Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and is particularly prevalent in East Asia, especially Japan.Although dysregulation of the alternative complement pathway is central in atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3GN), its contribution to IgANparticularly in East Asian populations-remains insufficiently elucidated.Structural alterations and rare variants in CFH, CFI, and CFHR genes may act as susceptibility or modifying factors shaping disease heterogeneity and progression.Methods: We enrolled biopsy-proven IgAN cases (N=134) and agematched juvenile ESRD controls (N=94).Copy-number variation in the CFHR cluster was assessed.Whole-genome sequencing identified structural variants and rare mutations in CFH, CFI, and CFHR.In IgAN, glomerular complement deposition (C3, C4) was evaluated by immunofluorescence to correlate genotype with histopathological activation.Results: The CFHR1/3 deletion was observed in 13 of 228 subjects overall (5.7%), including 5 of 134 IgAN cases (3.7%), consistent with its relative rarity in East Asian populations despite a directionally protective association in IgAN.CFHR gene rearrangements were detected in both IgAN and ESRD controls, suggesting partial-though not uniform-genetic overlap across renal diseases.The CFHR1/4 deletion was detected in 4 subjects overall and associated with relatively weak glomerular C3 deposition.Pathogenic or likely pathogenic variants (ACMG) in complement regulatory genes occurred in 4% of IgAN cases-higher than reported in non-East Asian cohorts.Ethnicity-focused analyses suggested enrichment of East Asian-specific structural polymorphisms at the CFHR locus that may contribute to Japan's disproportionate IgAN burden.Notably, across IgAN cases harboring DelCFHR1/3, DelCFHR1/4, or pathogenic complement regulatory variants, renal function tended to be relatively preserved, suggesting a potentially favorable prognosis.Biopsy-based staining further revealed heterogeneous C3 deposition patterns that correlated with CFHR structural variants.Conclusion: Integrated MLPA, WGS, and renal biopsy analyses indicate that complement regulatory gene abnormalities function primarily as disease modifiers in IgAN.While there is genetic overlap with aHUS and C3GN, IgAN remains immune-complex-driven, with complement dysregulation acting as a secondary amplifier rather than a primary trigger.The identification of CFHR1/4 deletion in a subset of patients, together with enrichment of ACMG-classified pathogenic variants and the relative preservation of renal function in specific complementrelated subgroups, underscores population-specific biology and supports complement modulation as a therapeutic avenue in East Asian IgAN.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
Sato et al. (Wed,) studied this question.