Akihisa Hidaka

Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: the Japan Public Health Center-based prospective study

The association between alcohol consumption, genetic polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and gastric cancer risk is not completely understood. We investigated the association between ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms, alcohol consumption and the risk of gastric cancer among Japanese subjects in a population-based, nested, case-control study (1990-2004). Among 36 745 subjects who answered the baseline questionnaire and provided blood samples, 457 new gastric cancer cases matched to 457 controls were used in the analysis. The odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated using logistic regression models. No association was observed between alcohol consumption, ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms and gastric cancer risk. However, considering gene-environmental interaction, ADH1C G allele carriers who drink ≥150 g/week of ethanol had a 2.5-fold increased risk of gastric cancer (OR = 2.54, 95% CI = 1.05-6.17) relative to AA genotype carriers who drink 0 to <150 g/week (P for interaction = 0.02). ALDH2 A allele carriers who drink ≥150 g/week also had an increased risk (OR = 2.08, 95% CI = 1.05-4.12) relative to GG genotype carriers who drink 0 to < 150 g/week (P for interaction = 0.08). To find the relation between alcohol consumption and gastric cancer risk, it is important to consider both alcohol consumption level and ADH1C and ALDH2 polymorphisms.

Plasma insulin, C-peptide and blood glucose and the risk of gastric cancer: The Japan Public Health Center-based prospective study

To date, the association between diabetes mellitus (DM) and gastric cancer has been controversial, including the underlying mechanism. We investigated the association between plasma diabetic biomarkers (insulin, C‐peptide, and blood glucose) and gastric cancer risk. In addition, homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of β‐cell function (HOMA‐β) were calculated. A total of 36,745 subjects aged 40–69 years in the Japan Public Health Center‐based prospective study (JPHC) who returned the baseline questionnaire and provided blood samples were followed from 1990 to 2004. In the present analysis, 477 cases and 477 matched controls were used. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for developing gastric cancer were calculated using conditional logistic regression models. Plasma insulin was positively associated with increased risk of gastric cancer; compared to tertile 1, ORs were 1.69 (95% CI = 1.11–2.59) and 2.01 (1.19–3.38) for tertiles 2 and 3, respectively (p for trend = 0.009). In men, C‐peptide was also positively associated with a significant risk; corresponding ORs were 1.42 (0.85–2.38) and 1.91 (1.03–3.54), respectively (p for trend = 0.04). These findings were confirmed for blood samples from the fasting group (≥8 hr after a meal). Higher HOMA‐IR was also associated with increased risk, whereas no association was observed for blood glucose. Our findings suggest that Japanese population with higher insulin and C‐peptide levels derived from insulin resistance have an elevated risk of gastric cancer.

Fish, n-3 PUFA consumption, and pancreatic cancer risk in Japanese: a large, population-based, prospective cohort study.

BACKGROUND Most previous prospective studies in Western countries found no association between consumption of fish and n-3 (ω-3) polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), for which the main source is fish, and pancreatic cancer risk. However, prospective evidence is still lacking among populations who have a relatively higher fish consumption. OBJECTIVE We investigated the association between fish and n-3 PUFA consumption and pancreatic cancer risk in a population-based, prospective study in Japanese men and women. DESIGN The Japan Public Health Center-based Prospective Study (JPHC study) has enrolled 140,420 subjects. We analyzed data on 82,024 eligible participants aged 45-74 y without a history of cancer who responded to a validated food-frequency questionnaire that included 138 items in 1995 for cohort I and in 1998 for cohort II. Participants were followed through 2010. HRs and corresponding 95% CIs for the highest compared with lowest quartile were calculated by using multivariable-adjusted Cox proportional hazards regression models. RESULTS During 1,068,774 person-years of follow-up, 449 newly diagnosed pancreatic cancers were identified. After the exclusion of pancreatic cancer cases in the first 3 y of follow-up, we found an inverse association of marine n-3 PUFA (EPA+DPA+DHA) and DHA consumption with pancreatic cancer risk: compared with the lowest quartile, multivariate-adjusted HRs in the highest quartile were 0.70 (95% CI: 0.51, 0.95; P-trend = 0.07) and 0.69 (0.51, 0.94; P-trend = 0.03), respectively. Associations for total fish, n-3 PUFA, EPA, and DPA consumption were similar but were not significant. CONCLUSION High n-3 PUFA, especially marine n-3 PUFAs, and DHA consumption was associated with a lower risk of pancreatic cancer in a population with a large variation in fish consumption, although the data apply to only a portion of the JPHC study subjects.

High hemoglobin A1c levels within the non-diabetic range are associated with the risk of all cancers

Previous studies have reported associations between diabetes and cancer risk. However, specific association of hemoglobin A1c (HbA1c) levels with cancer risk remains inconclusive. We followed 29,629 individuals (11,336 men; 18,293 women) aged 46–80 years who participated in the Japan Public Health Center‐based prospective study who had HbA1c measurements available and were cancer‐free at baseline. Cancer incidence was assessed by systemic surveys. We estimated hazard ratios (HRs) for cancer risk with adjustment for age sex, geographic area, body mass index, smoking status, physical activity, alcohol, coffee, vegetable and total energy consumption, and history of cardiovascular disease. After a median follow‐up of 8.5 years, 1,955 individuals had developed cancer. Higher HbA1c levels within both the non‐diabetic and diabetic ranges in individuals without known diabetes were associated with overall cancer risk. Compared with individuals without known diabetes and HbA1c levels of 5.0–5.4%, the HRs for all cancers were 1.27 (95% confidence interval, 1.07–1.52); 1.01 (0.90–1.14); 1.28 (1.09–1.49); and 1.43 (1.14–1.80) for individuals without known diabetes and HbA1c levels <5.0%, 5.5–5.9%, 6.0–6.4%, and ≥6.5%, respectively, and 1.23 (1.02–1.47) for individuals with known diabetes. The lowest HbA1c group had the highest risk of liver cancer, and HbA1c levels were linearly associated with the risk of all cancers after excluding liver cancer (P for linear trend, 0.004). In conclusion, our findings corroborate the notion that glycemic control in individuals with high HbA1c levels may be important not only to prevent diabetes but also to prevent cancer.

