Galactosylation of IgA1 Is Associated with Common Variation in <i>C1GALT1</i>.

Abstract

IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in <i>O</i>-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 (h²), 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 <i>C1GALT1</i> gene that strongly associated with Gd-IgA1 level (<i>β</i>=0.26; <i>P</i>=2.35×10^-9). This association was replicated in a genome-wide association study of separate cohorts comprising 308 patients with membranous GN from the UK (<i>P</i><1.00×10^-6) and 622 controls with normal kidney function from the UK (<i>P</i><1.00×10^-10), and in a candidate gene study of 704 Chinese patients with IgAN (<i>P</i><1.00×10^-5). The same extended haplotype associated with elevated Gd-IgA1 levels in all cohorts studied. <i>C1GALT1</i> encodes a galactosyltransferase enzyme that is important in <i>O</i>-galactosylation of glycoproteins. These findings demonstrate that common variation at <i>C1GALT1</i> influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1 <i>O</i>-glycosylation may vary between white and Chinese patients with IgAN.