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1.  Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A 
Nature communications  2014;5:4613.
The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P < 5×10−8) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4×10−9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations.
PMCID: PMC4180879  PMID: 25105248
2.  Impaired 8-Hydroxyguanine Repair Activity of MUTYH Variant p.Arg109Trp Found in a Japanese Patient with Early-Onset Colorectal Cancer 
Purpose. The biallelic inactivation of the 8-hydroxyguanine repair gene MUTYH leads to MUTYH-associated polyposis (MAP), which is characterized by colorectal multiple polyps and carcinoma(s). However, only limited information regarding MAP in the Japanese population is presently available. Since early-onset colorectal cancer (CRC) is a characteristic of MAP and might be caused by the inactivation of another 8-hydroxyguanine repair gene, OGG1, we investigated whether germline MUTYH and OGG1 mutations are involved in early-onset CRC in Japanese patients. Methods. Thirty-four Japanese patients with early-onset CRC were examined for germline MUTYH and OGG1 mutations using sequencing. Results. Biallelic pathogenic mutations were not found in any of the patients; however, a heterozygous p.Arg19∗  MUTYH variant and a heterozygous p.Arg109Trp MUTYH variant were detected in one patient each. The p.Arg19∗ and p.Arg109Trp corresponded to p.Arg5∗ and p.Arg81Trp, respectively, in the type 2 nuclear-form protein. The defective DNA repair activity of p.Arg5∗ is apparent, while that of p.Arg81Trp has been demonstrated using DNA cleavage and supF forward mutation assays. Conclusion. These results suggest that biallelic MUTYH or OGG1 pathogenic mutations are rare in Japanese patients with early-onset CRC; however, the p.Arg19∗ and p.Arg109Trp MUTYH variants are associated with functional impairments.
PMCID: PMC3988950  PMID: 24799981
3.  Behavioral and clinical correlates of serum bilirubin concentrations in Japanese men and women 
A considerable interest has been drawn to potential protective effects of bilirubin against oxidative stress-related diseases. Smoking is known to be associated with lower concentrations of serum bilirubin, but other behavioral correlates of serum bilirubin have not been well studied. In this cross-sectional study, we examined the associations of behavioral and clinical factors with serum total bilirubin in Japanese men and women.
The study subjects comprised of 4802 men and 6414 women aged 49–76 years who participated in the baseline survey of an ongoing cohort study on lifestyle-related diseases in Fukuoka, Japan. With consideration to time of the day of blood sampling and fasting hours, the associations with smoking, alcohol intake, body mass index, physical activity, coffee, tea, blood pressure, glycated hemoglobin (HbA1c), HDL cholesterol and non-HDL cholesterol with serum bilirubin were evaluated by analysis of covariance and multiple linear regression analysis.
While smoking was negatively associated with serum bilirubin, alcohol consumption was positively associated with serum bilirubin in both men and women. Coffee consumption was associated with lower bilirubin concentrations in both sexes. In the multiple linear regression analysis, HDL cholesterol was positively and HbA1c was negatively associated with bilirubin in both men and women, and the associations were more evident in women.
Smoking, alcohol use and coffee consumption were important behavioral correlates of serum bilirubin in Japanese men and women. Serum HDL cholesterol was a measurable clinical correlate of bilirubin in women.
PMCID: PMC3852517  PMID: 24090309
Bilirubin; Coffee; Smoking; Alcohol; High-density lipoprotein cholesterol
4.  CYP1A1, GSTM1, GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men 
AIM: To investigate the role of functional genetic polymorphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas.
METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied were CYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other lifestyle factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test.
RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1. A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There was no measurable effect modification of smoking even regarding the combination of the genetic polymorphisms of the phase I and phase II enzymes.
CONCLUSION: Combination of the CYP1A1*2C and NQO1 609CC genotypes was associated with a decreased risk of colorectal adenomas regardless of smoking status.
PMCID: PMC3703190  PMID: 23840148
Colorectal adenoma; Smoking; Polymorphism; CYP1A1; GSTM1; GSTT1; NQO1
5.  Dietary polyphenols and colorectal cancer risk: The Fukuoka colorectal cancer study 
AIM: To investigate the associations between dietary intake of polyphenols and colorectal cancer.
