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GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway
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نویسنده
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kiryluk k. ,li y. ,moldoveanu z. ,suzuki h. ,reily c. ,hou p. ,xie j. ,mladkova n. ,prakash s. ,fischman c. ,shapiro s. ,ledesma r.a. ,bradbury d. ,ionita-laza i. ,eitner f. ,rauen t. ,maillard n. ,berthoux f. ,floege j. ,chen n. ,zhang h. ,scolari f. ,wyatt r.j. ,julian b.a. ,gharavi a.g. ,novak j.
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منبع
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plos genetics - 2017 - دوره : 13 - شماره : 2
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چکیده
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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. © 2017 kiryluk et al.
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آدرس
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dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of microbiology,university of alabama at birmingham,birmingham,al, United States, division of nephrology,dept. of internal medicine,juntendo university faculty of medicine,tokyo, Japan, dept. of microbiology,university of alabama at birmingham,birmingham,al,united states,dept. of medicine,university of alabama at birmingham,birmingham,al, United States, renal div.,peking university first hospital,peking university institute of nephrology,beijing, China, dept. of nephrology,ruijin hospital,shanghai jiao tong university school of medicine,shanghai, China, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of biostatistics,mailman school of public health,columbia university,new york,ny, United States, dept. of nephrology,rwth university of aachen,aachen,germany,kidney diseases research,bayer pharma ag,wuppertal, Germany, dept. of nephrology,rwth university of aachen,aachen, Germany, nephrology,dialysis,and renal transplantation dept.,university north hospital,saint etienne, France, nephrology,dialysis,and renal transplantation dept.,university north hospital,saint etienne, France, dept. of nephrology,rwth university of aachen,aachen, Germany, dept. of nephrology,ruijin hospital,shanghai jiao tong university school of medicine,shanghai, China, renal div.,peking university first hospital,peking university institute of nephrology,beijing, China, div. of nephrology,azienda ospedaliera spedali civili of brescia,montichiari hospital,univ of brescia,brescia,italy,dept. of medical and surgical specialties,radiological sciences,university of brescia,brescia, Italy, div. of pediatric nephrology,university of tennessee health sciences center,memphis,tn,united states,children's foundation research institute,le bonheur children's hospital,memphis,tn, United States, dept. of microbiology,university of alabama at birmingham,birmingham,al,united states,dept. of medicine,university of alabama at birmingham,birmingham,al, United States, dept. of medicine,div. of nephrology,college of physicians and surgeons,columbia university,new york,ny, United States, dept. of microbiology,university of alabama at birmingham,birmingham,al, United States
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Authors
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