Galactosylation of IgA1 Is Associated with Common Variation in .

IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in -glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in white and Chinese populations. Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. White patients with IgAN exhibited significantly higher Gd-IgA1 levels than did Chinese patients. Among individuals without IgAN, Gd-IgA1 levels did not correlate with kidney function. Gd-IgA1 level heritability (h), estimated by comparing midparental and offspring Gd-IgA1 levels, was 0.39. Genome-wide association analysis by linear regression identified alleles at a single locus spanning the gene that strongly associated with Gd-IgA1 level (=0.26; =2.35×10). This association was replicated in a genome-wide association study of separate cohorts comprising 308 patients with membranous GN from the UK (<1.00×10) and 622 controls with normal kidney function from the UK (<1.00×10), and in a candidate gene study of 704 Chinese patients with IgAN (<1.00×10). The same extended haplotype associated with elevated Gd-IgA1 levels in all cohorts studied. encodes a galactosyltransferase enzyme that is important in -galactosylation of glycoproteins. These findings demonstrate that common variation at influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1 -glycosylation may vary between white and Chinese patients with IgAN.