04453nas a2200889 4500008004100000022001400041245011700055210006900172260001300241300001300254490000600267520190600273653004202179653001002221653003902231653000902270653001202279653001102291653003002302653003202332653001702364653003402381653003102415653001102446653002802457653001102485653002802496653000902524653001602533653002202549653001402571653003602585653001402621100001802635700002202653700001802675700001902693700002302712700002302735700002002758700001702778700002402795700002002819700001902839700002002858700001802878700002102896700002902917700002102946700002202967700001802989700001603007700002303023700001203046700002403058700002503082700002303107700002303130700002303153700002303176700002203199700002203221700002303243700001703266700002403283700002203307700002403329700001803353700002503371700002503396700002303421700002503444700001503469700002103484710002203505856003603527 2011 eng d a1553-740400aGenetic association for renal traits among participants of African ancestry reveals new loci for renal function.0 aGenetic association for renal traits among participants of Afric c2011 Sep ae10022640 v73 a
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 m(2)), 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.
10aAdaptor Proteins, Vesicular Transport10aAdult10aAfrican Continental Ancestry Group10aAged10aAnimals10aFemale10aGene Knockdown Techniques10aGenetic Association Studies10aGenetic Loci10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKCNQ1 Potassium Channel10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aNeoplasm Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aZebrafish1 aLiu, Ching-Ti1 aGarnaas, Maija, K1 aTin, Adrienne1 aKöttgen, Anna1 aFranceschini, Nora1 aPeralta, Carmen, A1 ade Boer, Ian, H1 aLu, Xiaoning1 aAtkinson, Elizabeth1 aDing, Jingzhong1 aNalls, Michael1 aShriner, Daniel1 aCoresh, Josef1 aKutlar, Abdullah1 aBibbins-Domingo, Kirsten1 aSiscovick, David1 aAkylbekova, Ermeg1 aWyatt, Sharon1 aAstor, Brad1 aMychaleckjy, Josef1 aLi, Man1 aReilly, Muredach, P1 aTownsend, Raymond, R1 aAdeyemo, Adebowale1 aZonderman, Alan, B1 ade Andrade, Mariza1 aTurner, Stephen, T1 aMosley, Thomas, H1 aHarris, Tamara, B1 aRotimi, Charles, N1 aLiu, Yongmei1 aKardia, Sharon, L R1 aEvans, Michele, K1 aShlipak, Michael, G1 aKramer, Holly1 aFlessner, Michael, F1 aDreisbach, Albert, W1 aGoessling, Wolfram1 aCupples, Adrienne, L1 aKao, Linda1 aFox, Caroline, S1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/1327