title: Genetic variability in enzymes of metabolic pathways conferring protection against non-enzymatic glycation versus diabetes-related morbidity and mortality.
abstract: BACKGROUND
  We hypothesized that genetic variability in genes encoding enzymes metabolizing glycolytic intermediates produced in excess under hyperglycemic conditions [i.e., transketolase (TKT), transaldolase, TKT-like protein 1, fructosamine 3-kinase (FN3K), glyoxalase 1 and glucose-6-phosphate dehydrogenase] could influence progression of diabetic nephropathy (DN) and diabetes-related morbidity and mortality.
  
  
  METHODS
  A total of 19 single nucleotide polymorphisms (SNPs) in six candidate genes were studied in 314 type 2 diabetic subjects with variable stage of kidney disease (normo- and microalbuminuria, proteinuria, end-stage renal disease). SNP selection criteria were based on known functional effect and gene coverage. SNPs were detected using polymerase chain reaction based methods. Subjects were followed up for median of 38 months. Time-to-event analysis considered three end-points: 1) DN progression by at least one stage; 2) major cardiovascular event; and 3) all-cause mortality.
  
  
  RESULTS
  We found combined effect of TKT SNP rs11130362 and FN3K SNP rs1056534 on DN progression (p<0.01). Additionally, TKT rs3736156 alone and also in combination with the previous two SNPs exhibited significant effect on incidence of major cardiovascular events (p<0.01 and p=0.01, respectively).
  
  
  CONCLUSIONS
  Genetic variability in rate-limiting enzymes of pathways proposed to confer hypothetical protection against hyperglycemia might act as an important determinant of hyperglycemia toxicity in long-standing diabetes.
authors.forename: Veronika
authors.initials: V
authors.lastname: Tanhäuserová
authors.forename: Katarína
authors.initials: K
authors.lastname: Kuricová
authors.forename: Lukáš
authors.initials: L
authors.lastname: Pácal
authors.forename: Vendula
authors.initials: V
authors.lastname: Bartáková
authors.forename: Jitka
authors.initials: J
authors.lastname: Rehořová
authors.forename: Jan
authors.initials: J
authors.lastname: Svojanovský
authors.forename: Jindřich
authors.initials: J
authors.lastname: Olšovský
authors.forename: Jana
authors.initials: J
authors.lastname: Bělobrádková
authors.forename: Kateřina
authors.initials: K
authors.lastname: Kaňková
mesh_terms: D000368:Aged; D000483:Alleles; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000209:etiology / Q000401:mortality / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D007674:Kidney Diseases / Q000150:complications; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D014174:Transketolase / Q000235:genetics*
chemical_list: D014174:Transketolase; D017853:Phosphotransferases (Alcohol Group Acceptor); C414347:fructosamine-3-kinase