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

Author

Listed:
  • 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

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.Author summary: O-glycosylation is a common type of post-translational modification of proteins; specific abnormalities in the mechanism of O-glycosylation have been implicated in cancer, inflammatory and blood diseases. However, the molecular basis of abnormal O-glycosylation in these complex disorders is not known. We studied the genetic basis of defective O-glycosylation of serum immunoglobulin A1 (IgA1), that represents the key pathogenic defect in IgA nephropathy, the most common form of primary glomerulonephritis worldwide. We report our results of the first genome-wide association study for this trait using serum assays in 2,633 individuals of European and East-Asian ancestry. In our genome scan, we observed two significant signals with large effects, on chromosomes 7p21.3 and Xq24, jointly explaining about 7% of trait variability. These signals implicate two genes that encode molecular partners essential for enzymatic O-glycosylation of IgA1 and mucins, and represent potential new targets for therapy.

Suggested Citation

  • 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, 2017. "GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway," PLOS Genetics, Public Library of Science, vol. 13(2), pages 1-22, February.
  • Handle: RePEc:plo:pgen00:1006609
    DOI: 10.1371/journal.pgen.1006609
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    Cited by:

    1. Lili Liu & Atlas Khan & Elena Sanchez-Rodriguez & Francesca Zanoni & Yifu Li & Nicholas Steers & Olivia Balderes & Junying Zhang & Priya Krithivasan & Robert A. LeDesma & Clara Fischman & Scott J. Heb, 2022. "Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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