METHODS: The study subjects were derived from the Fukuoka colorectal cancer study, a community-based case-control study. The study subjects were 816 cases of colorectal cancer and 815 community-based controls. The consumption of 148 food items was assessed by a computer-assisted interview. We used the consumption of 97 food items to estimate dietary intakes of total, tea and coffee polyphenols. The Phenol-Explorer database was used for 92 food items. Of the 5 foods which were not listed in the Phenol-Explorer Database, polyphenol contents of 3 foods (sweet potatoes, satoimo and daikon) were based on a Japanese study and 2 foods (soybeans and fried potatoes) were estimated by ORAC-based polyphenol contents in the United States Department of Agriculture Database. Odds ratios (OR) and 95%CI of colorectal cancer risk according to quintile categories of intake were obtained by using logistic regression models with adjustment for age, sex, residential area, parental history of colorectal cancer, smoking, alcohol consumption, body mass index 10 years before, type of job, leisure-time physical activity and dietary intakes of calcium and n-3 polyunsaturated fatty acids.
RESULTS: There was no measurable difference in total or tea polyphenol intake between cases and controls, but intake of coffee polyphenols was lower in cases than in controls. The multivariate-adjusted OR of colorectal cancer according to quintile categories of coffee polyphenols (from the first to top quintile) were 1.00 (referent), 0.81 (95%CI: 0.60-1.10), 0.65 (95%CI: 0.47-0.89), 0.65 (95%CI: 0.46-0.89) and 0.82 (95%CI: 0.60-1.10), respectively (Ptrend = 0.07). Similar, but less pronounced, decreases in the OR were also noted for the third and fourth quintiles of total polyphenol intake. Tea polyphenols and non-coffee polyphenols showed no association with colorectal cancer risk. The site-specific analysis, based on 463 colon cancer cases and 340 rectal cancer cases, showed an inverse association between coffee polyphenols and colon cancer. The multivariate-adjusted OR of colon cancer for the first to top quintiles of coffee polyphenols were 1.00 (referent), 0.92 (95%CI: 0.64-1.31), 0.75 (95%CI: 0.52-1.08), 0.69 (95%CI: 0.47-1.01), and 0.68 (95%CI: 0.46-1.00), respectively (Ptrend = 0.02). Distal colon cancer showed a more evident inverse association with coffee polyphenols than proximal colon cancer. The association between coffee polyphenols and rectal cancer risk was U-shaped, with significant decreases in the OR at the second to fourth quintile categories. There was also a tendency that the OR of colon and rectal cancer decreased in the intermediate categories of total polyphenols. The decrease in the OR in the intermediate categories of total polyphenols was most pronounced for distal colon cancer. Intake of tea polyphenols was not associated with either colon or rectal cancer. The associations of coffee consumption with colorectal, colon and rectal cancers were almost the same as observed for coffee polyphenols. The trend of the association between coffee consumption and colorectal cancer was statistically significant.
CONCLUSION: The present findings suggest a decreased risk of colorectal cancer associated with coffee consumption.
PMCID: PMC3645387  PMID: 23674876
Colorectal cancer; Colon cancer; Rectal cancer; Polyphenols; Coffee; Tea
6.  Effects of 16-Week Consumption of Caffeinated and Decaffeinated Instant Coffee on Glucose Metabolism in a Randomized Controlled Trial 
Objective. Observational studies have shown a protective association between coffee consumption and type 2 diabetes mellitus whereas caffeine or caffeinated coffee acutely deteriorates glucose tolerance. We investigated the effects of chronic drinking of instant coffee on glucose and insulin concentrations during a 75 g oral glucose tolerance test. Methods. Overweight men with a mild-to-moderate elevation of fasting plasma glucose were randomly allocated to a 16-week intervention of consuming 5 cups of caffeinated (n = 17) or decaffeinated (n = 15) instant coffee per day or no coffee (n = 13). Results. The caffeinated coffee group showed statistically significant decreases in the 2-hour concentrations and the area under the curve of glucose while neither decaffeinated coffee nor coffee group showed such a change. Waist circumstance decreased in the caffeinated coffee group, increased in the decaffeinated coffee group, and did not change in the noncoffee group (P = 0.002). With adjustment for the change in waist circumference, caffeinated and decaffeinated coffee consumption were associated with a modest decrease in the postload glucose levels. Conclusion. Both caffeinated and decaffeinated coffee may be protective against deterioration of glucose tolerance.
