Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
Vyšlo v časopise: Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002264 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002264
1. CoreshJSelvinEStevensLAManziJKusekJW 2007 Prevalence of chronic kidney disease in the United States. JAMA 298 2038 2047
2. FoxCSMuntnerP 2008 Trends in diabetes, high cholesterol, and hypertension in chronic kidney disease among U.S. adults: 1988–1994 to 1999–2004. Diabetes Care 31 1337 1342
3. KottgenAGlazerNLDehghanAHwangSJKatzR 2009 Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41 712 717
4. KottgenAPattaroCBogerCAFuchsbergerCOldenM 2010 New loci associated with kidney function and chronic kidney disease. Nat Genet 42 376 384
5. FoxCSYangQCupplesLAGuoCYLarsonMG 2004 Genomewide Linkage Analysis to Serum Creatinine, GFR, and Creatinine Clearance in a Community-Based Population: The Framingham Heart Study. J Am Soc Nephrol 15 2457 2461
6. U.S. Renal Data System, USRDS 2008 Annual Data Report, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008
7. IgoRPJrIyengarSKNicholasSBGoddardKALangefeldCD 2011 Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study. Am J Nephrol 33 381 389
8. SchellingJRAbboudHENicholasSBPahlMVSedorJR 2008 Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes 57 235 243
9. IyengarSKAbboudHEGoddardKASaadMFAdlerSG 2007 Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes 56 1577 1585
10. KaoWHKlagMJMeoniLAReichDBerthier-SchaadY 2008 MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40 1185 1192
11. KoppJBSmithMWNelsonGWJohnsonRCFreedmanBI 2008 MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40 1175 1184
12. GenoveseGFriedmanDJRossMDLecordierLUzureauP 2010 Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329 841 845
13. HsuCYLinFVittinghoffEShlipakMG 2003 Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States. J Am Soc Nephrol 14 2902 2907
14. HunsickerLGAdlerSCaggiulaAEnglandBKGreeneT 1997 Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 51 1908 1919
15. KeatingBJTischfieldSMurraySSBhangaleTPriceTS 2008 Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS ONE 3 e3583 doi:10.1371/journal.pone.0003583
16. ChambersJCZhangWLordGMvan derHPLawlorDA 2010 Genetic loci influencing kidney function and chronic kidney disease. Nat Genet 42 373 375
17. LoKSWilsonJGLangeLAFolsomARGalarneauG 2011 Genetic association analysis highlights new loci that modulate hematological trait variation in Caucasians and African Americans. Hum Genet 129 307 317
18. BogerCAChenMHTinAOldenMKottgenA 2011 CUBN Is a Gene Locus for Albuminuria. J Am Soc Nephrol
19. AshworthSTengBKaufeldJMillerETossidouI 2010 Cofilin-1 inactivation leads to proteinuria–studies in zebrafish, mice and humans. PLoS ONE 5 e12626 doi:10.1371/journal.pone.0012626
20. HentschelDMMengelMBoehmeLLiebschFAlbertinC 2007 Rapid screening of glomerular slit diaphragm integrity in larval zebrafish. Am J Physiol Renal Physiol 293 F1746 F1750
21. Neumann-HaefelinEKramer-ZuckerASlanchevKHartlebenBNoutsouF 2010 A model organism approach: defining the role of Neph proteins as regulators of neuron and kidney morphogenesis. Hum Mol Genet 19 2347 2359
22. VallonVGrahammerFVolklHSanduCDRichterK 2005 KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl Acad Sci U S A 102 17864 17869
23. UnokiHTakahashiAKawaguchiTHaraKHorikoshiM 2008 SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40 1098 1102
24. HuCWangCZhangRMaXWangJ 2009 Variations in KCNQ1 are associated with type 2 diabetes and beta cell function in a Chinese population. Diabetologia 52 1322 1325
25. OhshigeTTanakaYArakiSBabazonoTToyodaM 2010 A single nucleotide polymorphism in KCNQ1 is associated with susceptibility to diabetic nephropathy in japanese subjects with type 2 diabetes. Diabetes Care 33 842 846
26. CrowderRJEnomotoHYangMJohnsonEMJrMilbrandtJ 2004 Dok-6, a Novel p62 Dok family member, promotes Ret-mediated neurite outgrowth. J Biol Chem 279 42072 42081
27. SchuchardtAD'AgatiVLarsson-BlombergLCostantiniFPachnisV 1994 Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367 380 383
28. HsuYHZillikensMCWilsonSGFarberCRDemissieS 2010 An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits. PLoS Genet 6 e1000977 doi:10.1371/journal.pgen.1000977
29. SatoMCismowskiMJToyotaESmrckaAVLucchesiPA 2006 Identification of a receptor-independent activator of G protein signaling (AGS8) in ischemic heart and its interaction with Gbetagamma. Proc Natl Acad Sci U S A 103 797 802
30. SatoMJiaoQHondaTKurotaniRToyotaE 2009 Activator of G protein signaling 8 (AGS8) is required for hypoxia-induced apoptosis of cardiomyocytes: role of G betagamma and connexin 43 (CX43). J Biol Chem 284 31431 31440
31. Kramer-ZuckerAGWiessnerSJensenAMDrummondIA 2005 Organization of the pronephric filtration apparatus in zebrafish requires Nephrin, Podocin and the FERM domain protein Mosaic eyes. Dev Biol 285 316 329
32. DrummondIA 2005 Kidney development and disease in the zebrafish. J Am Soc Nephrol 16 299 304
33. HentschelDMParkKMCilentiLZervosASDrummondI 2005 Acute renal failure in zebrafish: a novel system to study a complex disease. Am J Physiol Renal Physiol 288 F923 F929
34. HyvarinenJParikkaMSormunenRRametMTryggvasonK 2010 Deficiency of a transmembrane prolyl 4-hydroxylase in the zebrafish leads to basement membrane defects and compromised kidney function. J Biol Chem
35. HinkesBWigginsRCGbadegesinRVlangosCNSeelowD 2006 Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38 1397 1405
36. CoreshJAstorBCMcQuillanGKusekJGreeneT 2002 Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 39 920 929
37. FoxCSLarsonMGLeipEPCulletonBWilsonPW 2004 Predictors of new-onset kidney disease in a community-based population. JAMA 291 844 850
38. KlahrSLeveyASBeckGJCaggiulaAWHunsickerL 1994 The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 330 877 884
39. HuangLLiYSingletonABHardyJAAbecasisG 2009 Genotype-imputation accuracy across worldwide human populations. Am J Hum Genet 84 235 250
40. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
41. DrummondIAMajumdarAHentschelHElgerMSolnica-KrezelL 1998 Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function. Development 125 4655 4667
42. WingertRASelleckRYuJSongHDChenZ 2007 The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet 3 e189 doi:10.1371/journal.pgen.0030189
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
