Interaction between <i>G</i><i>ALNT12</i> and <i>C1GALT1</i> Associates with Galactose-Deficient IgA1 and IgA Nephropathy.

Abstract

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. 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. We discovered two loci, in <i>C1GALT1</i> and <i>GALNT12,</i> 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 <i>C1GALT1</i> with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, <i>P</i>=1.20×10^-9); the locus we identified at <i>GALNT12</i> (rs7856182; β=0.73, <i>P</i>=2.38×10^-9) was novel. Of more interest, we found that <i>GALNT12</i> exhibits genetic interactions with <i>C1GALT1</i> in both galactose-deficient IgA1 levels (<i>P</i>=1.40×10^-2) and disease risk (<i>P</i>=6.55×10^-3). <i>GALNT12</i> mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. Our data identify <i>GALNT12</i> 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.