GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.
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...
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Public Library of Science (PLoS)
2017-02-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1006609 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Krzysztof Kiryluk |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a1383fb1ffad4d53aeb9cfe36dabf45f |
| institution | Matheson Library |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2017-02-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-a1383fb1ffad4d53aeb9cfe36dabf45f2025-06-26T05:30:59ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-02-01132e100660910.1371/journal.pgen.1006609GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.Krzysztof KirylukYifu LiZina MoldoveanuHitoshi SuzukiColin ReilyPing HouJingyuan XieNikol MladkovaSindhuri PrakashClara FischmanSamantha ShapiroRobert A LeDesmaDrew BradburyIuliana Ionita-LazaFrank EitnerThomas RauenNicolas MaillardFrancois BerthouxJürgen FloegeNan ChenHong ZhangFrancesco ScolariRobert J WyattBruce A JulianAli G GharaviJan NovakAberrant 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.https://doi.org/10.1371/journal.pgen.1006609 |
| spellingShingle | 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 GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genetics |
| title | GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. |
| title_full | GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. |
| title_fullStr | GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. |
| title_full_unstemmed | GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. |
| title_short | GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. |
| title_sort | gwas for serum galactose deficient iga1 implicates critical genes of the o glycosylation pathway |
| url | https://doi.org/10.1371/journal.pgen.1006609 |
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