The present chapter aims to illustrate some key concepts of genetic association studies, with an emphasis on meta-analysis as a powerful study design to summarize quantitatively the results of the scientific literature. Additionally, a systematic review of the published meta-analyses of the effect of methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphisms on cancer risk is reported. MTHFR plays a central role in folate metabolism by irreversibly catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulating form of folate and a cosubstrate for homocysteine methylation to methionine. The C677T polymorphism has been investigated in relation to cancer, as the MTHFR TT genotype is related to DNA hypomethylation, particularly in individuals with reduced plasma folate concentrations. The results of the present review of the published meta-analyses support a protective effect of the 677 TT genotype on colorectal cancer and adult lymphoblastic leukemia, while an increased risk for gastric cancer, with the former probably resulting from the increased levels of the MTHFR substrate (which is essential for DNA synthesis) due to the variant allele, and the latter from impaired folate levels (acid folic protects from cancer by limiting aberrant DNA methylation). Additional large studies collecting data on folate serum levels might help to clarify the result of the complex interaction of dietary folate intake and MTHFR genotype on cancer risk.
- Gene polymorphism
- Genetic epidemiology
- Methylenetetrahydrofolate reductase
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)