Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients

Abstract

Hyperhomocysteinemia is frequent in hemodialysis patients and represents an independent risk factor for vascular disease in these patients. Elevated total homocysteine (tHcy) plasma levels can results from defective remethylation of Hcy to methionine due to decreased activity of the enzyme methylenetetrahydrofolate reductase (MTHFR). A genetic aberration in the MTHFR gene (677 C to T substitution) has been shown to result in reduced MTHFR activity. We tested the hypothesis that elevation of tHcy plasma levels in hemodialysis patients is influenced by the 677 C to T mutation of the MTHFR gene and examined the relation of the genotype with tHcy, folate and vitamin B12 plasma levels in these patients. The allelic frequency of the MTHFR mutation was evaluated in 203 patients maintained on chronic hemodialysis treatment. Total Hcy, folate, vitamin B12 levels and the MTHFR mutation were analyzed in 69 of the 203 patients and in 69 age- and sex-matched healthy control subjects. The allelic frequency of the 677 C to T transition in the MTHFR gene in hemodialysis patients was 34.7% versus 35.5% in healthy controls. Of 203 patients 26 (12.8%) were homozygous for the mutation (+/+) versus 10.2% in healthy subjects. The heterozygous (+/-) genotype was identified in 43.8% of patients versus 50.7% in controls. The mean tHcy level in hemodialysis patients was 28.7 +/- 11.0 mumol/liter versus 10.0 +/- 3.0 mumol/liter in control subjects. The mean tHcy levels were 36.4 +/- 13.4 mumol/liter in (+/+) patients and 12.2 +/- 4.5 mumol/liter in (+/+) controls, 28.7 +/- 10.8 mumol/liter in (+/-) patients and 9.9 +/- 2.7 mumol/liter in (+/-) controls and 25.4 +/- 8.5 mumol/liter in (-/-) hemodialysis patients versus 9.7 +/- 2.8 mumol/liter in (-/-) controls: There was no significant difference of folate and vitamin B12 concentrations in patients and controls with different MTHFR genotypes. Analysis of covariance including age, gender, folate concentrations, vitamin B12 levels, albumin and creatinine as covariables revealed a significant influence of the (+/+) genotype, albumin and folate status on tHcy levels in hemodialysis patients. Together, our data demonstrate that the extent of hyperhomocysteinemia in hemodialysis patients is not only the result of uremia or folate status, but is also genetically determined by the (+/+) MTHFR genotype. The presence of the 677 C to T mutation in the MTHFR gene does not appear to represent a risk factor for development of end-stage renal disease.

Homocysteine-lowering therapy does not lead to reduction in cardiovascular outcomes in chronic kidney disease patients: a meta-analysis of randomised, controlled trials

“…However, it could not be observed in other studies (31,32) , since Hcy concentration decreased in all genotypes. Another confounding factor that could affect the outcomes of Hcy-lowering therapy among patients on dialysis might be the dialysis procedure and membrane pore size.…”

Effects of Folic Acid Before and After Vitamin B12 on Plasma Homocysteine Concentrations in Hemodialysis Patients with Known MTHFR Genotypes

“…In individuals with healthy renal function, the T/T genotype causes only a 25% increase in tHcy concentration compared with persons with other genotypes (6 ), but in patients with end-stage renal disease undergoing maintenance dialysis, the T/T genotype causes a 40% to 100% increase in tHcy (7 ).…”

“…Further studies demonstrated that the C/C genotype matched with low LPH-specific mRNA expression and low lactase activity in intestinal biopsies, suggesting primary adult hypolactasia, whereas the genotypes C/T and T/T matched with high LPH-specific mRNA expression and high lactase activity, strongly suggesting lactase persistence (7)(8)(9)(10)(11). A second described SNP, LPH G3 A Ϫ22018 , is thought to be only in linkage disequilibrium with the SNP C3 T Ϫ13910 (11 ).…”

“…A single-nucleotide polymorphism (SNP) upstream of the LPH gene at position Ϫ13910 (C3 T Ϫ13910 ) was reported to perfectly match with phenotypic hypolactasia and lactose malabsorption for the C/C genotype (7 ). Further studies demonstrated that the C/C genotype matched with low LPH-specific mRNA expression and low lactase activity in intestinal biopsies, suggesting primary adult hypolactasia, whereas the genotypes C/T and T/T matched with high LPH-specific mRNA expression and high lactase activity, strongly suggesting lactase persistence (7)(8)(9)(10)(11).…”

Maintenance of activities of daily living despite risk from genetic polymorphism in hemodialysis patients under nutritional management who survived an average of 30 years

“…The serum Hcy level was higher in patients with TT genotype than in those with other genotypes, and the relationship between Hcy and genotype was stronger in the low folate intake [9]. The frequency of the TT genotype was 13.7 % in a study of hemodialysis patients, and it was higher (23.8 %) in patients with a cardiovascular disorder, showing that the MTHFR polymorphism is an important factor that influences the serum Hcy level [10,11]. However, there have been only a few studies of Japanese patient with renal failure and hemodialysis patients, and the MTHFR C677T polymorphism has not been investigated in longterm hemodialysis patients.…”