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Genetic association for renal traits among participants of African ancestry reveals new loci for renal function.
Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
| Title | Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Liu, C-T, Garnaas, MK, Tin, A, Köttgen, A, Franceschini, N, Peralta, CA, de Boer, IH, Lu, X, Atkinson, E, Ding, J, Nalls, M, Shriner, D, Coresh, J, Kutlar, A, Bibbins-Domingo, K, Siscovick, D, Akylbekova, E, Wyatt, S, Astor, B, Mychaleckjy, J, Li, M, Reilly, MP, Townsend, RR, Adeyemo, A, Zonderman, AB, de Andrade, M, Turner, ST, Mosley, TH, Harris, TB, Rotimi, CN, Liu, Y, Kardia, SLR, Evans, MK, Shlipak, MG, Kramer, H, Flessner, MF, Dreisbach, AW, Goessling, W, Cupples, AL, W Kao, L, Fox, CS |
| Corporate/Institutional Authors | CKDGen Consortium |
| Journal | PLoS Genet |
| Volume | 7 |
| Issue | 9 |
| Pagination | e1002264 |
| Date Published | 2011 Sep |
| ISSN | 1553-7404 |
| Keywords | Adaptor Proteins, Vesicular Transport, Adult, African Continental Ancestry Group, Aged, Animals, Female, Gene Knockdown Techniques, Genetic Association Studies, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, KCNQ1 Potassium Channel, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Neoplasm Proteins, Phenotype, Polymorphism, Single Nucleotide, Zebrafish |
| Abstract | <p>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.</p> |
| DOI | 10.1371/journal.pgen.1002264 |
| Alternate Journal | PLoS Genet. |
| PubMed ID | 21931561 |
| PubMed Central ID | PMC3169523 |
| Grant List | N01HC55020 / HL / NHLBI NIH HHS / United States N01-HB-72992 / HB / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States N01-HB-97068 / HB / NHLBI NIH HHS / United States N01-HB-97053 / HB / NHLBI NIH HHS / United States N01-HB-72997 / HB / NHLBI NIH HHS / United States N01-HB-73003 / HB / NHLBI NIH HHS / United States N01-HC-45205 / HC / NHLBI NIH HHS / United States N01-HC-95162 / HC / NHLBI NIH HHS / United States N01-HC-05187 / HC / NHLBI NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States S06GM008016-380111 / GM / NIGMS NIH HHS / United States U01 HL053916 / HL / NHLBI NIH HHS / United States N01HC55018 / HL / NHLBI NIH HHS / United States R01 HL046380 / HL / NHLBI NIH HHS / United States N01 AG062101 / AG / NIA NIH HHS / United States S06GM008016-320107 / GM / NIGMS NIH HHS / United States R01-HL087660 / HL / NHLBI NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS 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