CFHR3*B Haplotype, Complement Activation, and Risk of IgA Nephropathy

作者：Yongji Zhang, Honghong Zou, Xinran Ni, Fenghong Tie, Boyang Xu, Yuqi Kang, Weiyi Xiang, Yaxin Li, Changhao Jia, Ying Tan, Lijun Liu, Jicheng Lv, Junyu Xiao, Gaosi Xu, Lei Yu, Ming‐Hui Zhao, Zhu Li, Hong Zhang · 发表于：Journal of the American Society of Nephrology · 年份：2025 · DOI：10.1681/asn.0000000983 · 被引用次数：1 · 研究领域：Renal Diseases and Glomerulopathies、Monoclonal and Polyclonal Antibodies Research、Complement system in diseases

KEY POINTS: CFHR3*B haplotype was a susceptibility variant for IgA nephropathy diagnosis by enhancing complement activation. The rs446868A variant in CFHR3*B elevated CFHR3 transcription and was associated with higher circulating FHR3 levels in patients with IgA nephropathy. FHR3241Ser variant enhanced C3b binding and complement activation, accelerating IgA deposition-induced complement activation in IgA nephropathy. 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 patients with IgA nephropathy and 630 healthy controls. Luciferase activity assays were performed to assess the transcriptional activity of CFHR3*B haplotype. The coding variant rs138675433 (FHR3 241Pro versus FHR3 241Ser ) 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 patients with IgA nephropathy. The CFHR3*BB genotype correlated with lower circulating C3 levels and greater glomerular C3 deposition. Luciferase ...