Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility

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, Pmeta = 6.6×10−8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 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 (Pmeta = 3.2×10−7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 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（Systemic lupus erythematosus, SLE）是一种复杂的多基因自身免疫性疾病，与补体激活增强密切相关。位于1号染色体q32区域的补体调节因子H（complement regulator factor H, CFH）及其5种CFH相关蛋白（CFHR1-CFHR5）编码基因的变异，已被证实与多种人类疾病相关，可能通过导致补体激活失调而增加SLE的易感风险。本研究针对覆盖CFH-CFHRs区域的60个单核苷酸多态性（single nucleotide polymorphism, SNP），在来自4个族裔的15864名病例-对照受试者中开展了SLE关联分析。研究在欧洲裔美国人（European Americans, EA）和非裔美国人（African Americans, AA）中检测到了显著的SLE等位基因关联，该关联可归因于CFH基因第11内含子中的内含子变异rs6677604（Pmeta=6.6×10⁻⁸，比值比（odds ratio, OR）=1.18），以及CFHR1与CFHR4之间的基因间变异rs16840639（Pmeta=2.9×10⁻⁷，OR=1.17），而非此前已报道的CFH基因外显子关联变异（包括I62V、Y402H、A474A及D936E）。此外，rs6677604与SLE的等位基因关联后续在亚洲人群（Asians, AS）中得到了验证。单倍型分析显示，由rs6677604和rs16840639标记的潜在致病变异，定位于一个约146kb的区块内，该区块从CFH基因内含子9延伸至CFHR1下游。在该区块中，CFHR3与CFHR1的缺失（CFHR3-1Δ）——这是一种通过多重连接依赖探针扩增（multiplex ligation-dependent probe amplification）技术检测的潜在致病变异——分别在欧洲裔美国人和亚洲人群中由rs6677604标记，在非裔美国人中由rs16840639标记。基于欧洲裔美国人、非裔美国人和亚洲人群中标签SNP的基因型关联结果，CFHR3-1Δ纯合缺失（Pmeta=3.2×10⁻⁷，OR=1.47）相较于杂合缺失（Pmeta=3.5×10⁻⁴，OR=1.14）会带来更高的SLE患病风险。本研究结果表明，SLE关联区块内的CFHR3-1Δ缺失，而非此前报道的CFH基因外显子变异，可能参与了欧洲裔美国人、非裔美国人和亚洲人群的SLE发病过程，为补体调节因子在SLE发病机制中的作用提供了新的认识。