Genetic studies of IgA nephropathy: past, present, and future

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and an important cause of kidney disease in young adults. Highly variable clinical presentation and outcome of IgAN suggest that this diagnosis may encompass multiple subsets of disease that are not distinguishable by currently available clinical tools. Marked differences in disease prevalence between individuals of European, Asian, and African ancestry suggest the existence of susceptibility genes that are present at variable frequencies in these populations. Familial forms of IgAN have also been reported throughout the world but are probably underrecognized because associated urinary abnormalities are often intermittent in affected family members. Of the many pathogenic mechanisms reported, defects in IgA1 glycosylation that lead to formation of immune complexes have been consistently demonstrated. Recent data indicates that these IgA1 glycosylation defects are inherited and constitute a heritable risk factor for IgAN. Because of the complex genetic architecture of IgAN, the efforts to map disease susceptibility genes have been difficult, and no causative mutations have yet been identified. Linkage-based approaches have been hindered by disease heterogeneity and lack of a reliable noninvasive diagnostic test for screening family members at risk of IgAN. Many candidate-gene association studies have been published, but most suffer from small sample size and methodological problems, and none of the results have been convincingly validated. New genomic approaches, including genome-wide association studies currently under way, offer promising tools for elucidating the genetic basis of IgAN.

Fig. 1

An overview of trends in the published genetic association studies of sporadic immunoglobulin A nephropathy (IgAN): a Trends in the numbers of genetic association studies by publication year and ethnicity (data from 1994 to mid-2009); b proportions of published genetic associations by nationality of study cohorts; c trends in the average size of IgAN cohorts by publication year (mean ± standard error); and d number of cases and controls per study by ethnicity. Only studies that use DNA-based genotyping are included

Fig. 2

Immunoglobulin A1 (IgA1) glycosylation pathway. Hinge region of human IgA1 contains serine (Ser) and threonine (Thr) residues, and some of them become O-glycosylated in B-cells’ Golgi apparatus. The predominating configuration of IgA1 glycans contains galactose (Gal) residues. Circulating IgA1 from IgA nephropathy (IgAN) patients is, to a large degree, galactose deficient and contains terminally sialylated N-acetylgalactosamine (GalNAc). GalNAcT2 UDP-GalNAc-transferase 2, C1GalT1 Core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase, Cosmc C1GALT1-specific chaperone 1, ST6GalNAc II N-acetylgalactosaminide alpha-2,6-sialyltransferase II, NeuAc N-acetylneuraminic acid (sialic acid)

Fig. 3

The model of immunoglobulin A nephropathy (IgAN) pathogenesis in patients with high levels of galactose-deficient IgA1. Inherited defect of IgA1 glycosylation is not sufficient to cause the disease. Additional environmental or genetic factors are probably required for renal injury, which is likely mediated by antiglycan antibody production and immune complex formation