title: TCF7L2 variants associate with CKD progression and renal function in population-based cohorts.
abstract: Genetic variants may increase susceptibility to both diabetes and kidney disease. Whether known diabetes-associated variants in the transcription factor 7-like 2 (TCF7L2) gene are associated with chronic kidney disease (CKD) progression and markers of kidney function is unknown. Participants of the Atherosclerosis Risk in Communities Study (ARIC; n = 11,061 self-identified white and n = 4014 black), Framingham Heart Offspring Cohort (FHS; n = 2468), and Heredity and Phenotype Intervention Heart Study (HAPI; n = 861) were genotyped at five (ARIC) and two (FHS) common TCF7L2 variants. The diabetes-conferring risk alleles at rs7903146 and rs7901695 were significantly associated with CKD progression among ARIC participants overall and among those without baseline diabetes. The overall adjusted hazard ratios per rs7903146 T allele were 1.17 (95% confidence interval [CI] 1.04 to 1.32) for white individuals and 1.20 (95% CI 1.03 to 1.41) for black individuals. Similarly, the overall hazard ratios per rs7901695 C allele were 1.19 (95% CI 1.06 to 1.34) for white individuals and 1.27 (95% CI 1.09 to 1.48) for black individuals. The FHS cohort supported these results: The rs7903146 T allele was significantly associated with lower estimated GFR (P = 0.01) and higher cystatin C (P = 0.004) in adjusted analyses overall and among those without diabetes. In the HAPI cohort, the rs7901695 C allele was significantly associated with lower estimated GFR in adjusted analyses (P = 0.049), as were several variants upstream and downstream of TCF7L2 (P < 0.003). No identified variant in the ARIC or FHS cohorts was associated with albuminuria. In conclusion, several population-based samples suggest that variants in the TCF7L2 gene are associated with reduced kidney function or CKD progression, overall and specifically among participants without diabetes.
authors.affiliation: Department of Epidemiology and Welch Center for Prevention, Epidemiology & Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Evadnie
authors.initials: E
authors.lastname: Rampersaud
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Afshin
authors.initials: A
authors.lastname: Parsa
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
mesh_terms: D000328:Adult; D000368:Aged; D002908:Chronic Disease; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
chemical_list: D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein