Impact of Genetic Polymorphism of methylenetetrahydrofolate reductase C677T on Development of Hyperhomocysteinemia and Related Oxidative Changes in Egyptian β-Thalassemia Major Patients

Abstract

Backgroundβ-thalasemia major (β-TM) patients often suffer from various vascular complications together with increased oxidative stress. Hyperhomocysteinemia (Hhcy) has been defined as a risk factor for these complications. Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to cause Hhcy particularly in individuals with low B-vitamins. However, the status of homocysteine (hcy) in β-TM has not yet been adequately defined.AimTo evaluate the genetic polymorphism of MTHFR C677T among β-TM patients and its prospective contribution to Hhcy and related oxidative changes.Subjects and MethodsGenotyping for MTHFR C677T was done by PCR-RFLP technique. Plasma hcy, vitamin B12, folate, malondialdehyde (MDA), total antioxidant capacity (TAC), oxidized low density lipoprotein (oxLDL), total nitric oxide (NOx) and lipid profile were determined in 66 β-TM patients and 66 control subjects of matched age and sex.ResultsThe prevalence of MTHFR 677TT genotype was significant among β-TM patients (12%) compared to (3%) controls (OR = 4.9, 95%CI:1.2–24.2,P = 0.03). A strong association between Hhcy and MTHFR TT genotype was observed (OR = 7.7, 95%CI:2.8–20.9) where all β-TM patients with TT genotype were hyperhomocystienemic (≥ 15 μmol/l) and having sub-optimal folate level than those with CT or CC genotypes. Hyperhomocystienemic patients have suffered from increased oxidative stress characterized by significant increase in plasma MDA and oxLDL, and a significant reduction of plasma TAC and total NOx. Lipid profile of those patients was severely affected indicated by reduction in HDL and HDL/LDL and elevation in atherogenic index as compared with CC genotype. Other measured parameters were not significantly different among β-TM patients with different MTHFR genotypes.ConclusionThis study suggests that Egyptian β-TM patients with MTHFR 677TT genotype could be at increasing risk of developing Hhcy particularly with folate deficiency. This state of Hhcy may account potentially for most oxidative changes and atherogenic vascular complications frequently reported in β-TM patients.

MTHFR (C677T, A1298C) and MTRR (A66G) polymorphisms associated with the risk of megaloblastic anemia in China

“…Vitamin B12 and MCV levels were also higher in GG and AG genotypes than in AA genotype. Recent studies had shown that MTHFR 677TT genotype is associated with high Hcy and low folic acid concentrations in β-thalassemia patients [18], and Li concluded that C667T, A1298C, and A66G polymorphisms could elevate the risk of folate deficiency [19]. Lin also reported MA patients with vitamin B12 deficiency and MTHFR (C667T) mutation [20] which was consistent with our results.…”

Food Intervention with Folate Reduces TNF-α and Interleukin Levels in Overweight and Obese Women with the MTHFR C677T Polymorphism: A Randomized Trial

“…For all these reasons, we suggest an antioxidant-rich diet for young women with MTHFR C677T polymorphism. It provides essential nutrients like folate, an important vitamin in the regulation of inflammatory response, cell damage, DNA repair, antioxidant capacity (CAT), Hcy levels, and stability of the MTHFR enzyme [3,16,55,[78][79][80]. Considering that nutrigenetics explains the interaction of gene-nutrients [81,82], our results corroborate with several studies that have reported the importance of personalized nutritional intervention reducing C677T polymorphism effects and preventing many diseases [15,17,27,[83][84][85].…”

Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis

“…A large number of studies have investigated the association between the rs1801133 polymorphism and CAD risk, as well as the underlying mechanisms, but most of them just focused on homosysteine. It was widely reported that the rs1801133 polymorphism influences the plasma levels of homosysteine in various populations such as Americans [ 25 ], Africans [ 17 , 26 , 27 ], Asians [ 18 , 28 , 29 ], Turkish [ 30 , 31 ] and Brazilians [ 32 ]. In methionine cycle, homocysteine is formed after the removal of adenosine from S-adenosine homocysteine.…”

“…A large number of studies have investigated the associations of the rs1801133 polymorphism with CAD and lipid levels. In some of these studies, the T allele of the rs1801133 polymorphism was reported to be associated with an increased risk of CAD [ 10 – 12 ] and elevated levels of TG [ 13 , 14 ], TC [ 13 – 15 ] and LDL-C [ 13 – 16 ], and reduced levels of HDL-C [ 13 , 17 ]. However, the results obtained from other studies did not support these findings [ 18 – 22 ].…”