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RESEARCH PRODUCT
Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes
Menno PruijmThor AspelundRuth J. F. LoosRuth J. F. LoosPhilipp S. WildWolfgang KoenigOzren PolasekJacques S. BeckmannJacques S. BeckmannChrista MeisingerAida Karina DieffenbachJozef LazarYi-an KoLyudmyla KedenkoMatthias NauckThomas IlligAlessandro LucianiChristian FuchsbergerClaudia LangenbergNan Cher YeoBénédicte StengelKatalin SusztakKarlhans EndlichLinda T. HirakiZoltán KutalikZoltán KutalikNicole EndlichRonit KatzLenore J. LaunerVladan MijatovicGerjan NavisChristian GiegerHoward J. JacobIris M. HeidMathias GorskiDavid S. SiscovickBernhard K. KrämerJohn ChalmersMelanie WaldenbergerPeter VollenweiderNicole SoranzoNicole SoranzoIgor RudanRon T. GansevoortJeffrey R. O'connellChristian MüllerMargot HaunJoshua C. DennyOlivier DevuystRainer RettigHolly KramerJian'an LuanTamara B. HarrisMarie MetzgerChristian M. ShafferMing-huei ChenGiovanni MalerbaReiner BiffarMan LiJosef CoreshHarald GrallertBelen PonteIan H. De BoerBarbara KolleritsMyriam RheinbergerVincent ChourakiJean-charles LambertKatja ButterbachAlbert V. SmithGeorg EhretAudrey Y. ChuAudrey Y. ChuAntonio LupoCaroline S. FoxCaroline S. FoxAlan R. ShuldinerPavel HametShih-jen HwangYong LiSylvia E. RosasDaniel TaliunNiek VerweijLuigi FerrucciUwe VölkerBraxton D. MitchellH BrennerSven BergmannBernhard PaulweberMatthew HoffmanSylvia StrackeRossella SoriceRobert J. CarrollFlorian KronenbergJing Hua ZhaoQiong YangJohanne TremblayPeter P. PramstallerVilmundur GudnasonMurielle BochudDaniel AckermannHans L. HillegeNicholas J. WarehamMark WoodwardMark WoodwardMark WoodwardEric BoerwinkleUwe LendeckelGuo LiGeorg HomuthI. Mateo LeachGudny EiriksdottirCristian PattaroAndrew D. PatersonHenry VölzkeGérard WaeberCarsten A. BögerGiovanni GambaroMeredith C. FosterHenri WallaschofskiAdrienne TinCatherine HelmerBamidele O. TayoMatthias OldenAnna KöttgenAnna KöttgenToshiko TanakaCaroline HaywardTanguy CorreStefan CoassinAlexander TeumerTanja ZellerH.-erich WichmannH.-erich WichmannAfshin ParsaAllison ZappaPim Van Der Harstsubject
Male0301 basic medicinediabetes geneEndocrinology Diabetes and MetabolismGenome-wide association studyKidneyGLOMERULAR-FILTRATION-RATECathepsin CGene Knockout TechniquescubilinSettore MED/14 - NEFROLOGIADiabetic NephropathiesMODULATES PROTEINURIAddc:616HERITABILITYDiabetesGenetics/Genomes/Proteomics/MetabolomicsMiddle AgedRISK POPULATION COHORTS3. Good healthINSIGHTSKidney TubulesFemaleSulfotransferasesmedicine.symptomRAB38AdultEXPRESSIONmedicine.medical_specialtyRenal functionReceptors Cell Surface610 Medicine & healthSingle-nucleotide polymorphismBiologyPolymorphism Single NucleotidealbuminuriaDiabetes Mellitus Experimental03 medical and health sciencesDiabetes mellitusInternal medicineInternal MedicinemedicineAnimalsHumansGenetic Predisposition to DiseaseAgedMORTALITYKIDNEY-DISEASEmedicine.diseaseCubilinRatsMinor allele frequency030104 developmental biologyEndocrinologyDiabetes Mellitus Type 2rab GTP-Binding ProteinsCOLLABORATIVE METAANALYSISAlbuminuria570 Life sciences; biologyalbuminuria diabetes cubilinGenome-Wide Association StudyKidney diseasedescription
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10−10). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10–7) and 13% for RAB38/CTSC (P = 5.8 × 10−7). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-03-01 |