用多重连接依赖性探针扩增测量的一个可能的因果变异，由 rs6677604 在 EA 和 AS 中标记，由 rs16840639 在 AA 中标记。根据 EA、AA 和 AS 中标记 SNP 的基因型关联推断，CFHR3-1Δ（P(meta) = 3.2×10(-7)，OR = 1.47）纯合缺失比杂合缺失（P(meta) = 3.5×10(-4)，OR = 1.14）赋予更高的 SLE 风险。这些结果表明，SLE 相关块内的 CFHR3-1Δ 缺失，而不是先前描述的 CFH 外显子 SNP，可能导致 EA、AA 和 AS 中 SLE 的发展，为补体调节剂在 SLE 发病机制中的作用提供了新的见解。
