polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus

• Published in: Diabetologia Vol. 53; no. 12; pp. 2562 - 2568
• Main Authors: Alkhalaf, A, Bakker, S. J. L, Bilo, H. J. G, Gans, R. O. B, Navis, G. J, Postmus, D, Forsblom, C, Groop, P. H, Vionnet, N, Hadjadj, S, Marre, M, Parving, H. H, Rossing, P, Tarnow, L
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.12.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Adult; Associated diseases and complications; Biological and medical sciences; Carnosinase gene; Case-Control Studies; CNDP1; Cross-sectional studies; Diabetes; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - mortality; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - diagnosis; Diabetic Nephropathies - genetics; Diabetic Nephropathies - mortality; Diabetic nephropathy; Dipeptidases - genetics; Disease Progression; End-stage renal disease; Endocrine pancreas. Apud cells (diseases); Endocrinology; Endocrinopathies; Epidemiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; European Continental Ancestry Group - genetics; Female; Five leucine repeat; Follow-Up Studies; Genetic Predisposition to Disease; Health risk assessment; Human Physiology; Humans; insulin-dependent diabetes mellitus; Internal Medicine; Kidney diseases; Kidney Failure, Chronic - diagnosis; Kidney Failure, Chronic - etiology; Kidney Failure, Chronic - genetics; Kidney Failure, Chronic - mortality; Kidneys; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Middle Aged; Mortality; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Polymorphism; Polymorphism, Single Nucleotide - physiology; Prognosis; Renal failure; Survival Analysis; Urinary system involvement in other diseases. Miscellaneous; Denmark; Netherlands; France; Aarhus Denmark; Paris France; Finland; Five leucine repeat; End-stage renal disease; Diabetic nephropathy; Carnosinase gene; Type 1 diabetes; Endocrinopathy; Kidney disease; Immunopathology; Urinary system disease; Chronic renal failure; Mortality; Autoimmune disease; Leucine; CNDP1; Concomitant disease; Gene; Aminoacid; Polymorphism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1863-0

Aims/hypothesis Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). Methods In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria <30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation. Results The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03). Conclusions/interpretation CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.