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Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA methylation and synthesis. Two functional, common polymorphisms (C677T and A1298C) are known in the MTHFR gene. MTHFR activity is lowered in individuals with the 677TT genotype and is somewhat reduced in those with the 1298CC genotype. We reviewed the consistency of reported associations of these polymorphisms with colorectal cancer and adenoma with consideration of the effects of nutritional status. A total of 16 studies have addressed the association between MTHFR C677T polymorphism and colorectal cancer in 10 countries. Decreased risk of colorectal cancer associated with the 677TT genotype has fairly consistently been observed, with few exceptions. This decrease was observable in people with either high or low folate status. Alteration in the thymidylate pool associated with MTHFR activity is postulated as an underlying mechanism. Studies on the A1298C polymorphism are limited, and their results are variable. Almost all of seven studies of colorectal adenoma have found no association between C677T polymorphism and adenoma, but the 677TT genotype seems to be related to increased risk when folate status is poor. Reduced availability of methyl groups for DNA methylation might be more relevant to adenoma formation. Although the underlying mechanisms still remain to be clarified, epidemiological findings regarding MTHFR C677T polymorphism provide strong evidence that adequate folate status confers protection from colorectal cancer. (Cancer Sci 2005; 96: 535 –542)

Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population Fumihiko Takeuchi 1 , 2 , Masakuni Serizawa 3 , Ken Yamamoto 4 , Tomomi Fujisawa 5 , Eitaro Nakashima 6 , 7 , Keizo Ohnaka 8 , Hiroshi Ikegami 9 , Takao Sugiyama 10 , Tomohiro Katsuya 5 , Makoto Miyagishi 3 , Naoki Nakashima 11 , Hajime Nawata 12 , Jiro Nakamura 6 , Suminori Kono 13 , Ryoichi Takayanagi 14 and Norihiro Kato 3 1 Department of Medical Ecology and Informatics, Research Institute, International Medical Center of Japan, Tokyo, Japan; 2 Wellcome Trust Sanger Institute, Cambridge, U.K; 3 Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan; 4 Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; 5 Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; 6 Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan; 7 Department of Metabolism and Endocrine Internal Medicine, Chubu Rosai Hospital, Nagoya, Japan; 8 Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 9 Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, Osaka, Japan; 10 Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan; 11 Department of Medical Informatics, Kyushu University Hospital, Fukuoka, Japan; 12 Fukuoka Prefectural University, Fukuoka, Tokyo, Japan; 13 Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 14 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Corresponding author: Norihiro Kato, nokato{at}ri.imcj.go.jp . Abstract OBJECTIVE To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population. RESEARCH DESIGN AND METHODS In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs ( P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 × 10 –5 for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population. RESULTS Four loci—1 novel with suggestive evidence ( PEPD on 19q13, P = 1.4 × 10 –5 ) and three previously reported—were identified; the association of CDKAL1 , CDKN2A / CDKN2B, and KCNQ1 were confirmed ( P < 10 –19 ). Moreover, significant associations were replicated in five other candidate loci: TCF7L2 , IGF2BP2 , SLC30A8 , HHEX , and KCNJ11 . There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population. CONCLUSIONS The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 28, 2008. Accepted April 7, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

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)

Heterocyclic aromatic amines formed in cooked meat may be an underlying mechanism for the red meat-colorectal cancer (CRC) association. These compounds require bioactivaction by N-acetyltransferase 2 (NAT2). An interaction effect between red meat consumption and NAT2 in increasing CRC risk has been inconsistently reported in whites. We investigated this interaction in two populations in which the high-activity rapid NAT2 phenotype is 10- and 2-fold more common than in whites. We meta-analyzed four studies of Japanese (2,217 cases, 3,788 controls) and three studies of African Americans (527 cases, 4,527 controls). NAT2 phenotype was inferred from an optimized seven-SNP genotyping panel. Processed and total red meat intakes were associated with an increased CRC risk in Japanese and in both ethnic groups combined (P's ≤ 0.002). We observed an interaction between processed meat intake and NAT2 in Japanese (P = 0.04), African Americans (P = 0.02), and in both groups combined (P = 0.006). The association of processed meat with CRC was strongest among individuals with the rapid NAT2 phenotype (combined analysis, OR for highest vs. lowest quartile: 1.62, 95% CI: 1.28-2.05; Ptrend = 8.0×10-5), intermediate among those with the intermediate NAT2 phenotype (1.29, 95% CI: 1.05-1.59; Ptrend = 0.05) and null among those with the slow phenotype (Ptrend = 0.45). A similar interaction was found for NAT2 and total red meat (Pinteraction = 0.03). Our findings support a role for NAT2 in modifying the association between red meat consumption and CRC in Japanese and African Americans.

