Effect of the MTHFR C677T and A1298C Polymorphisms on Survival in Patients With Advanced CKD and ESRD: A Prospective Study

Background Abnormalities in the gene regulating methylenetetrahydrofolate reductase (MTHFR) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease (CKD) populations. Study Design Gene association study. Setting & Participants This was a substudy of 677 patients from 21 Veterans Affairs medical centers participating in a randomized clinical trial (Homocysteinemia in Kidney and End-Stage Renal Disease [HOST]) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels. Of 677 patients, 213 (31%) were treated by using dialysis (end-stage renal disease [ESRD]) and 464 (69%) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min (advanced CKD). Predictor Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene. Outcomes Unadjusted and adjusted all-cause mortality. Measurements DNA was extracted from blood samples and amplified by means of polymerase chain reaction. Results The adjusted hazard ratio in a recessive model of the relationship between the C677T polymorphism and all-cause mortality in all patients was 1.47 (95% confidence interval, 1.00 to 2.16; P = 0.05). In patients with ESRD with the mutant TT genotype, the adjusted hazard ratio for mortality in all patients was 2.27 (95% confidence interval, 1.07 to 4.84; P = 0.03); patients with advanced CKD showed a similar, although not significant, trend. The risk of myocardial infarction ( P = 0.05) and composite risk of myocardial infarction, stroke, lower-extremity amputation, and mortality ( P = 0.02) were greater in patients with ESRD with the mutant T allele at nucleotide 677. The overall relationship between the A1298C polymorphism and mortality was not significant ( P = 0.6). Limitations Participants were 98% men; DNA samples were not obtained at enrollment in HOST; linkage disequilibrium with another causal polymorphism is a potential confounding factor; and power was reduced by the limited number of participants. Conclusions These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD.