Polymorphism in Methylenetetrahydrofolate Reductase Gene: Its Impact on Plasma Homocysteine Levels and Carotid Atherosclerosis in ESRD Patients Receiving Hemodialysis

Abstract

The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism has been shown to be associated with cardiovascular disease in healthy subjects as well as in patients with end-stage renal disease (ESRD). In this study, we examined the allelic frequency and genotype distribution of the MTHFR gene in 151 Chinese ESRD patients receiving hemodialysis and 135 healthy controls. In addition, we investigated the relationship between the MTHFR gene polymorphism and the plasma homocysteine (Hcy) level as well as the intima-media thickness of common carotid artery (CC-IMT) in these patients. The allelic frequency of the MTHFR gene with the C677T mutation in ESRD patients was 24.5% and that in healthy controls was 23%. Mean plasma Hcy level of the ESRD patients (23.1 ± 7.4 µmol/l) was significantly higher than that of the controls (10.1 ± 5.0 µmol/l), but did not correlate with vitamin B₆ and vitamin B₁₂ status. Moreover, the extent of hyperhomocysteinemia was genetically affected by the C677T mutation of the MTHFR gene. The plasma Hcy levels for the patients with the CC, CT and TT genotypes of the MTHFR gene were 22.3 ± 6.8, 22.8 ± 7.3, and 28.3 ± 2.8 µmol/l, respectively. In addition, we found that the patients bearing the TT genotype had the highest CC-IMT (0.93 ± 0.07 mm), whereas the lowest values (0.79 ± 0.13 mm) were observed in those who had the CC genotype. One-way ANOVA showed that the CC-IMT in the patients with the TT genotype was significantly greater than that of the patients with the CC genotype (p < 0.05). Moreover, the mean CC-IMT of the patients carrying either TT or CT genotype of the MTHFR gene was significantly higher than that of the patients bearing the CC genotype (0.86 ± 0.14 vs. 0.79 ± 0.13 mm, p = 0.002). Multiple regression analysis, in which the change in CC-IMT was used as the dependent variables, identified age, smoking, the MTHFR genotype (CC = 0, CT = 1, TT = 2) and diabetes mellitus as the independent variables significantly associated with the increase of CC-IMT (p < 0.001). These risk factors jointly explained 43.9% of the CC-IMT variation and age explained most of the variation (R² = 0.34). We conclude that both the TT genotype and the T allele of the MTHFR gene are associated with the increase of CC-IMT in hemodialysis patients. The C677T mutation of the MTHFR gene may be an independent risk factor that predicts the development of carotid atherosclerosis in ESRD patients.

Methylenetetrahydrofolate Reductase Gene C677T Polymorphism, Plasma Homocysteine and Folate in End-Stage Renal Disease Dialysis and Non-Dialysis Patients

“…The TDT analysis revealed no significant deviation in the transmission of the MTHFR C677T alleles both in dialyzed and conservatively treated CRF patients, thus suggesting no impact of this polymorphism on the risk of the development of end-stage renal disease. Similar results were obtained in the case-control study of Lim et al [16], where 151 Taiwanese patients on maintenance hemodialysis presented MTHFR genotype distribution similar to 135 healthy subjects. As previously shown in the study of Kimura et al [11], our subpopulation of dialyzed CRF patients carrying TT genotype tended to be younger at time of the study and at initiation of renal replacement therapy (p = 0.06, table 3), also with shorter time from diagnosis of chronic renal failure to the onset of renal replacement therapy (5.5 ± 7.2, 7.0 ± 5.4, 8.2 ± 6.6 years for the TT, CT and CC genotypes, respectively).…”

Prevalence of methylenetetrahydrofolate gene (MTHFR) C677T polymorphism among chronic hemodialysis patients and its association with cardiovascular disease: a cross-sectional analysis

“…Fukasawa et al [22] reported that the MTHFR C677T point mutation could serve as an important indicator for identifying susceptibility to arteriovenous fistulae obstruction in hemodialysis patients. The C677T mutation of the MTHFR gene was found to be an independent risk factor for carotid atherosclerosis in ESRD in one study [23].…”

The relationship of the methylenetetrahydrofolate reductase C677T gene polymorphism in Turkish type 2 diabetic patients with and without nephropathy

“…Hyperhomocysteinemia and diabetes mellitus are both associated with premature vascular disease [9][10][11]. There are several studies concerning the molecular bases of vascular complications related to increased homocysteine levels [11][12][13]. The relationship between homocysteine levels and diabetic complications is still an unresolved issue.…”