From Susceptibility Loci to Therapeutic Targets: The Genetic Architecture of IgA Nephropathy
- 1Department of Nephrology, Transplantology and Internal Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland
Abstract
IgA nephropathy is the most common primary glomerulonephritis worldwide and a leading cause of chronic kidney disease and kidney failure in young and middle-aged adults, characterized by considerable ethnic differences in incidence and prognosis. This review summarises the evidence that these differences are, at least in part, genetically determined and maps the identified susceptibility loci onto the pathogenic sequence of the disease. Worldwide prevalence gradient increases with eastward and northward distance from Africa, while showing the significance of ancestry rather than environment in diaspora populations. Familial clustering provides support for an inherited component, while methylation differences between monozygotic twins discordant for IgAN point to an additional epigenetic layer. Genome-wide association studies (GWAS) in Han Chinese, European, and Korean cohorts have identified susceptibility loci implicated in antigen presentation, mucosal and intestinal IgA immunity, complement regulation, and innate immune signaling. Mapping these loci onto the four-hit hypothesis shows that inherited variation acts at distinct, potentially separable nodes. The MHC region contributes approximately half of the SNP-based heritability, while the CFH/CFHR locus provides the strongest signal outside the MHC. The complement arm has become the principal therapeutic target because it is currently the most pharmacologically tractable. We conclude by reviewing mechanism-directed therapies together with the safety questions and patient-selection issues that accompany them.
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BibTeX
@article{dopierala2026from,
title = {{From Susceptibility Loci to Therapeutic Targets: The Genetic Architecture of IgA Nephropathy}},
author = {Mikołaj Dopierała and Nadja Nitz and Jakub Bursy and Antonina Garbowska and Wiktoria Dopierała and Krzysztof Schwermer and Krzysztof Pawlaczyk},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27198821},
url = {https://www.mdpi.com/1422-0067/27/19/8821},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From Susceptibility Loci to Therapeutic Targets: The Genetic Architecture of IgA Nephropathy
AU - Mikołaj Dopierała
AU - Nadja Nitz
AU - Jakub Bursy
AU - Antonina Garbowska
AU - Wiktoria Dopierała
AU - Krzysztof Schwermer
AU - Krzysztof Pawlaczyk
PY - 2026
DA - 2026/10/02
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198821
UR - https://www.mdpi.com/1422-0067/27/19/8821
AB - IgA nephropathy is the most common primary glomerulonephritis worldwide and a leading cause of chronic kidney disease and kidney failure in young and middle-aged adults, characterized by considerable ethnic differences in incidence and prognosis. This review summarises the evidence that these differences are, at least in part, genetically determined and maps the identified susceptibility loci onto the pathogenic sequence of the disease. Worldwide prevalence gradient increases with eastward and northward distance from Africa, while showing the significance of ancestry rather than environment in diaspora populations. Familial clustering provides support for an inherited component, while methylation differences between monozygotic twins discordant for IgAN point to an additional epigenetic layer. Genome-wide association studies (GWAS) in Han Chinese, European, and Korean cohorts have identified susceptibility loci implicated in antigen presentation, mucosal and intestinal IgA immunity, complement regulation, and innate immune signaling. Mapping these loci onto the four-hit hypothesis shows that inherited variation acts at distinct, potentially separable nodes. The MHC region contributes approximately half of the SNP-based heritability, while the CFH/CFHR locus provides the strongest signal outside the MHC. The complement arm has become the principal therapeutic target because it is currently the most pharmacologically tractable. We conclude by reviewing mechanism-directed therapies together with the safety questions and patient-selection issues that accompany them.
SN - 1422-0067
ER -