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Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: Family Investigation of Nephropathy and Diabetes (FIND)

Please always quote using this URN: urn:nbn:de:bvb:20-opus-180545
  • 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 aDiabetic 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.show moreshow less

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Author: Sudha K. Iyengar, John R. Sedor, Barry I. Freedman, W. H. Linda Kao, Matthias Kretzler, Benjamin J. Keller, Hanna E. Abboud, Sharon G. Adler, Lyle G. Best, Donald W. Bowden, Allison Burlock, Yii-Der Ida Chen, Shelley A. Cole, Mary E. Comeau, Jeffrey M. Curtis, Jasmin Divers, Christiane Drechsler, Ravi Duggirala, Robert C. Elston, Xiuqing Guo, Huateng Huang, Michael Marcus Hoffmann, Barbara V. Howard, Eli Ipp, Paul L. Kimmel, Michael J. Klag, William C. Knowler, Orly F. Kohn, Tennille S. Leak, David J. Leehey, Man Li, Alka Malhotra, Winfried März, Viji Nair, Robert G. Nelson, Susanne B. Nicholas, Stephen J. O’Brien, Madeleine V. Pahl, Rulan S. Parekh, Marcus G. Pezzolesi, Rebekah S. Rasooly, Charles N. Rotimi, Jerome I. Rotter, Jeffrey R. Schelling, Michael F. Seldin, Vallabh O. Shah, Adam M. Smiles, Michael W. Smith, Kent D. Taylor, Farook Thameem, Denyse P. Thornley-Brown, Barbara J. Truitt, Christoph Wanner, E. Jennifer Weil, Cheryl A. Winkler, Philip G. Zager, Robert P. Igo, Jr, Robert L. Hanson, Carl D. Langefeld
URN:urn:nbn:de:bvb:20-opus-180545
Document Type:Journal article
Faculties:Medizinische Fakultät / Medizinische Klinik und Poliklinik I
Language:English
Parent Title (English):PLoS Genetics
Year of Completion:2015
Volume:11
Issue:8
Pagenumber:e1005352
Source:PLoS Genetics 11(8):e1005352 (2015). DOI: 10.1371/journal.pgen.1005352
DOI:https://doi.org/10.1371/journal.pgen.1005352
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Family Investigation of Nephropathy and Diabetes; diabetic kidney disease; genome-wide association study
Release Date:2019/05/15
Licence (German):License LogoCC 0: Public Domain Dedication