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RESEARCH PRODUCT
Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen
Emma AhlqvistCatherine GodsonDarrell AndrewsPer-henrik GroopRaimund WeitgasserAndrzej S. KrolewskiKristine E. LeeLina RadzevicieneStuart J. McgurnaghanColin N. A. PalmerJoanne B. ColeJoanne B. ColeShelley B. BullAndrew P. BorightLars StechemesserKatalin SusztakBarbara E.k. KleinWei-min ChenKerstin BrismarKerstin BrismarCarol ForsblomJani K. HaukkaBeata GyorgyBeata GyorgyAdam M. SmilesJose C. FlorezHarvest F. GuNiina SandholmLeif GroopLeif GroopGareth J. MckayMaria HughesMark I. MccarthyJoel N. HirschhornJoel N. HirschhornAthina SpiliopoulouMichael MauerSamy HadjadjNicolae Mircea PanduruNicolae Mircea PanduruHelen M. ColhounJingchuan GuoRobert G. NelsonMatthias KretzlerValdis PīrāgsMarcus G. PezzolesiTarunveer S. AhluwaliaRasa VerkauskieneMichel MarreLinda T. HirakiJanet K. Snell-bergeonBernhard PaulweberStephen S. RichErkka ValoChen Di LiaoDavid M. MaahsVita RovīteRachel G. MillerEoin P. BrennanPeter RossingPeter RossingNatalie R. Van ZuydamMaria Luiza CaramoriJan SkupienRany M. SalemA. Peter MaxwellPaul M. MckeigueMaria LajerGianpaolo ZerbiniChengxiang QiuDavid-alexandre TrégouëtDavid-alexandre TrégouëtHenrik FalhammarHenrik FalhammarJennifer ToddJennifer ToddRajasree MenonJelizaveta SokolovskaValma HarjutsaloAnna MöllstenRonald KleinXiaoyu GaoViji NairJihwan ParkAmy Jayne McknightJing Jing CaoSilvia MaestroniEdita PrakapieneIan H. De BoerFinian MartinAndrew D. PatersonSuna Onengut-gumuscuRoss DoyleHyun Min KangAngelo J. CantyAndrew C. LiuTina CostacouCarine M. Boustany-karisubject
Collagen Type IVMale0301 basic medicineEXPRESSIONNEPHROPATHY030232 urology & nephrologyPROTEINGenome-wide association studyRECEPTOR TYROSINE KINASESBiologySUSCEPTIBILITYBioinformaticsurologic and male genital diseasesAutoantigensNephropathyEnd stage renal diseaseCohort StudiesDiabetic nephropathy03 medical and health sciences0302 clinical medicineSDG 3 - Good Health and Well-beingDiabetes mellitusGlomerular Basement MembranemedicineHumansDiabetic NephropathiesAlport syndromeLetter to the EditorCOMPLICATIONSNITRIC-OXIDEMUTATIONS1184 Genetics developmental biology physiologyGeneral Medicinemedicine.diseaseGENE3. Good healthDiabetes Mellitus Type 1030104 developmental biologyNephrology3121 General medicine internal medicine and other clinical medicineMutationAlbuminuria/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_beingFemale3111 Biomedicinemedicine.symptomCOLLECTIN 11 CL-11Genome-Wide Association StudyKidney diseasedescription
BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-01-01 |