Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults

Reduction of 5,10-methylenetetrahydrafolate (methyleneTHF), a donor far met hylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methyl THF), the primary methyl donor for methionine synthesis, is catalyzed by 5, 10-methylenetetrahydrofolate reductase (MTHFR). A common 677 C --> T polymo rphism in the MTHFR gene results in thermolability and reduced MTHFR activi ty that decreases the pool of methylTHF and increases the pool of methylene THF. Recently, another polymorphism in MTHFR (1298 A --> C) has been identi fied that also results in diminished enzyme activity. We tested whether car riers of these variant alleles are protected from adult acute leukemia. We analyzed DNA from a case-control study in the United Kingdom of 308 adult a cute leukemia patients and 491 age- and sex-matched controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. The MTHFR 677TT genotype was lower among 71 acute lymphocytic: leuke mia (ALL) cases compared with 114 controls, conferring a 4.3-fold decrease in risk of ALL [odds ratio (OR = 0.23; 95% Cl = 0.06-0.81]. We observed a 3 -fold reduction in risk of ALL in individuals with the MTHFR 1298AC polymor phism (OR = 0.33; 95% CI = 0.15-0.73) and a 14-fold decreased risk of ALL i n those with the MTHFR 1298CC Variant allele (OR = 0.07; 95% Cl = 0.00-1.77 ). In acute myeloid leukemia, no significant difference in MTHFR 677 and 12 98 genotype frequencies was observed between 237 cases and 377 controls. In dividuals with the MTHFR 677TT, 1298AC and 1298CC genotypes have a decrease d risk of adult ALL, but not acute myeloid leukemia, which suggests that fo late inadequacy may play a key role in the development of ALL.