The CNDP1 (CTG)₅ Polymorphism Is Associated with Biopsy-Proven Diabetic Nephropathy, Time on Hemodialysis, and Diabetes Duration

Abstract

Considering that the homozygous CNDP1 (CTG)5 genotype affords protection against diabetic nephropathy (DN) in female patients with type 2 diabetes, this study assessed if this association remains gender-specific when applying clinical inclusion criteria (CIC-DN) or biopsy proof (BP-DN). Additionally, it assessed if the prevalence of the protective genotype changes with diabetes duration and time on hemodialysis and if this occurs in association with serum carnosinase (CN-1) activity. Whereas the distribution of the (CTG)5 homozygous genotype in the no-DN and CIC-DN patients was comparable, a lower frequency was found in the BP-DN patients, particularly in females. We observed a significant trend towards high frequencies of the (CTG)5 homozygous genotype with increased time on dialysis. This was also observed for diabetes duration but only reached significance when both (CTG)5 homo- and heterozygous patients were included. CN-1 activity negatively correlated with time on hemodialysis and was lower in (CTG)5 homozygous patients. The latter remained significant in female subjects after gender stratification. We confirm the association between the CNDP1 genotype and DN to be likely gender-specific. Although our data also suggest that (CTG)5 homozygous patients may have a survival advantage on dialysis and in diabetes, this hypothesis needs to be confirmed in a prospective cohort study.

Carnosinase concentration, activity, and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy

“…While in the univariate analysis (CTG) 5 homozygosity was significantly associated with low serum CNDP1 concentrations (Table 3, single variable analysis p=0.04) in the multivariate analysis (CTG) 5 homozygosity only reached borderline significance for the association with serum CNDP1 concentrations. The association however becomes significant when analysis is only confined to the hemodialysis patients within this cohort as reported (Albrecht et al 2017). This is consistent with several previous publications (Janssen et al 2005;Everaert et al 2011) and also in line with the notion that the (CTG) n polymorphism in the signal peptide influences the efficacy of CNDP1 secretion (Riedl et al 2007).…”

CNDP1, NOS3, and MnSOD Polymorphisms as Risk Factors for Diabetic Nephropathy among Type 2 Diabetic Patients in Malaysia

“…Diabetic patients with the lowest number of leucine repeats are less susceptible to DN. Individuals with homozygous or heterozygous allele for more than 5 leucine repeats have reduced serum carnosine concentration [27]. Carnosine ( β -alanyl-L-histidine) has been reported to have served as an oxygen-free radical scavenger [28], natural ACE inhibitor, and cleave advanced glycation end product [29, 30].…”

Serum Carnosinase-1 and Albuminuria Rather than theCNDP1Genotype Correlate with Urinary Carnosinase-1 in Diabetic and Nondiabetic Patients with Chronic Kidney Disease

“…We and others have demonstrated that the CNDP1 (CTG) n polymorphism is associated with susceptibility to developing DN in T2DM [11][12][13][14][15]. The shortest allelic form, i.e., the CNDP1 (CTG) 5 or Mannheim allele, is more common in the absence of nephropathy and is associated with low CN-1 enzymatic activities and low serum concentrations [10,11,16]. Nonetheless, it should also be mentioned that other studies failed to demonstrate this association in cohorts of different ethnicities [17,18].…”