CFB rs1270942 — Alternative Complement Pathway and Lupus Risk
Complement Factor B (CFB) is the central amplification enzyme of the alternative complement pathway11 alternative complement pathway
One of three complement activation pathways; the alternative pathway provides continuous low-level surveillance and amplifies the classical and lectin pathways, the arm of the innate immune system responsible for continuous immune surveillance and the amplification of inflammation. The rs1270942 variant sits within an intron of the CFB gene in the major histocompatibility complex (MHC) class III region on chromosome 6 and was identified in the landmark 2008 SLEGEN genome-wide association study22 identified in the landmark 2008 SLEGEN genome-wide association study
Harley et al. Nature Genetics 2008 — 720 SLE cases, 2,337 controls, >317,000 SNPs as one of the strongest non-HLA signals for systemic lupus erythematosus (SLE), with an odds ratio of 2.35 and p=1.3×10⁻⁵¹.
The Mechanism
CFB encodes the complement factor B protein, which binds to activated C3b on foreign or damaged surfaces to form the alternative pathway C3 convertase (C3bBb). This convertase amplifies complement deposition on target surfaces, tags them with opsonins, activates inflammatory signaling, and triggers the terminal membrane attack complex. In healthy individuals, the alternative pathway operates at low constitutive levels to clear cellular debris, apoptotic cells, and immune complexes — functions essential for preventing autoimmunity.
The Evidence
The association between rs1270942 and SLE is among the strongest in the MHC class III region outside of classical HLA alleles. The original SLEGEN GWAS33 SLEGEN GWAS
Harley JB et al. 2008 — this was the first large-scale GWAS specifically in women with SLE found per-allele OR=2.35 (p=1.3×10⁻⁵¹) for SLE risk in European ancestry women.
Functional evidence for CFB's causal role in lupus nephritis is compelling. CFB-deficient MRL/lpr mice44 CFB-deficient MRL/lpr mice
Watanabe et al. J Immunol 2000 develop significantly less proteinuria, less glomerular IgG deposition, and lower renal damage scores compared to CFB-sufficient lupus mice, establishing that alternative pathway amplification through factor B drives kidney damage. Mechanistically, review of complement pathway involvement in LN55 review of complement pathway involvement in LN
Satyam et al. Transl Res 2022 shows intra-renal upregulation of CFB and complement factor D during renal flares, and elevated alternative pathway biomarkers in renal tissue predict worse renal outcomes66 predict worse renal outcomes
Activation at biopsy associated with faster progression to end-stage renal disease independent of classical pathway markers. Furthermore, antisense oligonucleotides that suppress factor B production77 suppress factor B production
Grossman et al. 2016 — significant reduction in CFB levels achieved in mice, with dose-dependent improvement in renal scores substantially improve renal pathology in lupus nephritis models, directly validating factor B as a therapeutic target and mechanistic driver.
The G allele shows marked ancestral frequency variation: ~13% in Europeans, dropping to ~5% in Africans and <0.1% in East Asians.
Practical Implications
Carriers of the G allele — especially GG homozygotes — face substantially elevated SLE risk. SLE predominantly affects women aged 15–45 (female-to-male ratio ~9:1). If you carry this variant and have personal or family history of SLE, early rheumatologic evaluation is warranted.
Hydroxychloroquine, the backbone of SLE management, does not directly inhibit complement but reduces flare frequency and may limit the triggers that activate complement cascades.
Interactions
The rs1270942 G allele operates within the broader SLE genetic architecture centered on the MHC region, where multiple complement genes (C2, C4A, C4B, CFB) form an ancestral MHC haplotype that dramatically increases lupus susceptibility. The extended MHC class III haplotype harboring the CFB G allele is in partial LD with HLA-DR3/DQ2 alleles, making disentanglement of independent effects complex.
For interactions with rs7574865 (STAT4) and rs10516487 (BANK1) — genes in the JAK-STAT and B-cell signaling pathways — the biological pathways are distinct from complement but converge on SLE pathogenesis.
The C3 variant rs2230199 (C3 R102G) is also in this complement pathway family, affecting the downstream amplification substrate. When both CFB and C3 carry risk alleles, the alternative pathway amplification loop may be further dysregulated, though direct interaction data in SLE are limited.