Gene SymbolCFH
Full NameComplement Factor H
Chromosomal Location1q31.3
Ensembl IDENSG00000005381
Associated DiseasesAge-Related Macular Degeneration, Atypical Hemolytic Uremic Syndrome, Alzheimer's Disease
The CFH gene encodes complement factor H, a crucial soluble regulator of the alternative complement pathway. Factor H is the primary negative regulator of alternative pathway activation, preventing spontaneous C3b deposition on host cells and controlling complement amplification. The gene is located on chromosome 1q31.3 and encodes a protein of 1,121 amino acids [1].
Factor H is a member of the regulators of complement activation (RCA) protein family. It contains 20 short consensus repeat (SCR) domains, also known as complement control protein (CCP) modules. Each SCR domain is approximately 60 amino acids long and contains four conserved cysteine residues forming two disulfide bonds. The protein is synthesized primarily in the liver and circulates in plasma at concentrations of approximately 0.4-0.6 mg/mL [2].
Factor H functions as the main soluble regulator of the alternative complement pathway:
- Decay-Accelerating Activity: Factor H binds to C3b and accelerates the decay of the C3 convertase (C3bBb), displacing the Bb subunit [3]
- Cofactor Activity: Factor H serves as a cofactor for factor I-mediated cleavage and inactivation of C3b
- Host Recognition: Factor H recognizes host-specific markers including heparan sulfate, sialic acid, and glycosaminoglycans, distinguishing self from foreign surfaces
- Alternative Pathway Control: By limiting alternative pathway amplification, factor H prevents excessive complement activation and tissue damage
- N-terminal domains (1-4): Mediate decay-accelerating and cofactor activity
- Central domains (5-7): Bind C3b and C3d
- C-terminal domains (18-20): Mediate host surface recognition and attachment
CFH has been implicated in Alzheimer's disease pathogenesis through multiple mechanisms:
- Elevated CFH levels have been observed in AD brain tissue and cerebrospinal fluid [4]
- CFH colocalizes with amyloid plaques in AD brain
- The Y402H polymorphism (rs1061170) has been associated with altered AD risk in some populations
- CFH may modulate neuroinflammation through complement regulation
- Interaction between CFH and amyloid-beta may influence plaque formation [5]
CFH is the most significant genetic risk factor for AMD:
- The Y402H polymorphism (rs1061170) confers 2-4 fold increased risk for AMD [6]
- This variant affects binding to choroidal neovascularization membranes
- CFH polymorphisms interact with other complement genes (C2, CFB, C3) in AMD risk [7]
- CFH deficiency in mouse models leads to retinal complement deposition
- CFH variants may influence MS susceptibility and disease progression
- CSF CFH levels are elevated in MS patients
- CFH may regulate demyelination through complement modulation
- Anti-CFH antibodies have been detected in some MS patients
- Atypical Hemolytic Uremic Syndrome (aHUS): CFH mutations cause uncontrolled complement activation
- C3 Glomerulopathy: CFH autoantibodies and mutations cause C3 deposition
- Membranoproliferative Glomerulonephritis: CFH-related pathologies
- Liver: Primary site of synthesis (hepatocytes)
- Brain: Expressed by astrocytes, microglia, and neurons
- Eye: Retinal pigment epithelial cells express CFH
- Kidney: Glomerular mesangial and epithelial cells
- Various tissues: Widely expressed, with highest levels in liver
CFH expression is regulated by:
- Inflammatory cytokines (IL-6, TNF-α) upregulate hepatic CFH
- Acute phase response increases CFH levels
- Corticosteroids suppress CFH expression
- Aging alters CFH regulation and function
- Y402H (rs1061170): Most studied AMD-associated variant, affects ligand binding
- V62I (rs800292): Common variant with potential protective effects
- E936D: Another AMD-associated variant
- Y402H allele frequency varies significantly across populations
- Highest frequency in European populations (~35%)
- Lower frequency in Asian and African populations
- CFH replacement therapy for CFH deficiency (experimental)
- CFH inhibitors being developed for AMD treatment
- Gene therapy approaches under investigation
- CSF CFH levels as potential neurodegenerative disease biomarker
- CFH Y402H as genetic risk marker for AMD
- NCBI Gene: CFH (3070)
- UniProt: Complement factor H (P08603)
- Wu et al., Structure-function relationships of factor H (2019)
- Zhu et al., Complement factor H in Alzheimer's disease (2010)
- Matschke et al., Complement factor H and Alzheimer disease (2016)
- Klein et al., Complement factor H polymorphism in age-related macular degeneration (2005)
- Haines et al., Complement factor H variant increases risk for AMD (2005)
- Sivakumar et al., CFH variants in AMD (2011)
- Ferreira et al., Factor H in neuroinflammation (2010)