Methylenetetrahydrofolate-reductase gene C677T variant and kidney-transplant survival

Autor: Gerd Offermann, O Liangos, Arya M. Sharma, Joachim Beige, Reinhold Kreutz, Armin Distler
Rok vydání: 1998
Předmět:
Zdroj: Nephrology Dialysis Transplantation. 13:2351-2354
ISSN: 1460-2385
DOI: 10.1093/ndt/13.9.2351
Popis: Background. Hyperhomocysteinaemia, a risk factor for atherosclerosis, is common in haemodialysis and cular disease renal-transplant patients. As atherosclerotic lesions in hyperhomocysteinaemia resemble those of chronic allograft injury, we examined the hypothesis that the Introduction C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene, which is linked to elevated plasma Chronic allograft rejection, characterized by progresshomocysteine levels in patients with renal failure, deter- ive loss of function and sclerotic vascular lesions in mines renal allograft survival. the transplant biopsy, is the most important determinMethods. DNA was prospectively collected from 336 ant of long-term kidney transplant survival [1,2]. patients undergoing renal transplantation in our clinic Furthermore, cardiovascular morbidity in renalbetween 1988 and 1994 and their corresponding allograft recipients is high and remains the leading donors. Patient and allograft survival was analysed by cause of premature mortality in these patients [3,4]. It blinded review of all case records over a follow-up has been known for nearly two decades that homocystperiod of 36 months. Additionally, we recruited 83 eine (Hcy), a small sulphur-containing amino acid, is patients surviving with a functional kidney allograft markedly elevated in patients on maintenance haemofor at least 10 years (mean: 156, range 120‐240 dialysis [5] and in renal transplant recipients [6 ]. months). MTHFR-C677T genotype was determined by Recently, hyperhomocysteinaemia has been implicated a PCR-RFLP technique. The influence of genotype on as an independent risk factor for the development of transplant survival was analysed by Kaplan‐Meyer atherosclerotic lesions both in patients with normal life-table analysis and two-tailed global log-rank [7,8] and impaired renal function [9,10]. Interestingly, testing. the vascular lesions found in patients suVering from Results. Frequency of the MTHFR-C677T allele in the homocysteinuria or other conditions with elevated cohort group was identical in recipients (0.35) and plasma Hcy are characterized by fibromuscular thickdonors (0.34), and comparable to that in the long- ening of small arterial vessels [11] and resemble those term allograft survivors (0.37). Furthermore, life-table found in chronic allograft injury [1,12,13]. Clearly this analysis revealed a similar allograft survival over 36 raises the question of whether elevated plasma Hcy months between the genotype groups (CC 74%, CT adversely influences long-term renal graft survival by 69%, TT 75%). Other risk factors including donor and promoting vascular sclerosis in the kidney allograft. recipient age, hypertension, body-mass index, and In 1995, a common genetic variant of the number of rejection therapies were evenly distributed gene encoding for methylenetetrahydrofolate-reductase between the diVerent genotype groups. (MTHFR), a cytosolic flavoprotein involved in the Conclusions. These findings do not support the enzymatic remethylation and therefore elimination of hypothesis that the C677T variant of the MTHFR Hcy, was described [14]. This variant, consisting of a gene is an important determinant of renal-transplant cytosine (C ) to thymidine ( T ) transition at nucleotide survival. position 677 leading to the exchange of a highly conserved alanine to valine in the mature protein, has been associated with reduced activity and increased
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