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.


METHODS
Gene association study.


METHODS
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).


METHODS
Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene.


RESULTS
Unadjusted and adjusted all-cause mortality.


METHODS
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).


CONCLUSIONS
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.
Jamison
Rex L
RL
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. rjamison@stanford.edu
Shih
Mei-Chiung
MC
Humphries
Donald E
DE
Guarino
Peter D
PD
Kaufman
James S
JS
Goldfarb
David S
DS
Warren
Stuart R
SR
Gaziano
J Michael
JM
Lavori
Philip
P
D000368:Aged; D000483:Alleles; D002423:Cause of Death / Q000639:trends; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000401:mortality*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D013997:Time Factors
D004247:DNA; D042965:Methylenetetrahydrofolate Reductase (NADPH2)