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Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.

Gale, DP; Molyneux, K; Wimbury, D; Higgins, P; Levine, AP; Caplin, B; Ferlin, A; ... Barratt, J; + view all (2017) Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1. J Am Soc Nephrol , 28 (7) pp. 2158-2166. 10.1681/ASN.2016091043. Green open access

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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.

Type: Article
Title: Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1681/ASN.2016091043
Publisher version: http://dx.doi.org/10.1681/ASN.2016091043
Language: English
Additional information: Copyright © 2017 by the American Society of Nephrology. Final publication is available from JASN http://dx.doi.org/10.1681/ASN.2016091043.
Keywords: Genome Wide Association Study, IgA, IgA nephropathy, SNP, glomerulonephritis, human genetics
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1542949
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