Transketolase (TKT) gene variability as a potencial susceptibility factor for diabetic nephropathy

PÁCAL, Lukáš, Andrea STEJSKALOVÁ, Veronika TANHÄUSEROVÁ and Kateřina KAŇKOVÁ. Transketolase (TKT) gene variability as a potencial susceptibility factor for diabetic nephropathy. In 20th Annual Meeting Edinburgh, Scotland, May 11 - 12, 2007. 2007.

Basic information

• Original name: Transketolase (TKT) gene variability as a potencial susceptibility factor for diabetic nephropathy
• Name in Czech: Transketolase (TKT) gene variability as a potencial susceptibility factor for diabetic nephropathy
• Authors: PÁCAL, Lukáš (203 Czech Republic, guarantor), Andrea STEJSKALOVÁ (203 Czech Republic), Veronika TANHÄUSEROVÁ (203 Czech Republic) and Kateřina KAŇKOVÁ (203 Czech Republic).
• Edition: 20th Annual Meeting Edinburgh, Scotland, May 11 - 12, 2007, 2007.

Other information

• Original language: English
• Type of outcome: Conference abstract
• Field of Study: 30202 Endocrinology and metabolism
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• RIV identification code: RIV/00216224:14110/07:00019057
• Organization unit: Faculty of Medicine
• Keywords in English: transketolase; polymorphism; diabetic nephropathy
• Tags: diabetic nephropathy, polymorphism, transketolase
• Tags: International impact, Reviewed

Abstract

Objective: Accumulation of proximal glycolytic intermediates - due to the allosteric inhibition of enzymes, changed NADH/NAD+ ratio and modification of the glycolytic enzyme glyceraldehyd-3-phosphate dehydrogenase provides substrates for the metabolic pathways plays contributing to the pathogenesis of diabetic complications (such as formation of Advanced Glycation End-products (AGEs), polyols, hexosamines etc.). Pentose phosphate pathway (PPP) represents potentially "protective" mechanism in hyperglycemia since shunting of cumulated glycolytic intermediates (esp. triosephosphates) into the PPP reactions supposedly "disburdens" glycolysis and quantitatively limits processing of glycolytic intermediates in the alternative metabolic pathways. We hypothesized that genetic variability in the rate-limiting enzyme of the PPP non-oxidative branch - transketolase - contributes to an interindividual variability in the onset and progression of diabetic nephropathy (DN). Subjects and Methods: Study comprised 421 subjects (204 DM non-DN and 217 DM+DN subjects) In the first phase, SNPs with MAF >10% in the Caucasian population were selected with the density 1 per haplotype block (htSNPs) in the TKT gene (MIM no. 606781, chrom. 3p14.3). In pilot experiments those with high pair-wise LD were excluded, remaining 6 SNPs (rs2279323, rs3736156, rs1051483, rs12487632, rs968702 and rs13101181) to be genotyped in the whole study sample. SNPs were detected by means of polymerase chain reaction (PCR) using fluorescent-labelled probes (TaqMan, Applied Biosystems). Haplotypes were constructed based on genotype data using Bayesian algorithm (PHASE). Differences in haplotype frequencies between the groups will be tested by permutation testing. Logistic regression (incl. input variables such as age and gender, DM duration, fasting glycemia, HbA1c, microalbuminuria, proteinuria and GFR), survival analysis (Kaplan-Meier) and Cox proportional hazard regression were used to assess the risk of disease-associated haplotypes. Conclusions: Results suggest that TKT variability might play a role in the individual susceptibility to the development of DN.

Abstract (in Czech)

Objective: Accumulation of proximal glycolytic intermediates - due to the allosteric inhibition of enzymes, changed NADH/NAD+ ratio and modification of the glycolytic enzyme glyceraldehyd-3-phosphate dehydrogenase provides substrates for the metabolic pathways plays contributing to the pathogenesis of diabetic complications (such as formation of Advanced Glycation End-products (AGEs), polyols, hexosamines etc.). Pentose phosphate pathway (PPP) represents potentially "protective" mechanism in hyperglycemia since shunting of cumulated glycolytic intermediates (esp. triosephosphates) into the PPP reactions supposedly "disburdens" glycolysis and quantitatively limits processing of glycolytic intermediates in the alternative metabolic pathways. We hypothesized that genetic variability in the rate-limiting enzyme of the PPP non-oxidative branch - transketolase - contributes to an interindividual variability in the onset and progression of diabetic nephropathy (DN). Subjects and Methods: Study comprised 421 subjects (204 DM non-DN and 217 DM+DN subjects) In the first phase, SNPs with MAF >10% in the Caucasian population were selected with the density 1 per haplotype block (htSNPs) in the TKT gene (MIM no. 606781, chrom. 3p14.3). In pilot experiments those with high pair-wise LD were excluded, remaining 6 SNPs (rs2279323, rs3736156, rs1051483, rs12487632, rs968702 and rs13101181) to be genotyped in the whole study sample. SNPs were detected by means of polymerase chain reaction (PCR) using fluorescent-labelled probes (TaqMan, Applied Biosystems). Haplotypes were constructed based on genotype data using Bayesian algorithm (PHASE). Differences in haplotype frequencies between the groups will be tested by permutation testing. Logistic regression (incl. input variables such as age and gender, DM duration, fasting glycemia, HbA1c, microalbuminuria, proteinuria and GFR), survival analysis (Kaplan-Meier) and Cox proportional hazard regression were used to assess the risk of disease-associated haplotypes. Conclusions: Results suggest that TKT variability might play a role in the individual susceptibility to the development of DN.

Links

• NR9443, research and development project: Name: Genetická variabilita enzymů pentózového cyklu jako faktor modulující nástup a progresi diabetické nefropatie

Investor: Ministry of Health of the CR, Genetic variability of pentose phosphate pathway as a modulating factor of the onset and progression of diabetic nephropathy