Background and Objectives: Recent observational studies have suggested a positive association of white rice and protective associations of green tea and coffee with the risk of diabetes. However, none have examined the interaction between these dietary factors on the risk of diabetes. We prospectively investigated the effect modification of green tea and coffee on the association between rice and incident diabetes in elderly Japanese men and women. Methods and Study Design: Among subjects who participated in the baseline survey (2004-2007), 11717 (91 %) subjects responded to the follow-up survey (2010-2012). By using multiple logistic regression analysis, ORs of incident diabetes were calculated according to categories of cereal food, green tea, and coffee intakes, examining also the effect modification of green tea and coffee. Results: 464 new cases of diabetes were identified. Women, but not men, showed a positive association of rice intake (trend p=0.008) and an inverse association of green tea intake (trend p=0.02) with incident diabetes. Coffee showed no association with incident diabetes either in men or women. In the analysis stratified by green tea intake, the association between rice and diabetes disappeared among women with an intake of >=7 cups/d of green tea (interaction p=0.08). Conclusions: Rice intake was associated with an increased risk of diabetes only in women, and women with a higher intake of green tea had a lower risk of diabetes. A high intake of green tea may be protective against increased risk of diabetes with a higher intake of rice in women.

Background It is uncertain whether smoking is related to colorectal cancer risk. Cytochrome P-450 CYP1A1, glutathione-S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1) are important enzymes in the metabolism of tobacco carcinogens, and functional genetic polymorphisms are known for these enzymes. We investigated the relation of cigarette smoking and related genetic polymorphisms to colorectal cancer risk, with special reference to the interaction between smoking and genetic polymorphism. Methods We used data from the Fukuoka Colorectal Cancer Study, a population-based case-control study, including 685 cases and 778 controls who gave informed consent to genetic analysis. Interview was conducted to assess lifestyle factors, and DNA was extracted from buffy coat. Results In comparison with lifelong nonsmokers, the odds ratios (OR) of colorectal cancer for <400, 400-799 and ≥800 cigarette-years were 0.65 (95% confidence interval [CI], 0.45-0.89), 1.16 (0.83-1.62) and 1.14 (0.73-1.77), respectively. A decreased risk associated with light smoking was observed only for colon cancer, and rectal cancer showed an increased risk among those with ≥400 cigarette-years (OR 1.60, 95% CI 1.04-2.45). None of the polymorphisms under study was singly associated with colorectal cancer risk. Of the gene-gene interactions studied, the composite genotype of CYP1A1*2A or CYP1A1*2C and GSTT1 polymorphisms was associated with a decreased risk of colorectal cancer, showing a nearly statistically significant ( P interaction = 0.06) or significant interaction ( P interaction = 0.02). The composite genotypes of these two polymorphisms, however, showed no measurable interaction with cigarette smoking in relation to colorectal cancer risk. Conclusions Cigarette smoking may be associated with increased risk of rectal cancer, but not of colon cancer. The observed interactions between CYP1A1 and GSTT1 polymorphisms warrant further confirmation.

Adiponectin is an adipocyte‐derived protein with an insulin‐sensitizing action. Circulating levels of adiponectin are inversely correlated with obesity, especially abdominal obesity. Some studies have suggested that low levels of circulating adiponectin might be related to increased risk of colorectal cancer and adenomas. The present study examined the relationship between total and high‐molecular‐weight (HMW) adiponectin to colorectal adenomas in the Self Defense Forces (SDF) Health Study. The study subjects comprised 656 cases of colorectal adenomas and 648 controls with normal colonoscopy among men receiving a preretirement health examination at two Self Defense Forces hospitals. Total and HMW adiponectin were slightly lower in adenoma cases than in controls; geometric means of total adiponectin were 5.42 µg/mL in cases and 5.63 µg/mL in controls (P = 0.13), and the corresponding values of HMW adiponectin were 2.47 µg/mL and 2.57 µg/mL, respectively (P = 0.29). Regardless of adjustment for body mass index and other lifestyle factors, total adiponectin was unrelated to the risk of colorectal adenomas. Total adiponectin levels were inversely related to the risk of large adenomas (≥ 5 mm), but not of small adenomas, with a nearly statistically significant decreasing trend (P = 0.06). However, the inverse association was largely ascribed to body mass index and other lifestyle factors. HMW adiponectin showed no clear association with either overall or size‐specific risk of colorectal adenomas. The study provided suggestive evidence for a protective association between adiponectin and large adenomas, but did not indicate a protective association independent of adiposity. (Cancer Sci 2008; 99: 781–786)

