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NDT Advance Access published online on January 5, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl717
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans

Barry I. Freedman1, Pamela J. Hicks2, Michele M. Sale1,3, Eric D. Pierson1, Carl D. Langefeld4, Stephen S. Rich4, Jianzhao Xu4, Caitrin McDonough2, Bart Janssen5, Benito A. Yard6, Fokko J. van der Woude6 and Donald W. Bowden1–3

1Department of Internal Medicine, 2Department of Biochemistry, 3Center for Human Genomics and 4Center for Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA, 5Institute of Human Genetics Heidelberg, and 6Fifth Medical Department, University Clinic Klinikum, Mannheim, Germany

Correspondence and offprint requests to: Barry I. Freedman, MD, Department of Internal Medicine, Section on Nephrology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1053, USA. Email: bfreedma{at}wfubmc.edu



  Abstract

Background. Four linkage analyses have identified a region on chromosome 18q22-23 that appears to harbour a diabetic nephropathy (DN) susceptibility locus. A trinucleotide repeat sequence in exon 2 of the carnosinase gene (CNDP1) residing on 18q22.3 was subsequently associated with DN in European Caucasians and Arabs.

Methods. We evaluated the role of the CNDP1 5 leucine/5 leucine (5-5) polymorphism (CNDP1 Mannheim) in diabetic end-stage renal disease (ESRD) susceptibility in 858 European Americans: 294 with type 2 DN-associated ESRD (DN-ESRD), 258 with diabetes mellitus (DM) lacking nephropathy and 306 healthy controls.

Results. Subjects with DM lacking nephropathy were significantly more likely to be homozygous for the 5-leucine repeat CNDP1 genotype (5-5), compared with those with DN–ESRD (P = 0.02). Healthy controls were also more likely to be homozygous for the 5-5 genotype, compared with those with DN–ESRD (P = 0.008). No significant difference in 5-5 genotype frequency was observed between healthy controls and DM cases without nephropathy (P = 0.74).

Conclusion. European Americans homozygous for the 5-5 leucine repeat polymorphism in the CNDP1 gene are at significantly reduced risk for developing diabetic ESRD. This replicates the CNDP1 gene association with DN that was initially detected in European Caucasians and in Arabs, and further demonstrates that the CNDP1 gene and carnosine pathway appear to play a role in susceptibility to DN.

Keywords: carnosinase; carnosine; diabetic nephropathy; end-stage renal disease; European Americans; genetics


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