GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.

Abstract

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.

• Authors: Krzysztof Kiryluk, Yifu Li, Zina Moldoveanu, Hitoshi Suzuki, Colin Reily, Ping Hou, Jingyuan Xie, Nikol Mladkova, Sindhuri Prakash, Clara Fischman, Samantha Shapiro, Robert A LeDesma, Drew Bradbury, Iuliana Ionita-Laza, Frank Eitner, Thomas Rauen, Nicolas Maillard, Francois Berthoux, Jürgen Floege, Nan Chen, Hong Zhang, Francesco Scolari, Robert J Wyatt, Bruce A Julian, Ali G Gharavi, Jan Novak
• Journal: PLoS genetics (PLoS Genet) Vol. 13 Issue 2 Pg. e1006609 (02 2017) ISSN: 1553-7404 [Electronic] United States
• PMID: 28187132 (Publication Type: Journal Article)

Chemical References

• C1GALT1C1 protein, human
• Immunoglobulin A
• Molecular Chaperones
• Nerve Tissue Proteins
• HECW1 protein, human
• Ubiquitin-Protein Ligases
• C1GALT1 protein, human
• Galactosyltransferases
• Galactose

Topics

• Alleles
• Asian People (genetics)
• Cell Line
• Cohort Studies
• Galactose (deficiency)
• Galactosyltransferases (genetics)
• Gene Expression Regulation
• Gene Frequency
• Gene Regulatory Networks
• Genetic Predisposition to Disease (ethnology, genetics)
• Genome-Wide Association Study (methods)
• Genotype
• Glomerulonephritis, IGA (blood, ethnology, genetics)
• Glycosylation
• Humans
• Immunoglobulin A (blood)
• Models, Genetic
• Molecular Chaperones (genetics)
• Nerve Tissue Proteins (genetics)
• Phenotype
• Polymorphism, Single Nucleotide
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics)
• Ubiquitin-Protein Ligases (genetics)
• White People (genetics)