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

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