Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)
| Autor: | Michael J. Klag, Yii-Der Ida Chen, Charles N. Rotimi, W. H. Linda Kao, Michael F. Seldin, Christoph Wanner, Alka Malhotra, Jeffrey M. Curtis, Barbara V. Howard, Xiuqing Guo, Sharon G. Adler, Barbara Truitt, Adam M. Smiles, Philip G. Zager, Denyse Thornley-Brown, Winfried März, Matthias Kretzler, Barry I. Freedman, Robert C. Elston, Huateng Huang, Farook Thameem, Man Li, Vallabh O. Shah, William C. Knowler, Ravi Duggirala, Jeffrey R. Schelling, Tennille S. Leak, Mary E. Comeau, Hanna E. Abboud, Christiane Drechsler, Orly F. Kohn, Lyle G. Best, Jerome I. Rotter, Benjamin J. Keller, Madeleine V. Pahl, Rulan S. Parekh, Robert L. Hanson, Jasmin Divers, Michael W. Smith, Michael M. Hoffmann, Robert G. Nelson, Carl D. Langefeld, Marcus G. Pezzolesi, John R. Sedor, Paul L. Kimmel, Eli Ipp, Stephen J. O'Brien, Shelley A. Cole, E. Jennifer Weil, Robert P. Igo, David J. Leehey, Allison Burlock, Susanne B. Nicholas, Cheryl A. Winkler, Rebekah S. Rasooly, Sudha K. Iyengar, Viji Nair, Kent D. Taylor, Donald W. Bowden |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
medicine.medical_specialty Linkage disequilibrium lcsh:QH426-470 030232 urology & nephrology Single-nucleotide polymorphism Genome-wide association study Disease Biology White People Nephropathy 03 medical and health sciences 0302 clinical medicine Diabetes mellitus Internal medicine Genetics medicine SNP Humans Diabetic Nephropathies Genetic Predisposition to Disease ddc:610 Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics 030304 developmental biology 0303 health sciences RNA-Binding Proteins Hispanic or Latino medicine.disease United States 3. Good health Black or African American lcsh:Genetics Diabetes Mellitus Type 2 Indians North American Kidney disease Research Article Genome-Wide Association Study |
| Zdroj: | PLoS Genetics Iyengar, SK; Sedor, JR; Freedman, BI; Kao, WHL; Kretzler, M; Keller, BJ; et al.(2015). Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND). PLoS Genetics, 11(8). doi: 10.1371/journal.pgen.1005352. UCLA: Retrieved from: http://www.escholarship.org/uc/item/9s22h1zt PLoS Genetics, Vol 11, Iss 8, p e1005352 (2015) |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | 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. Author Summary Type 2 diabetes is the most common cause of severe kidney disease worldwide and diabetic kidney disease (DKD) associates with premature death. Individuals of non-European ancestry have the highest burden of type 2 DKD; hence understanding the causes of DKD remains critical to reducing health disparities. Family studies demonstrate that genes regulate the onset and progression of DKD; however, identifying these genes has proven to be challenging. The Family Investigation of Diabetes and Nephropathy consortium (FIND) recruited a large multi-ethnic collection of individuals with type 2 diabetes with and without kidney disease in order to detect genes associated with DKD. FIND discovered and replicated a DKD-associated genetic locus on human chromosome 6q25.2 (rs955333) between the SCAF8 and CNKSR genes. Findings were supported by significantly different expression of genes in this region from kidney tissue of subjects with, versus without DKD. The present findings identify a novel kidney disease susceptibility locus in individuals with type 2 diabetes which is consistent across subjects of differing ancestries. In addition, FIND results provide a rich catalogue of genetic variation in DKD patients for future research on the genetic architecture regulating this common and devastating disease. |
| Databáze: | OpenAIRE |
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