Accumulating evidence suggests that vitamin D has anticarcinogenic effects. However, it is unclear whether the nutrient is involved in the early stage of colorectal carcinogenesis. We examined the association between circulating vitamin D concentrations and colorectal adenomas in Japanese men. The study subjects comprised 656 cases of colorectal adenomas and 648 controls with normal colonoscopy among male self defense officials receiving a pre‐retirement health examination between 1997 and 2004. Plasma or serum levels of 25‐hydroxyvitamin D [25(OH)D] were measured using a radioimmunoassay method. Logistic regression analysis was used to obtain odds ratios (OR) and 95% confidence intervals (CI) with adjustment for potential confounding variables. Overall, there was no measurable association between circulating 25(OH)D concentrations and colorectal adenomas. When the analysis was restricted to subjects whose blood was taken during the winter season (November–April), the prevalence odds of colorectal adenomas for the highest versus lowest quartile of 25(OH)D was statistically significantly decreased (OR = 0.58; 95% CI = 0.34–0.99). The reduction was more pronounced for the rectum (OR = 0.22) and distal colon (OR = 0.47) than for proximal colon (OR = 0.70). During the summer season (May–October), higher levels of 25(OH)D were associated with an increased odds of small, but not large, adenomas. The present study adds to evidence that high levels of circulating vitamin D measured during darker season is associated with decreased prevalence of adenomas in the distal sites of the colorectum. (Cancer Sci 2010)

Background: Statin therapy has been found to produce substantial reductions in low-density lipoprotein cholesterol (LDL-C) levels, resulting in a reduced risk for cardiovascular events. Recently, research interest has focused on modification of high-density lipoprotein cholesterol (HDL-C) levels for the potential prevention of cardiovascular events. The effects of pitavastatin and atorvastatin on HDL-C have not been directly compared. Objectives: This study compared the effects of pitavastatin and atorvastatin on HDL-C and other lipids and glucose metabolism in Japanese patients with elevated LDL-C levels and glucose intolerance. The tolerability of the 2 treatments was also compared. Methods: This was a multicenter, open-label, parallelgroup trial. Patients with LDL-C levels ≥ 140 mg/dL and glucose intolerance (defined according to Japanese criteria for borderline diabetes and World Health Organization criteria for impaired fasting glucose and impaired glucose tolerance) were randomly assigned to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d for 52 weeks. Levels of serum lipids and lipoproteins and measures of glucose metabolism (fasting insulin, fasting glucose, glycosylated hemoglobin, and homeostasis model assessment for insulin resistance) were obtained at baseline and at 8, 26, and 52 weeks of treatment. The effect of study drug on glucose metabolism was evaluated as a tolerability outcome. Tolerability was further assessed based on adverse events, either spontaneously reported or elicited by questioning; physical examination findings; and clinical laboratory test results. Study physicians rated the relationship of adverse events to study medication as unrelated, suspected, or probable. Results: Two hundred seven patients were enrolled in the study, and efficacy was evaluated in 173 patients (88 pitavastatin, 85 atorvastatin). Thirty-four patients were excluded for reasons including failure to start medication or lack of ≥ 6 months of follow-up. Women accounted for 62% (108/173) of the evaluable population, which had a mean age of 63.3 years and a mean weight of 63.0 kg; 89% (154/173) had diabetes mellitus. The percent change in HDL-C levels was significantly greater in the pitavastatin group compared with the atorvastatin group (8.2 vs 2.9, respectively; P = 0.031), as was the percent change in apolipoprotein (Apo) A-I (5.1 vs 0.6; P = 0.019). The percent change in LDL-C levels was significantly lower with atorvastatin compared with pitavastatin (−40.1 vs −33.0, respectively; P = 0.002), as were the percent changes in non-HDL-C (−37.4 vs −31.1; P = 0.004), Apo B (−35.1 vs −28.2; P < 0.001), and Apo E (−28.1 vs −17.8; P < 0.001). The significant results for these parameters were unchanged when all 189 subjects who received ≥ 1 dose of study medication were included in the analysis, using last-value-carried-forward methodology. There were no significant differences between treatments with respect to the measures of glucose metabolism. Both statins appeared to be well tolerated. Adverse events occurred in 9% (9/96) of the pitavastatin group and 14% (13/93) of the atorvastatin group ( P = NS). Two patients in the pitavastatin group and none in the atorvastatin group had an alanine aminotransferase value >3 times the upper limit of normal ( P = NS). Conclusions: In these patients with elevated LDL-C levels and glucose intolerance, 52 weeks of treatment with pitavastatin 2 mg/d was associated with significantly greater increases in HDL-C and Apo A-I levels than atorvastatin 10 mg/d. Both treatments were well tolerated.

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)