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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.

Interaction between G ALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy