J Am Soc Nephrol. 2025 Dec 15. doi: 10.1681/ASN.0000000983. Online ahead of print.
ABSTRACT
BACKGROUND: Complement activation is involved in IgA nephropathy. We previously identified that genetic deletion of CFHR3 and CFHR1 confers protection against IgA nephropathy by modulating complement activation. In addition, the CFHR3*B haplotype (rs385390C/rs446868A/rs138675433T/rs149352569T) has been linked to elevated CFHR3 transcription and higher risk of atypical hemolytic uremic syndrome.
METHODS: We evaluated the association between the CFHR3*B haplotype and IgA nephropathy susceptibility by using genetic analysis of 1108 IgA nephropathy patients and 630 healthy controls. Luciferase activity assays were performed to assess transcriptional activity of CFHR3*B haplotype. The coding variant rs138675433 (FHR3241Pro vs. FHR3241Ser) was assessed using recombinant proteins to determine its effect on complement regulation.
RESULTS: The CFHR3*B haplotype and CFHR3*BB genotype were significantly enriched in IgA nephropathy patients. The CFHR3*BB genotype correlated with reduced circulating C3 levels and increased glomerular C3 deposition. Luciferase activity assays demonstrated enhanced transcription activity conferred by the CFHR3*B haplotype, with rs446868 identified as the functional regulatory variant. Patients carrying the CFHR3*BB genotype exhibited elevated circulating FHR3 level. FHR3241Ser exhibited significantly enhanced C3b binding capacity and FH deregulation activity, promoting accelerated C3 convertase formation and increased hemolysis. Furthermore, FHR3241Ser augmented IgA deposition-induced complement activation on cultured mesangial cells in a dose-dependent manner.
CONCLUSIONS: Our results identified CFHR3*B haplotype as a susceptibility variant for IgA nephropathy diagnosis by accelerating complement activation, through rs446868A enhancing transcription activity and rs138675433T augmenting FHR3 function.
PMID:41563799 | DOI:10.1681/ASN.0000000983