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TCF7L2 Variants Associate with CKD Progression and Renal Function in Population-Based Cohorts

Anna Köttgen^*, Shih-Jen Hwang, Evadnie Rampersaud, Josef Coresh^*, Kari E. North, James S. Pankow^||, James B. Meigs^¶, Jose C. Florez^¶,**, Afshin Parsa, Daniel Levy, Eric Boerwinkle, Alan R. Shuldiner^,, Caroline S. Fox^, and W.H. Linda Kao^*

^* Department of Epidemiology and Welch Center for Prevention, Epidemiology & Clinical Research, Johns Hopkins University, Baltimore, Maryland; Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Department of Epidemiology and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina; ^|| Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota; ^¶ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; ^** Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas; Geriatrics Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland; and Division of Endocrinology, Hypertension, and Metabolism, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Correspondence: Dr. Caroline S. Fox, National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702; Phone: 508-935-3447; Fax: 508-626-1262; E-mail: foxca@nhlbi.nih.gov; or Dr. Linda Kao, 615 N. Wolfe Street, Room W6513, Baltimore, MD 21205; Phone: 410-614-0945; Fax: 410-955-0863; E-mail: wkao{at}jhsph.edu

Received for publication December 6, 2007. Accepted for publication April 23, 2008.

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.

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