biostudies-literatureWang YNNatural Science Foundation of Beijing MunicipalityPeking UniversityChinese Academy of Medical SciencesBeijing Nova ProgramBeijing Youth Top-notch Talent Support ProgramNational Natural Science Foundation of ChinaFok Ying Tung Education Foundation545-552https://www.ebi.ac.uk/biostudies/studies/S-EPMC7920185biostudies-literatureUnknown32(3)<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Journal of the American Society of Nephrology : JASNInteraction between <i>G</i><i>ALNT12</i> and <i>C1GALT1</i> Associates with Galactose-Deficient IgA1 and IgA Nephropathy.PMC79201852017000021223ZK31PKU2020LCXQ00382022010Z1911000011190048207073317103081970613Z1900232019RU023Wang YNChen PShi SFZhou XJHou PZhang XZhang HLv JCLiu LJYu GZfalseInteraction between <i>G</i><i>ALNT12</i> and <i>C1GALT1</i> Associates with Galactose-Deficient IgA1 and IgA Nephropathy.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.2021-01-01T00:00:00Z2021 Mar2026-05-30T15:10:27.853Z2025-04-19T22:38:49.513ZS-EPMC79201853359382410.1681/ASN.202006082310.1681/asn.2020060823