Interaction of MTHFR 1298C with ACE D allele augments the risk of diabetic nephropathy in Western Iran

DNA Cell Biol. 2012 Apr;31(4):553-9. doi: 10.1089/dna.2011.1364. Epub 2011 Sep 23.


The aim of the current study was to examine the influence of interaction between polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C with angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism on the risk of diabetic nephropathy (DN). In a case control study using polymerase chain reaction (PCR)- and PCR-restriction fragment length polymorphism (RFLP), the presence of three polymorphisms in 140 patients with type 2 diabetes mellitus (T2DM) with nephropathy including patients with micro- and macro-albuminuria and 72 patients with normoalbuminuria from Western Iran were investigated. In the presence of both MTHFR 677 T and ACE D alleles, there was a trend toward increased risk of DN 2.68-fold (p=0.054). The possession of both MTHFR 677 T and ACE D alleles increased the risk of macro-albuminuria four times (p=0.035). The concomitant presence of both MTHFR 1298 C and ACE D alleles increased the risk of macro-albuminuria 7.8-fold (p=0.012). In addition, the risk of progression from micro- to macro-albuminuria in the presence of both alleles tended to be increased (4.1-fold, p=0.09). Our study for the first time demonstrated a synergistic effect between ACE I/D with either MTHFR C677T or A1298C polymorphism on the increased risk of DN among patients with T2DM. We found that MTHFR 1298 C strongly interacts with the ACE D allele and augments the risk of DN in our population.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / epidemiology
  • Albuminuria / genetics*
  • DNA Primers / genetics
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Nephropathies / epidemiology
  • Diabetic Nephropathies / genetics*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Iran / epidemiology
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Middle Aged
  • Odds Ratio
  • Peptidyl-Dipeptidase A / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics*
  • Polymorphism, Restriction Fragment Length
  • Risk Factors


  • DNA Primers
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • ACE protein, human
  • Peptidyl-Dipeptidase A