title: Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study.
abstract: The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold ofP<1×10-6for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 inLINC00923replicated in the African American Study of Kidney Disease and Hypertension cohort (discoveryP=5.42×10-7; replicationP=0.039; combinedP=7.42×10-9). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7);P=4.90×10-6). Similarly, rs931891 inLINC00923associated with eGFR decline (P=1.44×10-4) in white patients without diabetes. In summary, SNPs inLINC00923, an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted.
authors.affiliation: Division of Nephrology and aparsa@medicine.umaryland.edu.|Department of Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Afshin
authors.initials: A
authors.lastname: Parsa
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.affiliation: Department of Biostatistics and Epidemiology and.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Department of Health Sciences, College of Health Professions and Social Work, Florida Gulf Coast University, Fort Myers, FL.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Gupta
authors.affiliation: Department of Biostatistics and Epidemiology and.
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
authors.affiliation: Molecular Genetic Epidemiology Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute and Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Limou
authors.affiliation: Department of Biostatistics and Epidemiology and.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xie
authors.affiliation: Departments of Medicine and.
authors.forename: Huichun
authors.initials: H
authors.lastname: Xu
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Amanda Hyre
authors.initials: AH
authors.lastname: Anderson
authors.affiliation: Division of Nephrology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Akinlolu
authors.initials: A
authors.lastname: Ojo
authors.affiliation: Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: John W
authors.initials: JW
authors.lastname: Kusek
authors.affiliation: Department of Medicine, Division of Nephrology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Lora
authors.affiliation: Department of Medicine, Section of Nephrology, Tulane University, New Orleans, Louisiana.
authors.forename: L Lee
authors.initials: LL
authors.lastname: Hamm
authors.affiliation: Department of Medicine, Section of Nephrology, Tulane University, New Orleans, Louisiana.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.affiliation: Department of Medicine, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine Mount Sinai, New York, New York.
authors.forename: Janina
authors.initials: J
authors.lastname: Jeff
authors.affiliation: Department of Medicine, The George Washington University School of Medicine, Washington, DC.
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Raj
authors.affiliation: Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Böger
authors.affiliation: Department of Medicine, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine Mount Sinai, New York, New York.
authors.forename: Erwin
authors.initials: E
authors.lastname: Bottinger
authors.affiliation: Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Salimi
authors.affiliation: Division of Nephrology, Department of Pediatrics and Medicine, Hospital for Sick Children, University Health Network and the University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rulan S
authors.initials: RS
authors.lastname: Parekh
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Harbor-University of California, Los Angeles Medical Center, Los Angeles, California.
authors.forename: Sharon G
authors.initials: SG
authors.lastname: Adler
authors.affiliation: Departments of Biostatistical Sciences and.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Biochemistry and.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.|Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Department of Medicine, Georgetown University Medical Center, Washington, DC; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Lipkowitz
authors.affiliation: Division of Intramural Research, National Heart, Lung and Blood Institute's Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.affiliation: Department of Biostatistics and Epidemiology and.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Harold I
authors.initials: HI
authors.lastname: Feldman
mesh_terms: D044383:Black People / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000235:genetics*; D044465:White People / Q000235:genetics*; D001741:Black or African American
keywords: chronic kidney disease; human genetics; polymorphisms; progression of chronic renal failure