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PLoS Genet. 2015 Aug 25;11(8):e1005352. doi: 10.1371/journal.pgen.1005352. eCollection 2015 Aug.

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

Author information

1
Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
2
Departments of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America; Departments of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States of America.
3
Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
4
Department of Epidemiology and Medicine, John Hopkins University, Baltimore, Maryland, United States of America.
5
Department of Internal Medicine/Nephrology, University of Michigan, Ann Arbor, Michigan, United States of America.
6
Department of Medicine/Nephrology, The University of Texas Health Science Center, San Antonio, Texas, United States of America.
7
Department of Medicine, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance, California, United States of America.
8
Missouri Breaks Industries Research, Timber Lake, South Dakota, United States of America.
9
Department of Biochemistry, Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
10
The Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, United States of America.
11
Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
12
Center for Public Health Genomics and Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, United States of America.
13
National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States of America.
14
University Hospital Würzburg, Renal Division and Comprehensive Heart Failure Center, Würzburg, Germany.
15
Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
16
Department of Clinical Chemistry, University Medical Center, Freiburg, Germany.
17
MedStar Health Research Institute, Hyattsville, Maryland, United States of America.
18
Department of Medicine, Section of Diabetes and Metabolism, Harbor-UCLA Medical Center, Torrance, California, United States of America.
19
Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America.
20
Johns Hopkins Bloomberg School of Public Health, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
21
Department of Medicine, University of Chicago Medicine, Chicago, Illinois, United States of America.
22
Department of Medicine, Loyola School of Medicine, Maywood, Illinois, United States of America.
23
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
24
Heidelberg University and Synlab Academy, University of Graz, Graz, Austria.
25
Department of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
26
Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg, Russia, and Oceanographic Center, Nova Southeastern University, Ft. Lauderdale, Florida, United States of America.
27
Department of Medicine, University of California, Irvine, Irvine, California, United States of America.
28
Departments of Paediatrics and Medicine, Hospital for Sick Children, University Health Network and the University of Toronto, Toronto, Ontario, Canada.
29
Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America.
30
National Institute of Diabetes and Digestive Disease, National Institutes of Health, Bethesda, Maryland, United States of America.
31
Center for Research on Genomics and Global Health, Bethesda, Maryland, United States of America.
32
Departments of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
33
Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Davis, California, United States of America.
34
Department of Biochemistry & Molecular Biology, University of New Mexico, Albuquerque, New Mexico, United States of America.
35
Joslin Diabetes Center, Section on Genetics and Epidemiology, Boston, Massachusetts, United States of America.
36
National Human Genome Research Institute, Rockville, Maryland, United States of America.
37
Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas, United States of America.
38
Nephrology, University of Alabama Birmingham, Birmingham, Alabama, United States of America.
39
Department of Medicine, Division of Nephrology, University Hospital Würzburg, Würzburg, Germany.
40
Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
41
Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America.

Abstract

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.

PMID:
26305897
PMCID:
PMC4549309
DOI:
10.1371/journal.pgen.1005352
[Indexed for MEDLINE]
Free PMC Article

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