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Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

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Citation: PLoS Genetics. 11(8):e1005352, 2015 Aug.PMID: 26305897Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Meta-Analysis | Research Support, N.I.H., ExtramuralSubject headings: *Diabetes Mellitus, Type 2/ge [Genetics] | *Diabetic Nephropathies/ge [Genetics] | African Americans/ge [Genetics] | Diabetes Mellitus, Type 2/co [Complications] | Diabetic Nephropathies/eh [Ethnology] | European Continental Ancestry Group/ge [Genetics] | Genetic Predisposition to Disease | Genome-Wide Association Study | Hispanic Americans/ge [Genetics] | Humans | Indians, North American/ge [Genetics] | RNA-Binding Proteins/ge [Genetics] | United StatesYear: 2015 Local holdings: Available online through MWHC library: 2005 - presentISSN:

1553-7390

Name of journal: PLoS geneticsAbstract: Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.All authors: Abboud HE, Adler SG, Best LG, Bowden DW, Burlock A, Chen YD, Cole SA, Comeau ME, Curtis JM, Divers J, Drechsler C, Duggirala R, Elston RC, Family Investigation of Nephropathy and Diabetes (FIND), Freedman BI, Guo X, Hanson RL, Hoffmann MM, Howard BV, Huang H, Igo RP Jr, Ipp E, Iyengar SK, Kao WH, Keller BJ, Kimmel PL, Klag MJ, Knowler WC, Kohn OF, Kretzler M, Langefeld CD, Leak TS, Leehey DJ, Li M, Malhotra A, Marz W, Nair V, Nelson RG, Nicholas SB, O'Brien SJ, Pahl MV, Parekh RS, Pezzolesi MG, Rasooly RS, Rotimi CN, Rotter JI, Schelling JR, Sedor JR, Seldin MF, Shah VO, Smiles AM, Smith MW, Taylor KD, Thameem F, Thornley-Brown DP, Truitt BJ, Wanner C, Weil EJ, Winkler CA, Zager PGFiscal year: FY2016Digital Object Identifier:

http://dx.doi.org/10.1371/journal.pgen.1005352

Date added to catalog: 2016-05-24

Holdings ( 1 )
Title notes ( 3 )

Holdings
Item type	Current library	Collection	Call number	Status	Date due	Barcode
Journal Article	MedStar Authors Catalog	Article	26305897	Available		26305897

Available online through MWHC library: 2005 - present

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

English