IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and the leading cause of end-stage kidney failure in East Asia.
In IgA nephropathy (IgAN) is diagnosed most commonly in the second or thIrd decade of life. The kidney biopsy shows predominant deposition of IgA-containing immune complexes in the glomerular mesangium. These immune complex deposition leads to glomerulonephritis, glomerular sclerosis, and progressive loss of kidney function.
The etiology of IgAN is poorly understood and the genetic architecture is complex. Based on the current pathogenesis model, the disease occurs in the setting of inherited defect that results in exaggerated production of IgA1 with aberrant O-glycosylation of its hinge region. This aberrantly glycosylated IgA1 is targeted by an IgA or IgG autoimmune response, resulting in production of immune complexes that injure the kidney. We have shown that the O-glycosylation defect is heritable and genome-wide association studies (GWAS) have implicated common variants in C1GALT1 and C1GALT1C1 in levels of aberrantly glycosylated IgA1. In addition, we have performed several GWAS’s in individuals of European and Asian ancestry and identified 15 significant associations for IgAN in HLA, ITGAM-ITGAX, VAV3, CARD9, CFHR1, DEFA, TNFSF13 loci. Most loci are either directly associated with risk of inflammatory bowel disease or maintenance of the intestinal epithelial barrier and response to mucosal pathogens.
GWAS identifies new loci for IgAN
(Kiryluk et al, Nat Genetics 2014)
The geo-spatial distribution of genetic risk parallels the known epidemiology of disease and the burden of risk alleles is associated with earlier onset of disease. The distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, pointing to host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
Geospatial distribution of genetic risk parallels the epidemiology of IgAN
(Kiryluk et al, Nat Genetics 2014; Kiryluk et al. PLoS Genetics 2012)
We are now engaged in larger GWAS and genome and exome sequencing projects in IgAN. These studies, conducted in >30,000 individuals, are identifying new loci for IgAN. In parallel, we are studying immunological mechanisms leading to activation of IgA producing cells and resultant increased production of galactose deficient IgA1. These studies are highlighting new pathways such as loci encoding cytokines and their cognate receptors, and dysregulated immune cell types that may be promising targets for therapy.
