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Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.

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 (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 (?=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.

SUBMITTER: Gale DP

PROVIDER: S-EPMC5491291 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Galactosylation of IgA1 Is Associated with Common Variation in <i>C1GALT1</i>.

Gale Daniel P DP Molyneux Karen K Wimbury David D Higgins Patricia P Levine Adam P AP Caplin Ben B Ferlin Anna A Yin Peiran P Nelson Christopher P CP Stanescu Horia H Samani Nilesh J NJ Kleta Robert R Yu Xueqing X Barratt Jonathan J

Journal of the American Society of Nephrology : JASN 20170216 7

IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in <i>O</i>-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 ...[more]

PMID: 28209808

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Project description:BACKGROUND:More and more studies demonstrated that genetic variation at C1GALT1 influences Gd-IgA1 level in IgAN. However, whether the expression of ?1, 3-galactosyltransferase (?1, 3Gal-T) was influenced may provide insights into how Gd-IgA1 levels are controlled in IgAN. METHODS:Thirty IgAN patients diagnosed in Tianjin Medical University General Hospital from April to September 2018 and 30 healthy volunteers whose age and gender matched with patients were enrolled in this study. Total Gd-IgA1 levels in plasma were determined by ELISA and C1GALT1 levels were determined by RT-PCR. Four databases (PubMed, EMBASE, CNKI, WanFang Medical Network) were searched to identify eligible studies that evaluated a difference in the expression of C1GALT1 in IgAN patients compared with total controls (non-IgAN and health controls). The C1GALT1C1 expression levels, which was indispensable to ?1, 3Gal-T of IgA1, was also been compared. RESULTS:Gd-IgA1 levels were remarkable higher in IgAN patients compared with healthy control. The expression levels of C1GALT1 gene were remarkably down-regulated in IgAN patients compared with healthy control. And the mRNA level of C1GALT1 was inversely correlated to Gd-IgA1 levels. In meta-analysis, six articles including 316 participants that analyzed the expression of ?1, 3Gal-T were met inclusion criteria. There was no significant difference in the expression of C1GALT1 between IgAN patients compared with controls. And we found patients with IgAN had lower levels of C1GALT1 gene expression in the B cells compared to controls. The C1GALT1C1 levels in the IgAN patients were not different from the levels in the control group, which were unchanged no matter according to different ethnic population, different control group and different cell source. Two studies including 46 persons compared enzymatic activity of ?1, 3Gal-T in B cells, and the result showed the ?1, 3Gal-T activity was decreased in B cells. CONCLUSIONS:We found expression levels of C1GALT1 were remarkably downregulated in IgAN patients and negatively correlated with higher levels of Gd-IgA1. Subsequent meta-analysis validated the low expression and activity of ?1, 3Gal-T in B cells in patients with IgAN. However, there was no apparent disparity in the aspect of C1GALT1C1 expression between IgAN and control groups.

Dataset Information

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.

Publications

Galactosylation of IgA1 Is Associated with Common Variation in <i>C1GALT1</i>.

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