IgAN is the most common form of glomerulonephritis and a significant cause of renal failure worldwide. IgAN patients exhibit characteristic circulating immune complexes that are enriched for abnormally glycosylated IgA1 (Gd-IgA1). Gd-IgA1 levels constitute a heritable risk factor for IgAN, suggesting a novel model of pathogenesis (picture). We are now validating measurement of Gd-IgA1 levels as a non-invasive screening tool for IgAN. In addition, using linkage analysis and genome-wide association study (GWAS), we have identified multiple regions of the genome containing genes that predispose to familial and sporadic IgAN. In a recent GWAS, we identified three independent loci in the major histocompatibility complex, a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that increase susceptibility to IgAN. These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. We are working on characterizing the associated genes and dysregulated pathways and studying their effects in additional populations.
Model for pathogenesis of IgA Nephropathy. An inherited defect results in increased production of galactose deficient IgA1 in IgA producing cells. Subsequently, a second “hit” (environmental, genetic, or acquired ) leads to generation of anti-glycan antibodies that initiates immune complex formation, leading to glomerular deposition and injury (from Kiryluk et. al. Pediatric Nephrology 2010).