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

• Published in: PLoS genetics Vol. 13; no. 2; p. e1006609
• Main Authors: Kiryluk, Krzysztof, Li, Yifu, Moldoveanu, Zina, Suzuki, Hitoshi, Reily, Colin, Hou, Ping, Xie, Jingyuan, Mladkova, Nikol, Prakash, Sindhuri, Fischman, Clara, Shapiro, Samantha, LeDesma, Robert A, Bradbury, Drew, Ionita-Laza, Iuliana, Eitner, Frank, Rauen, Thomas, Maillard, Nicolas, Berthoux, Francois, Floege, Jürgen, Chen, Nan, Zhang, Hong, Scolari, Francesco, Wyatt, Robert J, Julian, Bruce A, Gharavi, Ali G, Novak, Jan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.02.2017; Public Library of Science (PLoS)
• Subjects: Alleles; Asian Continental Ancestry Group - genetics; Asian people; Biology and Life Sciences; Blood diseases; Cell Line; Cohort Studies; Colleges & universities; Disease; Ethnicity; European Continental Ancestry Group - genetics; Galactose - deficiency; Galactose metabolism; Galactosyltransferases - genetics; Gene Expression Regulation; Gene Frequency; Gene Regulatory Networks; Genealogy; Genetic aspects; Genetic Predisposition to Disease - ethnology; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study - methods; Genomes; Genomics; Genotype; Glomerulonephritis, IGA - blood; Glomerulonephritis, IGA - ethnology; Glomerulonephritis, IGA - genetics; Glycosylation; Health aspects; Hospitals; Humans; Immunoglobulin A; Immunoglobulin A - blood; Immunoglobulins; Kidney diseases; Medicine; Models, Genetic; Molecular Chaperones - genetics; Nephrology; Nerve Tissue Proteins - genetics; Phenotype; Physical Sciences; Physicians; Physiological aspects; Polymorphism, Single Nucleotide; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA Interference; Rodents; Signal Transduction - genetics; Surgeons; Ubiquitin-Protein Ligases - genetics; United States; Beijing China; New York; Aachen Germany; United States > US; China; Alabama; Germany
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006609

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.