Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy

J Am Soc Nephrol. 2021 Mar;32(3):545-552. doi: 10.1681/ASN.2020060823. Epub 2021 Feb 16.

Abstract

Background: Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established.

Methods: To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis.

Results: We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, P=1.20×10-9); the locus we identified at GALNT12 (rs7856182; β=0.73, P=2.38×10-9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10-2) and disease risk (P=6.55×10-3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls.

Conclusions: Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.

Keywords: IgA; IgA nephropathy; glomerulonephritis; human genetics; immune complexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Cohort Studies
  • Epistasis, Genetic
  • Female
  • Galactose / chemistry
  • Galactosyltransferases / genetics*
  • Gene Frequency
  • Genome-Wide Association Study
  • Glomerulonephritis, IGA / enzymology
  • Glomerulonephritis, IGA / genetics*
  • Glomerulonephritis, IGA / immunology*
  • Glycosylation
  • Humans
  • Immunoglobulin A / blood*
  • Immunoglobulin A / chemistry
  • Male
  • Multifactorial Inheritance
  • N-Acetylgalactosaminyltransferases / genetics*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • RNA, Messenger / blood
  • RNA, Messenger / genetics
  • Risk Factors

Substances

  • Immunoglobulin A
  • RNA, Messenger
  • C1GALT1 protein, human
  • GALNT12 protein, human
  • Galactosyltransferases
  • N-Acetylgalactosaminyltransferases
  • Galactose