Advances in genetics of immunoglobulin a nephropathy

Familial aggregation of IgA nephropathy (IgAN) and variation in prevalence among different ethnicities indicate inherited factors contribute to disease pathogenesis. Studies have also shown that IgAN patients also have an inherited defect in O-glycosylation of IgA1. Recent genome-wide association studies (GWASs) have begun to elucidate genetic factors underlying the development of IgAN. These studies have demonstrated a strong association with MHC loci, highlighting an autoimmune component to disease. In addition, GWASs have identified loci involving the complement system (CFHR1/3 and ITGAM-ITGAX loci), the regulation of mucosal IgA production (TNFSF13 and LIF/OSM loci), innate immunity (DEFA, CARD9, ITGAM-ITGAX, VAV3, and ST6GAL1 loci), inflammatory response (KLF10 and UBR5), and epithelial cell polarization (ACCS). Many of the loci have been implicated in other immune-mediated and inflammatory diseases, highlighting shared pathogenesis with IgAN. The IgAN risk allele frequencies also strongly parallel the known geoepidemiology of disease and are also correlated with local pathogen diversity. These findings have helped develop a pathogenesis model and molecular candidates for disease. Analysis of larger cohorts and application of next-generation sequencing technologies are expected to identify additional genes that can further resolve pathogenesis.