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Cited by 0Renal Diseases and GlomerulopathiesComplement system in diseasesVasculitis and related conditions

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From Susceptibility Loci to Therapeutic Targets: The Genetic Architecture of IgA Nephropathy

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Dopierała, Mikołaj, Nitz, Nadja, Bursy, Jakub, Garbowska, Antonina, Dopierała, Wiktoria, Schwermer, Krzysztof, Pawlaczyk, Krzysztof·2026·International Journal of Molecular Sciences
DOI 10.3390/ijms27198821PMC PMC13664997
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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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Metadata

Authors
Dopierała, M., Nitz, N., Bursy, J., Garbowska, A., Dopierała, W., Schwermer, K., & Pawlaczyk, K.
Affiliations
Poznan University of Medical Sciences (PL)
Corresponding author
  • Dopierała, Mikołaj
  • Schwermer, Krzysztof
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2026-10-02
Volume
27
Issue
19
Pages
8821
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms27198821
PMC
PMC13664997
OpenAlex
W7215984342
Cited by
0
References
76
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
Topics
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Health Sciences › Medicine › Rheumatology › Vasculitis and related conditions
Keywords
IgA nephropathy, genetic susceptibility loci, MHC region, complement regulation, antigen presentation, epigenetic methylation, heritability, ethnic differences in prevalence, therapeutic target, chronic kidney disease
MeSH terms
Animals, Glomerulonephritis, IGA, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci

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