Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self‐Defense Forces Health Study

Abstract

Methylenetetrahydrofolate reductase is a key enzyme in folate metabolism, which affects DNA synthesis and methylation and is possibly linked to colorectal carcinogenesis. Alcohol and acetaldehyde have an adverse effect on folate metabolism. This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals. The study subjects were 452 cases of colorectal adenoma and 1050 controls with no polyp who underwent total colonoscopy. Genotypes were determined by the PCR-RFLP method using genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index, cigarette-years and alcohol intake. Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma. While high alcohol consumption was associated with a moderately increased risk of colorectal adenoma, neither of the two polymorphisms showed a significant effect on the association between alcohol and colorectal adenoma. F olate metabolism has drawn much attention in relation to colorectal carcinogenesis.(1,2) Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism. MTHFR irreversibly converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.(2) The substrate of MTHFR, 5,10-methylenetetrahydrofolate, is required for conversion of deoxyuridylate to thymidylate. Insufficient thymidylate results in uracil misincorporation into DNA, leading to single-strand and double-strand breaks and increasing the incidence of DNA misrepair.(3,4) On the other hand, 5-methyltetrahydrofolate is a methyl donor in the remethylation of homocystein to methionine, which is required for DNA methylation. Imbalanced DNA methylation has been implicated in colorectal carcinogenesis. (5,6) The MTHFR C677T polymorphism is a common functional polymorphism in exon 4, resulting in an alanine-tovaline substitution at codon 222.(7) The homozygous variant (677TT) has no more than 30% of normal enzyme activity, and heterozygotes (677CT) also seem to have lower activity of the enzyme.(7) Several, (8)(9)(10)(11)(12) but not all, (13)(14)(15) epidemiological studies have shown a decreased risk of colorectal cancer associated with the MTHFR 677TT genotype, especially in individuals with high folate intake and /or low alcohol intake. On the other hand, a limited number of studies addressed the relationship between the MTHFR C677T polymorphism and colorectal adenoma, a well-established precursor lesion of colorectal cancer. (16)(17)(18)(19)(20) These studies generally showed no association between the MTHFR C677T polymorphism and the risk of colorectal adenoma, but reported variable associations between alcohol intake and colorectal adenoma, dependent on the MTHFR C677T polymorphism. (16 -20) Alcohol has fairly consistently been shown to be associated with increas...

Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis

“…Ulvik et al (2004) found no association of MTHFR C677T and MTR (methionine synthase) A2756G with CRC risk, and Hirose et al (2005) revealed a decreased risk of CRC from ALDH2*2 and MTHFR 677T. More research on gene-gene interactions such as those involving MTR, thymidylate synthase, and ALDH2 will provide a more comprehensive insight into the associations studied here.…”

“…These two studies were discarded. Among 11 eligible articles (Chen et al 1998;Ulrich et al 1999;Levine et al 2000;Marugame et al 2000;Giovannucci et al 2003;Pufulete et al 2003;Boyapati et al 2004;Goode et al 2004;van den Donk et al 2005;Hirose et al 2005;Mitrou et al 2006), 27% (3/11) stated that the age and sex status were matched between the case and control populations. PCR-RFLP was used to validate the genotype in all of the studies.…”

Alcohol Drinking and One-Carbon Metabolism-Related Gene Polymorphisms on Pancreatic Cancer Risk

“…Referral patterns to our hospital were different between cases and controls; thus, relative geographic distributions of residences between cases and controls may be different. However, this finding would not lead to bias, because frequency of MTHFR C677T genotype is not different in Japanese (24,25). Second, this study may suffer from recall bias.…”

Alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

“…(19) Studies regarding the ALDH2 polymorphism and colorectal cancer or adenomas have all been done in Japan. (14,(20)(21)(22)(23) An approximately 3-fold increase in the risk of colorectal cancer has been observed for ALDH2*487Glu/Lys versus ALDH2*487Glu/Glu among alcoholics. (20) Another study 12 To whom correspondence should be addressed.…”