title: Galactosylation of IgA1 Is Associated with Common Variation inC1GALT1.
abstract: IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes inO-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 theC1GALT1gene 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.C1GALT1encodes a galactosyltransferase enzyme that is important inO-galactosylation of glycoproteins. These findings demonstrate that common variation atC1GALT1influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1O-glycosylation may vary between white and Chinese patients with IgAN.
authors.affiliation: Centre for Nephrology and d.gale@ucl.ac.uk.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gale
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Molyneux
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Wimbury
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Patricia
authors.initials: P
authors.lastname: Higgins
authors.affiliation: Division of Medicine, University College London, London, United Kingdom.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Levine
authors.affiliation: Centre for Nephrology and.
authors.forename: Ben
authors.initials: B
authors.lastname: Caplin
authors.affiliation: Centre for Nephrology and.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferlin
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; and.
authors.forename: Peiran
authors.initials: P
authors.lastname: Yin
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Centre for Nephrology and.
authors.forename: Horia
authors.initials: H
authors.lastname: Stanescu
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Centre for Nephrology and.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; and.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barratt
mesh_terms: D005260:Female; D005690:Galactose / Q000378:metabolism*; D005700:Galactosyltransferases / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D008297:Male
chemical_list: D007070:Immunoglobulin A; C505293:C1GALT1 protein, human; D005700:Galactosyltransferases; D005690:Galactose
keywords: Genome Wide Association Study; IgA; IgA nephropathy; SNP; glomerulonephritis; human genetics