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Title: Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.
Authors: Gale, Daniel P.
Molyneux, Karen
Wimbury, David
Higgins, Patricia
Levine, Adam P.
Caplin, Ben
Ferlin, Anna
Yin, Peiran
Nelson, Christopher P.
Stanescu, Horia
Samani, Nilesh J.
Kleta, Robert
Yu, Xueqing
Barratt, Jonathan
First Published: 16-Feb-2017
Publisher: American Society of Nephrology
Citation: Journal of the American Society of Nephrology, 2017
Abstract: 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 (h(2)), 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.
DOI Link: 10.1681/ASN.2016091043
ISSN: 1046-6673
eISSN: 1533-3450
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2017, the American Society of Nephrology. Deposited with reference to the publisher’s open access archiving policy.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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