title: The association of genetic variants of type 2 diabetes with kidney function.
abstract: Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations.
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. noraf@unc.edu
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Nawar M
authors.initials: NM
authors.lastname: Shara
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: V Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.forename: Sandy
authors.initials: S
authors.lastname: Laston
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Elisa T
authors.initials: ET
authors.lastname: Lee
authors.forename: Lyle G
authors.initials: LG
authors.lastname: Best
authors.forename: Jean W
authors.initials: JW
authors.lastname: Maccluer
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Cochran
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Barbara V
authors.initials: BV
authors.lastname: Howard
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Jason G
authors.initials: JG
authors.lastname: Umans
mesh_terms: D017668:Age of Onset; D000368:Aged; D000419:Albuminuria / Q000235:genetics / Q000503:physiopathology; D015415:Biomarkers / Q000652:urine; D003404:Creatinine / Q000652:urine; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D016014:Linear Models; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; C114987:wolframin protein; D003404:Creatinine