Abstract
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.
Highlights
Systemic lupus erythematosus (SLE) (OMIM 152700) is a debilitating autoimmune disease with strong genetic and environmental components, characterized by the production of autoantibodies resulting in tissue injury of multiple organs [1]
We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of CFHR3 and CFHR1 genes but not previously identified disease-associated exonic variants of complement regulator factor H (CFH)
This study provides the first evidence for consistent association between CFH/CFHRs and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE
Summary
SLE (OMIM 152700) is a debilitating autoimmune disease with strong genetic and environmental components, characterized by the production of autoantibodies resulting in tissue injury of multiple organs [1]. Common variants of C3 and C4 have been associated with risk of SLE [4,5,6] These findings indicate the important role of complement in the development of SLE. Complement factor H (CFH), a key regulator of the alternative complement pathway, modulates the innate immune responses to microorganisms, controls C3 activation and prevents inflammatory injury to self tissue [7,8]. CFH inhibits complement activation by preventing the formation and accelerating the decay of C3 convertase and acting as a cofactor for factor I-mediated degradation of C3b, both in plasma and on cell surfaces. SCR1-4 in the N-terminus mediate the cofactor/decay accelerating activity and SCR19-20 in the C-terminus are essential for cell surface regulation of CFH. CFHRs lack SCRs homologous to SCR1-4 of CFH, and do not exhibit cofactor/decay accelerating activity.
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