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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #176365
Title: THE MTHFR 1298A>C POLYMORPHISM AND GENOMIC DNA METHYLATION IN HUMAN LYMPHOCYTES

Author
item FRISO, SIMONETTA - UNIV OF VERONA, ITALY
item GIRELLI, DOMENICO - UNIV OF VERONA, ITALY
item TRABETTI, ELISABETTA - UNIV OF VERONA, ITALY
item OLIVIERI, OLIVIERO - UNIV OF VERONA, ITALY
item GUARINI, PATRIZIA - UNIV OF VERONA, ITALY
item PIGNATTI, PIERFRANCO - UNIV OF VERONA, ITALY
item CORROCHER, ROBERTO - UNIV OF VERONA, ITALY
item Choi, Sang-Woon

Submitted to: Cancer Epidemiology Biomarkers and Prevention
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/3/2005
Publication Date: 4/1/2005
Citation: Friso, S., Girelli, D., Trabetti, E., Olivieri, O., Guarini, P., Pignatti, P., Corrocher, R., Choi, S. 2005. The MTHFR 1298A>C polymorphism and genomic DNA methylation in human lymphocytes. Cancer Epidemiology Biomarkers and Prevention. 14(4):938-943.

Interpretive Summary: Some genes control the production of substances in the body that effect the metabolism of nutrients. One of these is methylenetetrahydrofolate reductase gene, MTHFR. Two forms of this gene that have different ordering of their DNA sequence (called polymorphism) have been previously identified and are known to be related to an increased risk of cancer based on folate levels. Folate is a vitamin in the B complex. In this study we investigated how one particular form of the MTHFR gene polymorphism, 1298A>C, effects cancer risk and how it may convey its effect through either the coexistence of the second known polymorphism, 677C>T, or from a different mechanism.

Technical Abstract: Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate co-enzymes in one-carbon metabolism for DNA synthesis and methylation, both implicated in carcinogenesis. Epidemiologic studies have shown that two functional polymorphisms in MTHFR gene, 677C>T and 1298A>C, are related to increased cancer risk. We aimed to analyze lymphocyte DNA from 198 subjects to evaluate whether the MTHFR 1298A>C polymorphism and folate status affect genomic DNA methylation, as a possible mechanism underlying the relationship between MTHFR polymorphisms and cancer susceptibility. Carriers of the 1298AA wild-type genotype showed lower genomic DNA methylation compared to 1298AC or 1298CC genotypes (3.72 vs.8.59 or 6.79 ng5-mCyt/ microgram DNA, P<0.0001 and P=0.007, respectively). When DNA methylation was evaluated according to plasma folate status, only 1298AA with low folate levels revealed diminished DNA methylation (P<0.0001). Moreover, when the two MTHFR polymorphisms were concomitantly evaluated at the low folate status, DNA methylation was reduced only in 1298AA/677TT compared to 1298AA/677CC (3.11vs7.29 ng 5-mCyt/microgram DNA, P=0.001) and to 1298CC/677CC genotypes (3.11vs.7.14 ng 5-mCyt/microgram DNA, P=0.004). However, the high prevalence of 677TT mutants within the 1298AA group (79%) and the similar biochemical features of 1298AA/677CC and 1298CC/677CC combined genotypes, suggest that the gene-nutrient interaction affecting DNA methylation in 1298AA is mainly due to the coexistence of the 677TT genotype and that the 1298A>C polymorphism may convey its protective effect not through this interaction, but through another pathway in one-carbon metabolism. Further mechanistic studies are warranted to investigate how single polymorphisms as well as MTHFR combined genotypes exert their effect on cancer susceptibility.