Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function

被引：102

作者：

Liu, Ching-Ti ^{[1
]}

Garnaas, Maija K. ^{[2
,3
,4
]}

Tin, Adrienne ^{[5
]}

Kottgen, Anna ^{[5
,6
]}

Franceschini, Nora ^{[7
]}

Peralta, Carmen A. ^{[8
,9
]}

de Boer, Ian H. ^{[10
,11
]}

Lu, Xiaoning ^{[1
]}

Atkinson, Elizabeth ^{[12
]}

Ding, Jingzhong ^{[13
]}

Nalls, Michael ^{[14
]}

Shriner, Daniel ^{[15
]}

Coresh, Josef ^{[16
]}

Kutlar, Abdullah ^{[17
]}

Bibbins-Domingo, Kirsten

Siscovick, David ^{[18
,19
]}

Akylbekova, Ermeg ^{[20
]}

Wyatt, Sharon ^{[21
]}

Astor, Brad ^{[22
]}

Mychaleckjy, Josef ^{[23
]}

Li, Man ^{[5
]}

Reilly, Muredach P. ^{[24
]}

Townsend, Raymond R. ^{[25
]}

Adeyemo, Adebowale ^{[15
]}

Zonderman, Alan B. ^{[26
]}

de Andrade, Mariza ^{[12
]}

Turner, Stephen T. ^{[27
]}

Mosley, Thomas H. ^{[28
]}

Harris, Tamara B. ^{[29
]}

Rotimi, Charles N. ^{[15
]}

Liu, Yongmei ^{[30
]}

Kardia, Sharon L. R. ^{[31
]}

Evans, Michele K. ^{[32
]}

Shlipak, Michael G.

Kramer, Holly ^{[33
]}

Flessner, Michael F. ^{[34
]}

Dreisbach, Albert W. ^{[35
]}

Goessling, Wolfram ^{[2
,3
,4
,36
]}

Cupples, L. Adrienne ^{[1
,37
]}

Kao, W. Linda ^{[4
]}

Fox, Caroline S. ^{[3
,38
,39
,40
]}

机构：

[1] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA

[2] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[5] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA

[6] Univ Hosp Freiburg, Div Renal, Freiburg, Germany

[7] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[8] Univ Calif San Francisco, Sch Med, Div Nephrol, San Francisco, CA USA

[9] San Francisco VA Med Ctr, San Francisco, CA USA

[10] Univ Washington, Div Nephrol, Seattle, WA 98195 USA

[11] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA

[12] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA

[13] Wake Forest Univ Hlth Sci, J Paul Sticht Ctr Aging, Winston Salem, NC USA

[14] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[15] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA

[16] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA

[17] Med Coll Georgia, Augusta, GA 30912 USA

[18] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[19] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[20] Jackson State Univ, Jackson, MS USA

[21] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA

[22] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[23] Ctr Publ Hlth Genom, Charlottesville, VA USA

[24] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA

[25] Univ Penn, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA

[26] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA

[27] Mayo Clin, Div Nephrol & Hypertens, Dept Internal Med, Rochester, MN USA

[28] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA

[29] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA

[30] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA

[31] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[32] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA

[33] Loyola Univ, Maywood, IL 60153 USA

[34] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA

[35] Univ Mississippi, Div Nephrol, Jackson, MS 39216 USA

[36] Brigham & Womens Hosp, Dept Med, Div Gastroenterol, Boston, MA 02115 USA

[37] NHLBI, Framingham Heart Study, Boston, MA USA

[38] NHLBI, Framingham Heart Study, Framingham, MA USA

[39] Ctr Populat Studies, Framingham, MA USA

[40] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA

来源：

PLOS GENETICS | 2011年 / 7卷 / 09期

基金：

美国国家卫生研究院;

关键词：

CHRONIC KIDNEY-DISEASE; DIABETIC-NEPHROPATHY; SERUM CREATININE; PROGRESSION; ZEBRAFISH; SUSCEPTIBILITY; PREDICTORS; MUTATIONS; FAILURE; SYSTEM;

D O I：

10.1371/journal.pgen.1002264

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 = 5.3x10(-7)) and FNDC1 (p-value = 3.0x10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6x10(-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.

引用

页数：14

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