Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies. uch attention has recently been drawn to the role of folate metabolism in colorectal carcinogenesis.1, 2) Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism. It irreversibly converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is the major form of folate in blood.2) The substrate of MTHFR, 5,10-methylenetetrahydrofolate, is required for conversion of deoxyuridylate to thymidylate. Depletion of 5,10-methylenetetrahydrofolate results in uracil misincorporation into DNA, and removal of this abnormal base may lead to single and double strand breaks.3, 4) Furthermore, insufficient thymidylate can increase DNA misrepair, resulting in overall DNA damage in the cell.5) On the other hand, 5-methyltetrahydrofolate provides the methyl group for methylation of homocysteine to methionine. Imbalanced DNA methylation, i.e., global genomic hypomethylation and methylation of usually unmethylated CpG sites, has been implicated in colorectal carcinogenesis. [6][7][8] Two common functional polymorphisms are known in the MTHFR gene; one is the C677T polymorphism in exon 4, resulting in an alanine-to-valine substitution at codon 222, 9) and the other is the A1298C in exon 7, resulting in a substitution of glutamate with alanine at codon 429.10) Individuals who are homozygous for the vari...

High intake of red meat has been associated with increased risk of colorectal cancer in Western countries. There has been much interest in the role of n-3 polyunsaturated fatty acids (PUFA) in colorectal cancer prevention, but epidemiological findings are limited and inconsistent. The objective of our study was to examine associations of meat, fish and fat intake with risk of colorectal cancer, paying particular attention to the subsite within the colorectum. Data were from the Fukuoka Colorectal Cancer Study, a population-based case-control study, covering 782 cases and 793 controls. Diet was assessed by interview, using newly developed personal-computer software for registering semiquantitative food frequencies. The intake of beef/pork, processed meat, total fat, saturated fat or n-6 PUFA showed no clear association with the overall or subsite-specific risk of colorectal cancer. There was an almost significant inverse association between n-3 PUFA and the risk of colorectal cancer; the covariate-adjusted odds ratio for the highest (median 3.94 g/day) versus lowest (median 1.99 g/day) quintile of energy-adjusted intake was 0.74 (95% confidence interval 0.52-1.06, trend P = 0.050). The consumption of fish and fish products was similarly inversely related to the risk although the association was not statistically significant. These associations were more evident for distal colon cancer; adjusted odds ratio for the highest versus lowest quintile of n-3 PUFA intake was 0.56 (95% confidence interval 0.34-0.92, trend P = 0.02). Our findings do not support the hypothesis that consumption of red meat increases colorectal cancer risk but do suggest that high intake of fish may decrease the risk, particularly of distal colon cancer. (Cancer Sci 2007; 98: 590-597)

The number of cases of colorectal cancer in Japan has increased over the past few decades, and incidence rates are now among the highest in the world. The present investigation within the Fukuoka Colorectal Cancer Study, including 778 cases and 767 controls aged 20-74 years, examined the association between physical activity and colorectal cancer risk by subsite. Employment-associated and leisure time physical activity was assessed by a questionnaire and interview. Division of sites into the proximal and distal colon, as well as the rectum, revealed clear site-dependent protective effects, with adjustment for smoking, alcohol consumption, BMI and age. In males, greater job-related physical activity was associated with significant reduction of risk in the distal colon and rectum (P = 0.047 and 0.02, respectively), whereas total and moderate or hard non-job physical activity exerted effects limited to the rectum (P = 0.01 and 0.004, respectively). In females, job-related physical activity and moderate or hard non-job physical activity was also protective, but only in the distal colon. Separate assessment of the influence of BMI 10 years previous to the study showed increase in risk with obesity in males but not in females, limited to distal colon and rectum. The results of the present study indicate that physical activity associated with work and leisure-time exerts beneficial effects in Japanese, but not on the proximal colon. (Cancer Sci 2006; 97: 1099-1104)

Objective. Few studies have suggested an inverse relation between coffee intake and serum concentrations of uric acid (UA), but none has addressed the relation in men and women separately. We examined the relation between coffee intake and serum UA levels in free-living middle-aged and elderly men and women in Fukuoka, Japan. Methods. Study subjects were derived from the baseline survey of a cohort study on lifestyle-related diseases, and included 11.662 men and women aged 49–76 years; excluded were those with medication for gout and hyperuricemia, use of diuretic drugs, and medical care for cancer or chronic kidney disease. Statistical adjustment was made for body mass index, alcohol use, hypertension, diabetes mellitus, and other factors. Results. There were inverse associations of coffee consumption with serum UA concentrations and hyperuricemia in men regardless of adjustment for covariates. Women showed a statistically significant, but weaker, inverse association between coffee and serum UA levels after allowance for the confounding factors. Conclusion. The findings add to evidence for a protective association between coffee intake and hyperuricemia.

Alcohol dehydrogenase and aldehyde dehydrogenase are key enzymes in alcohol metabolism and therefore may be of importance to colorectal cancer development. The present case-control study was conducted to determine the influence of ADH2, ADH3 and ALDH2 polymorphisms in Fukuoka, Japan, with 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly from the study area. A lcohol consumption has fairly consistently been related to an increased risk of colorectal cancer.(1) In a pooled analysis of eight cohort studies in North America and Europe, a consumption of ≥45 g of alcohol per day was associated with a 1.4-fold increase in the risk of colorectal cancer.(2) A positive association between alcohol and colon or colorectal cancer has also been observed in Asian countries, (3)(4)(5)(6)(7) with few exceptions.However, uncertainty remains as to the biological mechanisms for the association between alcohol use and colorectal cancer. Ethanol is first oxidized to acetaldehyde by ADH, and acetaldehyde is further metabolized to acetate by ALDH. Human ADH exhibits several isoenzymes, and functional polymorphisms are known for the ADH2 and ADH3 genes.(9) A polymorphism in exon 3 of the ADH2 gene, resulting in an arginine to histidine substitution in codon 47, affects the enzyme activity substantially. Individuals that are homozygous for the ADH2*47His allele (previously called ADH2*2) metabolize ethanol 40 times faster than those homozygous for the ADH2*47Arg allele (previously called ADH2*1).(10) The enzyme activity of ADH2*47His/ Arg genotype is in the intermediate range between the two homozygous genotypes.(11) The polymorphic site for the ADH3 gene is Ile349Val in exon 8. Maximal velocity is 2.5-fold greater in individuals homozygous for the ADH3*349Ile allele (previously called ADH3*1) than in those homozygous for the ADH3*349Val allele (previously called ADH3*2).(10) The ADH2*47His allele is fairly common in Asian populations and rare in Caucasians, while the ADH3*349Val allele is more frequent in Caucasians than in Asians.(12) ALDH2 is the gene encoding mitochondrial ALDH, which contributes the majority of acetaldehyde oxidation in human liver and contains a functional polymorphism of Glu487Lys, with the variant ALDH2*487Lys (previously called ALDH2*2) allele resulting in an inactive form. The ALDH2*487Lys allele is mainly found in Asian populations. (12,13) Several studies have investigated the relation of genetic polymorphisms of these alcohol-metabolizing enzymes to colorectal cancer and adenomas. As regards the ADH2 polymorphism and colorectal cancer, a moderate increase in the risk of colorectal cancer was observed for each of the Arg/His and Arg/Arg genotypes compared with the His/His genotype in Japan, (14) but not in Spain.(15) The ADH3 polymorphism was unrelated to colorectal cancer in two studies of Caucasians, (16,17) but one of these suggested an effect modification of alcohol consumption. (16) Two studies have examined the relation between ADH3 p...