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|Title:||Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.|
|Authors:||Gale, Daniel P.|
Levine, Adam P.
Nelson, Christopher P.
Samani, Nilesh J.
|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.|
|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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|Gale 2017.docx||Post-review (final submitted author manuscript)||802.23 kB||Unknown||View/Open|
|Gale 2017.pdf||Post-review (final submitted author manuscript)||1.49 MB||Adobe PDF||View/Open|
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