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Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia
Maja Krajinovic1, Stephanie Lamothe, Damian Labuda
1Centre de recherche, Hôpital Sainte-Justine, Montréal, QC, Canada.
Abstract:
The central role of methylenetetrahydrofolate reductase (MTHFR) in the folate metabolism renders MTHFR gene polymorphisms (C677T and A1298C) potential modulators of a variety of disorders whose development depends on folate/homocysteine imbalance. Here, we provide additional evidence on the protective role of these polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric cancer. A case-control study was conducted in 270 ALL patients and 300 healthy controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298 individuals were associated with reduced risk of ALL (crude odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6; respectively). Further stratification in patients born before and after January 1996 (approximate time of Health Canada recommendation for folic acid supplement in pregnancy) revealed that the protective effect of MTHFR variants is accentuated and present only in children born before 1996. Similar results were obtained when a transmission disequilibrium test was performed on a subset of children (n = 95) in a family-based study. This finding suggests gene-environment interaction and its role in the susceptibility to childhood ALL, which is consistent with previous findings associating either folate deficiency or MTHFR polymorphisms with risk of leukemia.
Insights
Methylenetetrahydrofolate reductase (MTHFR) gene variations may protect against childhood acute lymphoblastic leukemia (ALL). This protective effect was more pronounced in children born before folic acid fortification recommendations, suggesting gene-environment interactions influence ALL risk.
Area of Science:
- Genetics
- Oncology
- Nutritional Biochemistry
Background:
- Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism.
- MTHFR gene polymorphisms (C677T and A1298C) are implicated in various disorders linked to folate/homocysteine levels.
- Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and its etiology may involve folate metabolism.
Purpose of the Study:
- To investigate the potential protective role of MTHFR gene polymorphisms (C677T and A1298C) in childhood acute lymphoblastic leukemia (ALL).
- To explore the influence of gene-environment interactions, specifically folic acid fortification, on the association between MTHFR variants and ALL risk.
Main Methods:
- A case-control study involving 270 ALL patients and 300 healthy controls of French-Canadian descent.
- Genotyping for MTHFR C677T and A1298C polymorphisms.
- Stratification analysis based on birth year relative to folic acid fortification recommendations and family-based transmission disequilibrium test.
Main Results:
- Specific MTHFR genotypes (TT677/AA1298 and CC677/CC1298) were associated with a reduced risk of ALL.
- The protective association of MTHFR variants was significantly stronger in children born before January 1996 (pre-fortification).
- Family-based analysis corroborated the findings, supporting a gene-environment interaction.
Conclusions:
- MTHFR gene polymorphisms may confer a protective effect against childhood ALL.
- Folic acid fortification likely modifies the impact of MTHFR variants on ALL susceptibility.
- These findings highlight the importance of gene-environment interactions in the development of childhood ALL.
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