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CFHR3*B Haplotype, Complement Activation, and Risk of IgA Nephropathy
Yongji Zhang1,2,3,4,5, Honghong Zou1,2,3,4,5,6, Xinran Ni1,2,3,4,5
1Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
Journal of the American Society of Nephrology : JASN
|January 21, 2026
Summary
The CFHR3*B haplotype increases IgA nephropathy risk by enhancing complement activation. This variant elevates Factor H-related protein 3 (FHR3) levels and function, promoting disease progression.
Area of Science:
- Immunology
- Genetics
- Nephrology
Background:
- Complement activation plays a role in IgA nephropathy (IgAN).
- Previous studies linked CFHR3/CFHR1 deletion to IgAN protection.
- The CFHR3*B haplotype is associated with increased CFHR3 transcription and atypical hemolytic uremic syndrome risk.
Purpose of the Study:
- To investigate the association between the CFHR3*B haplotype and IgA nephropathy susceptibility.
- To determine the functional impact of the CFHR3*B haplotype on complement regulation and CFHR3 transcription.
Main Methods:
- Genetic analysis of 1108 IgAN patients and 630 controls.
- Luciferase activity assays to assess CFHR3 transcriptional activity.
- Recombinant protein analysis of the rs138675433 coding variant (FHR3241Ser).
Main Results:
- The CFHR3*B haplotype and CFHR3*BB genotype were more frequent in IgAN patients.
- CFHR3*BB genotype correlated with lower C3 levels and increased glomerular C3 deposition.
- The CFHR3*B haplotype enhanced CFHR3 transcription, with rs446868 as the functional variant. The FHR3241Ser variant showed increased C3b binding and Factor H deregulation, accelerating complement activation and hemolysis. FHR3241Ser augmented IgA deposition-induced complement activation in mesangial cells.
Conclusions:
- The CFHR3*B haplotype is a susceptibility variant for IgA nephropathy.
- This haplotype accelerates complement activation via enhanced transcription (rs446868A) and augmented FHR3 function (rs138675433T).
- These findings elucidate a novel mechanism linking complement dysregulation to IgAN pathogenesis.
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