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