Interaction ofMTHFR1298C withACED Allele Augments the Risk of Diabetic Nephropathy in Western Iran

Abstract

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.

ACE insertion/deletion (I/D) polymorphism and diabetic nephropathy

“…DN is manifested with microalbuminuria that subsequently can progress to macroalbuminuria (13,14). The ACE is a key component of renin angiotensin system (RAS) that plays an important role in blood pressure homeostasis by generating the vasoconstrictor peptide angiotensin II and by inactivating the vasodilator peptides bradykinin and angiotensin (1)(2)(3)(4)(5)(6)(7)15). ACE regulates microcirculation within the kidney through generating angiotensin II and in the presence of ACE D allele, the GFR increases in correlation with ACE plasma levels (1,16).…”

“…The association between concomitant presence of ACE I/D polymorphism with either MTHFR C677T or A1298C polymorphism and increased risk of DN among patients with T2DM has been demonstrated and has suggested a strong interaction between MTHFR 1298 C allele and the ACE D allele with highly increased risk of DN (1). It seems the presence of variations in more genes instead of a single genetic defect play a role in the susceptibility to DN.…”

Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Variants, Folate Intake, and Susceptibility to Breast Cancer

“…MTHFR is a key enzyme that catalyzes the remethylation of homocysteine to methionine through conversion of 5, 10-methylenetetrahydrofolate (5, 10-MTHF) to 5-methyltrahydrofolate (5-MTHF) (15). This enzyme plays a key role in the equilibrium of methyl group sources for DNA methylation and DNA synthesis (16).…”

“…This point mutation in the MTHFR gene might affect the enzyme regulation since the activity of the enzyme decreases in the presence of this mutation (15).…”

Angiotensin-converting enzyme insertion/deletion polymorphism associated with allergic rhinitis susceptibility: Evidence from 1410 subjects

“…15,16 ACE I/D polymorphism which plays a critical role in regulating ACE protein expression and is crucial in atopy, may influence the strength of immunological response and has been reported to be associated with atopic disorders, inflammatory diseases and cancers. [17][18][19][20][21][22] To date, a series of studies have focused on the relation between ACE I/D polymorphism and AR risk. [23][24][25][26][27][28] Nevertheless, the results were inconclusive and inconsistent.…”