PMCID: PMC3502017  PMID: 23193459
7.  No effect modification of serum bilirubin or coffee consumption on the association of gamma-glutamyltransferase with glycated hemoglobin in a cross-sectional study of Japanese men and women 
Oxidative stress has been implicated in the development of type 2 diabetes mellitus. Bilirubin is a potent endogenous antioxidant, and coffee is a major source of exogenous antioxidants. Serum gamma-glutamyltransferase (GGT), a marker of oxidative stress, is a strong predictor of the risk of type 2 diabetes mellitus. This study evaluated the effect modification of bilirubin and coffee consumption on the association of serum GGT with glycated hemoglobin (HbA1c) and the combined effect of bilirubin and coffee on HbA1c concentrations.
The subjects were 4492 men and 6242 women aged 49–76 years who participated in the baseline survey of an on-going cohort study on lifestyle-related diseases in Fukuoka, Japan. Geometric means of HbA1c were examined according to quartile categories of GGT, with stratification by serum total bilirubin (≥ 0.6 mg/dL versus less in men and ≥ 0.5 mg/dL versus less in women) and coffee consumption (< 1, 1–3 and ≥ 4 cups of per day). Statistical adjustment was made for age, smoking, alcohol use and body mass index by using analysis of covariance.
HbA1 concentrations increased progressively with increasing levels of GGT in both men and women. The increasing trend of HbA1c concentrations associated with GGT did not differ by either bilirubin status or coffee consumption. Both men and women with high bilirubin had consistently lower concentrations of HbA1c across the GGT quartiles. Higher coffee consumption was associated with lower concentrations of HbA1c in women with low bilirubin (trend P = 0.04), but not with high bilirubin (trend P = 0.37). There was no such association between coffee and HbA1c in men with either low or high bilirubin levels.
Bilirubin is possibly protective against deterioration of glucose metabolism. Further studies are needed regarding the combined effect of bilirubin and coffee on glucose metabolism.
PMCID: PMC3509408  PMID: 23092212
8.  Profile of Participants and Genotype Distributions of 108 Polymorphisms in a Cross-Sectional Study of Associations of Genotypes With Lifestyle and Clinical Factors: A Project in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study 
Journal of Epidemiology  2011;21(3):223-235.
Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene–environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005.
We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay.
The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35–69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001).
This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene–environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.
PMCID: PMC3899413  PMID: 21467728
allele frequency; cross-sectional studies; gene–environment interactions; Japan Multi-institutional Collaborative Cohort Study; polymorphism
9.  The Relation of Coffee Consumption to Serum Uric Acid in Japanese Men and Women Aged 49–76 Years 
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.
PMCID: PMC2925214  PMID: 20798877
10.  Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population 
Diabetes  2009;58(7):1690-1699.
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.
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.
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.
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.
PMCID: PMC2699880  PMID: 19401414
11.  Cigarette smoking, genetic polymorphisms and colorectal cancer risk: the Fukuoka Colorectal Cancer Study 
BMC Cancer  2010;10:274.
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.
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.
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 (Pinteraction = 0.06) or significant interaction (Pinteraction = 0.02). The composite genotypes of these two polymorphisms, however, showed no measurable interaction with cigarette smoking in relation to colorectal cancer risk.
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.
PMCID: PMC2906477  PMID: 20534171
12.  Alendronate improves QOL of postmenopausal women with osteoporosis 
Postmenopausal osteoporosis causes bone fracture as well as pain, physical, psychological and socially adverse effects, which affects a patient’s quality of life (QOL). The effect of alendronate on QOL was investigated compared with that of alfacalcidol in post-menopausal osteoporotic women.
