This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Friso, S. Articles by Choi, S.-W. Search for Related Content PubMed PubMed Citation Articles by Friso, S. Articles by Choi, S.-W.

The MTHFR 1298A>C Polymorphism and Genomic DNA Methylation in Human Lymphocytes

Departments of ¹ Clinical and Experimental Medicine and ² Biology and Genetics, University of Verona, Italy; and ³ Vitamin Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts

Requests for reprints: Simonetta Friso, Department of Clinical and Experimental Medicine, Policlinico Giambattista Rossi, Piazza Ludovico Antonio Scuro, 10, 37134 Verona, Italy. Phone: 39-045-580111; Fax: 39-045-580111. E-mail: simonetta.friso{at}univr.it

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes 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 the MTHFR 1298A>C polymorphism and folate status affecting 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 with 1298AC or 1298CC genotypes [3.72 versus 8.59 or 6.79 ng 5-methyl-2'-deoxycytidine (5-mCyt)/µg 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 with 1298AA/677CC (3.11 versus 7.29 ng 5-mCyt/µg DNA, P = 0.001) and 1298CC/677CC genotypes (3.11 versus 7.14 ng 5-mCyt/µg 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.

This article has been cited by other articles:

				P. W. B. Nanayakkara, J. C. Kiefte-de Jong, C. D. A. Stehouwer, F. J. van Ittersum, M. R. Olthof, R. M. Kok, H. J. Blom, C. van Guldener, P. M. ter Wee, and Y. M. Smulders Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2-4 chronic kidney disease Nephrol. Dial. Transplant., August 1, 2008; 23(8): 2586 - 2592. [Abstract] [Full Text] [PDF]

				L. S. Kristensen and A. Dobrovic Direct Genotyping of Single Nucleotide Polymorphisms in Methyl Metabolism Genes Using Probe-Free High-Resolution Melting Analysis Cancer Epidemiol. Biomarkers Prev., May 1, 2008; 17(5): 1240 - 1247. [Abstract] [Full Text] [PDF]

				R. J. Hung, M. Hashibe, J. McKay, V. Gaborieau, N. Szeszenia-Dabrowska, D. Zaridze, J. Lissowska, P. Rudnai, E. Fabianova, I. Mates, et al. Folate-related genes and the risk of tobacco-related cancers in Central Europe Carcinogenesis, June 1, 2007; 28(6): 1334 - 1340. [Abstract] [Full Text] [PDF]

				W.-H. Xu, M. J. Shrubsole, Y.-B. Xiang, Q. Cai, G.-m. Zhao, Z.-x. Ruan, J.-r. Cheng, W. Zheng, and X. O. Shu Dietary Folate Intake, MTHFR Genetic Polymorphisms, and the Risk of Endometrial Cancer among Chinese Women Cancer Epidemiol. Biomarkers Prev., February 1, 2007; 16(2): 281 - 287. [Abstract] [Full Text] [PDF]