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Published online September 19, 2007
Diabetes 56:3027-3032, 2007
DOI: 10.2337/db07-0675
© 2007 by the American Diabetes Association
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Variants in the Plasmacytoma Variant Translocation Gene (PVT1) Are Associated With End-Stage Renal Disease Attributed to Type 1 Diabetes

Meredith P. Millis, Danielle Bowen, Christopher Kingsley, Richard M. Watanabe, and Johanna K. Wolford

From the Translational Genomics Research Institute, Phoenix, Arizona

Address correspondence and reprint requests to Johanna K. Wolford, PhD, Translational Genomics Research Institute, 445 North Fifth St., Phoenix, AZ 85004. E-mail: jwolford{at}tgen.org

Abbreviations: ACR, albumin-to-creatinine ratio; ACTB, ß-actin; CEC, cortical epithelial cell; ESRD, end-stage renal disease; GoKinD, Genetics of Kidneys in Diabetes; PTEC, proximal tubule epithelial cell; SNP, single nucleotide polymorphism; tv6, transcript variant 6

OBJECTIVE— End-stage renal disease (ESRD) attributed to diabetes is strongly dependent on genetic factors. We previously reported association between variants in the plasmacytoma variant translocation gene (PVT1) and ESRD attributed to type 2 diabetes in Pima Indians. The objective of this study was to evaluate the extent to which these variants mediate susceptibility in other populations.

RESEARCH DESIGN AND METHODS— We genotyped 24 markers showing the strongest evidence for association in Pima Indians in unrelated Caucasians with type 1 diabetes from the Genetics of Kidneys in Diabetes (GoKinD) study. The study sample was comprised of 531 case subjects with ESRD and 564 control subjects with diabetes duration >20 years and a maximum urinary albumin-to-creatinine ratio <150 mg/g.

RESULTS— Markers rs13447075 (odds ratio [OR] 1.47 [95% CI 1.14–1.89] per copy of A allele; P = 0.003) and rs2648862 (2.66 [1.19–5.92] per copy of C allele; P = 0.008) were strongly associated with ESRD in analyses adjusting for age2, age3, duration of diabetes, and smoking status. We further identified a common haplotype containing the C allele at rs10808565 and the A allele at rs13447075 that was associated with ESRD (P = 0.003). PVT1 gene expression yields several isoforms, and rs13447075 is located within the coding region of one of these transcript variants. We identified expression of this isoform in four major human kidney cell types, including mesangial, cortical epithelial, epithelial, and proximal tubule cells.

CONCLUSIONS— These results are the first to provide confirmatory evidence supporting a role for PVT1 in mediating susceptibility to ESRD attributable to diabetes.


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