Patients and methods:
A total of 44 postmenopausal osteoporotic women (mean age 69.8 years) with back or joint pain, although capable of walking, were randomly assigned to two groups; group A (n = 25) received 5 mg/day of alendronate, and group B (n = 19) received 0.5 μg/day of alfacalcidol, for the first 4 months. For the following 2 months, the group A received 0.5 μg/day of alfacalcidol and the group B received 5 mg/day of alendronate in a crossover design. The patient’s QOL was evaluated by score of Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), and pain intensity using a visual analog scale (VAS). Bone metabolism was measured by bone mineral density (BMD) and a biomarker for bone resorption, urinary crosslinked N-terminal telopeptide of type I collagen (NTX).
With 4-month treatment, alendronate, but not alfacalcidol, improved pain-related QOL, reduced joint pain by VAS, and increased bone mineral density. Both treatments significantly reduced bone resorption, the inhibition was significantly higher with alendronate (−56.5%) compared with alfacalcidol (−18.1%). After crossover, the patients in group A received alfacalcidol and had a reduced total and daily living activity-related QOL scores, and increased upper back pain by VAS. The group B received alendronate had significantly reduced bone resorption after the 2 months.
Alendronate improves the QOL of Japanese postmenopausal women with osteoporosis by reducing pain intensity as well as increasing bone mineral density.
PMCID: PMC2861847  PMID: 20458350
osteoporosis; bisphosphonates; quality of life; pain; vitamin D
13.  Waist circumference and insulin resistance: a cross-sectional study of Japanese men 
Visceral obesity is positively related to insulin resistance. The nature of the relationship between waist circumference and insulin resistance has not been known in Japanese populations. This study examined the relationship between waist circumference and insulin resistance and evaluated the optimal cutoff point for waist circumference in relation to insulin resistance in middle-aged Japanese men.
Study subjects included 4800 Japanese men aged 39 to 60 years. Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR). The relationship of waist circumference with HOMA-IR was assessed by use of adjusted means of HOMA-IR and odds ratios of elevated HOMA-IR defined as the highest quintile (≥2.00). Receiver operating characteristics (ROC) curve analysis using Youden index and the area under curve (AUC) was employed to determine optimal cutoffs of waist circumference in relation to HOMA-IR.
Adjusted geometric means of HOMA-IR and prevalence odds of elevated HOMA-IR were progressively higher with increasing levels of waist circumference. In the ROC curve analysis, the highest value of Youden index was obtained for a cutoff point of 85 cm in waist circumference across different values of HOMA-IR. Multiple logistic regression analysis also indicated that the AUC was consistently the largest for a waist circumference of 85 cm.
Waist circumference is linearly related to insulin resistance, and 85 cm in waist circumference is an optimal cutoff in predicting insulin resistance in middle-aged Japanese men.
PMCID: PMC2635363  PMID: 19138424
15.  Sugars, sucrose and colorectal cancer risk: the Fukuoka colorectal cancer study 
A diet high in sugars may promote colorectal carcinogenesis, but it remains uncertain whether high intake of sugars or sucrose confers increased risk of colorectal cancer. The authors investigated the associations of sugars and sucrose intake with colorectal cancer risk in a community-based case–control study in Japan.
The study subjects comprised 816 incident cases of colorectal cancer and 815 community controls. Consumption frequencies and portion sizes of 148 food and beverage items were ascertained by a computer-assisted interview. The authors used the consumption of 29 food items to estimate sugars and sucrose intake. The odds ratios of colorectal cancer risk according to intake categories were obtained using a logistic regression model with adjustment for potential confounding variables.
Overall, intakes of sugars and sucrose were not related to colorectal cancer risk either in men or women. The association between sugars intake and colorectal cancer risk differed by smoking status and alcohol use in men, but not in women. In men, sugars intake tended to be associated with colorectal cancer risk inversely among never-smokers and positively among male ever-smokers (interaction p = 0.01). Sugars intake was associated with an increased risk among men with no alcohol consumption, but was unrelated to the risk among male alcohol drinkers (interaction p = 0.02). Body mass index did not modify the association with sugars intake in either men or women.
Sugars intake was associated with increased risk of colorectal cancer among smokers and non-alcohol drinkers in men selectively.
PMCID: PMC4025586  PMID: 24716480
colorectal cancer; fructose; sucrose; sugars

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