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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
PubMed

Insights

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.
Abstract

Keywords:
IGA nephropathycomplement

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