An investigation of functional polymorphisms in the folate metabolic pathway and their implications in leukemia risk.

다국어 초록 (Multilingual Abstract)

Major risk factors for most forms of leukemia are unknown. However, leukemia is unlikely caused by a single genetic defect or agent, but is most likely the result of gene-environment interactions. We tested whether two polymorphisms at positions C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene involved in folate metabolism play a role in leukemia risk. We analyzed DNA from a case-control study in the UK of 308 adult acute leukemia patients and 491 matched controls. We found the MTHFR 677TT genotype was lower among 71 acute lymphocytic leukemia (ALL) cases compared with 114 controls (OR = 0.23; 95% CI = 0.06–0.81). We also observed a 3.0-fold reduction in risk of ALL in MTHFR 1298AC variants (OR = 0.33; 95% CI = 0.15–0.73). In acute myeloid leukemia, no significant difference in MTHFR 677 and 1298 genotypes existed between 237 cases and 377 controls.
To help define a mechanism, we next investigated whether polymorphisms in the folate metabolizing genes, methionine synthase (MS A2756G), serine hydroxymethyltransferase (SHMT C1444T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in thymidylate synthase (TS) modulated ALL risk. We did not find that the MS A2756G polymorphism affected ALL risk (OR = 0.73; 95% CI: 0.37–1.5). However, we found that SHMT 1444CC individuals had a 5.1-fold increase in ALL risk (OR = 5.1; 95% CI: 1.7–15.2). We also observed that TS 2R2R individuals had a 3.2-fold elevated ALL risk compared to 2R3R variants (OR = 3.2; 95% CI: 1.3–7.6), and a 4.5-fold increase in ALL risk when compared with TS 3R3R genotypes (OR = 4.5; 95% CI: 1.4–14.3).
We next tested for genetic interactions using regression trees and conditional logistic regression. We found interaction between the SHMT and MS or TS genes. TS 3R3R individuals who were SHMT 1444CC versus SHMT 1444CT/TT had a 36-fold increased ALL risk (OR = 36; 95% CI = 2.5–510). Likewise, MS 2756AG individuals who were SMHT 1444CC versus SHMT 1444TT had a 37-fold elevated ALL risk (OR = 37; 95% CI = 2.7–490). This study suggests the role of uracil misincorporation and resultant chromosomal damage in the pathogenesis of ALL, and that genetic interactions involving low penetrance polymorphisms in folate metabolizing genes may be major determinants in ALL risk.