Gene polymorphism of methylene tetrahydrofolate reductase and methyltetrahydrofolate homocysteine methyltransferase and its relation to the level of homocysteine and other atherogenic factors in Egyptian thalassemic patients / Mei Ahmed Abdelmawla ; Supervised Amira A. Shaheen , Ilham Youssry Ibrahim , Sherine Maher Rizk

Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Biochemistry

Ý-thalasemia major (Ý-TM) patients often suffer from various vascular complications together with increased oxidative stress. Hyperhomocystienemia (Hhcy) is associated with increased oxidative changes and related vascular disorders. Plasma homocystiene (hcy) levels are determined by genetic and vitamin interactions. Genetic polymorphisms of methylenetetrahydrofolate reductase MTHFR C677T and methyltetrahydrofolate homocysteine methyltransferase MTR A2756G have been shown to cause Hhcy particularly in individuals with low folate. However, the status of hcy in Ý-TM patients has not yet been adequately defined. Therefore the present work was carried out to evaluate the genetic polymorphisms of MTHFR C677T and MTR A2756G among Ý-TM patients and their prospective contribution to Hhcy and related oxidative changes. Genotyping for MTHFR C677T and MTR A2756G were 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 Ý-TM patients and 66 control subjects of matched age and sex. The prevalence of MTHFR 677TT genotype among Ý-TM patients was 12% as compared to 3% in controls where the difference was significant (OR=4.9, P=0.03). The frequency of T allele was significantly higher in Ý-TM than in control (OR=3.3, p=0.003). Plasma hcy was markedly higher in patients with the TT genotype accompanied by sub-optimal folate level than those with CT or CC genotypes of the MTHFR gene. These patients with Hhcy 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 these patients was also perturbed by lowering HDL and HDL/LDL and elevating atherogenic index as compared with CC genotype. Moreover, plasma vitamin B12, total cholesterol, triglycerides and LDL-C were not significantly different among MTHFR genotypes. MTR A2756G gene polymorphism was not seen among Ý-TM patients as well as healthy controls. In conclusion, this study addressed an important role for MTHFR 677TT genotype in development of Hhcy in Ý-TM patients particularly with folate deficiency. It also strongly suggests that the adverse effects of Hhcy are at least partially mediated by oxidative stress. Our study supports the hypothesis that Hhcy may account for the incidence of atherogenic vascular complications often reported in Ý-TM patients. MTR A2756G gene polymorphism does not appear to be a significant genetic risk for Hhcy in Egyptian Ý-TM patients

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