Coffee and green tea consumption in relation to brain tumor risk in a Japanese population.

Few prospective studies have investigated the etiology of brain tumor, especially among Asian populations. Both coffee and green tea are popular beverages, but their relation with brain tumor risk, particularly with glioma, has been inconsistent in epidemiological studies. In this study, we evaluated the association between coffee and greed tea intake and brain tumor risk in a Japanese population. We evaluated a cohort of 106,324 subjects (50,438 men and 55,886 women) in the Japan Public Health Center‐Based Prospective Study (JPHC Study). Subjects were followed from 1990 for Cohort I and 1993 for Cohort II until December 31, 2012. One hundred and fifty‐seven (70 men and 87 women) newly diagnosed cases of brain tumor were identified during the study period. Hazard ratio (HR) and 95% confidence intervals (95%CIs) for the association between coffee or green tea consumption and brain tumor risk were assessed using a Cox proportional hazards regression model. We found a significant inverse association between coffee consumption and brain tumor risk in both total subjects (≥3 cups/day; HR = 0.47, 95%CI = 0.22–0.98) and in women (≥3 cups/day; HR = 0.24, 95%CI = 0.06–0.99), although the number of cases in the highest category was small. Furthermore, glioma risk tended to decrease with higher coffee consumption (≥3 cups/day; HR = 0.54, 95%CI = 0.16–1.80). No association was seen between green tea and brain tumor risk. In conclusion, our study suggested that coffee consumption might reduce the risk of brain tumor, including that of glioma, in the Japanese population.

Alcohol consumption, genetic variants in the alcohol- and folate metabolic pathways and colorectal cancer risk: the JPHC Study

The association between alcohol intake and colorectal cancer (CRC) may vary secondary to single nucleotide polymorphisms (SNPs) in two pathways related to alcohol intake. 375 cases of CRC were identified among 38 373 Japan Public Health Center-based prospective Study (JPHC Study) participants who had returned a baseline questionnaire, reported no diagnosis of any cancer and provided blood samples. For each case, two controls were selected on matching variables. Logistic regression models were used to determine matched Odds Ratios (OR) and 95% Confidence Intervals (CI) for the association between alcohol consumption, genetic polymorphisms of enzymes in the alcohol- and folate metabolic pathways (e.g. methylenetetrahydrofolate reductase (MTHFR) rs1801133) and CRC risk. Compared to never/occasional alcohol intake, moderate to heavy alcohol intake was associated with CRC (OR = 2.12, 95% CI, 1.34–3.36). When compared to the CC genotype, the MTHFR rs1801133 CT/TT genotype was inversely associated with CRC (OR = 0.72, 95% CI, 0.54–0.97). Never/occasional consumers of alcohol with the MTHFR rs1801133 CT/TT genotype were also at a reduced risk of CRC compared to never/occasional drinkers with the CC genotype (OR = 0.68, 95% CI, 0.47–0.98) (P for interaction = 0.27). The results indicate that the folate pathway is likely to be involved in alcohol-related CRC development.

Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort

Abstract Objective To evaluate the association between pre-diagnostic circulating vitamin D concentration and the subsequent risk of overall and site specific cancer in a large cohort study. Design Nested case-cohort study within the Japan Public Health Center-based Prospective Study cohort. Setting Nine public health centre areas across Japan. Participants 3301 incident cases of cancer and 4044 randomly selected subcohort participants. Exposure Plasma concentration of 25-hydroxyvitamin D measured by enzyme immunoassay. Participants were divided into quarters based on the sex and season specific distribution of 25-hydroxyvitamin D among subcohorts. Weighted Cox proportional hazard models were used to calculate the multivariable adjusted hazard ratios for overall and site specific cancer across categories of 25-hydroxyvitamin D concentration, with the lowest quarter as the reference. Main outcome measure Incidence of overall or site specific cancer. Results Plasma 25-hydroxyvitamin D concentration was inversely associated with the risk of total cancer, with multivariable adjusted hazard ratios for the second to fourth quarters compared with the lowest quarter of 0.81 (95% confidence interval 0.70 to 0.94), 0.75 (0.65 to 0.87), and 0.78 (0.67 to 0.91), respectively (P for trend=0.001). Among the findings for cancers at specific sites, an inverse association was found for liver cancer, with corresponding hazard ratios of 0.70 (0.44 to 1.13), 0.65 (0.40 to 1.06), and 0.45 (0.26 to 0.79) (P for trend=0.006). A sensitivity analysis showed that alternately removing cases of cancer at one specific site from total cancer cases did not substantially change the overall hazard ratios. Conclusions In this large prospective study, higher vitamin D concentration was associated with lower risk of total cancer. These findings support the hypothesis that vitamin D has protective effects against cancers at many sites.

CYP1A1, GSTM1, and GSTT1 genetic polymorphisms and gastric cancer risk among Japanese: A nested case‐control study within a large‐scale population‐based prospective study

Cytochrome P450 (CYP) 1A1 and glutathione S‐transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case–control study (457 cases and 457 matched controls) of our population‐based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild‐type genotype (OR = 1.65; 95% CI = 1.17–2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild‐type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild‐type genotypes in those who were never‐smokers, CYP1A1 variant alleles in those who smoked ≥30 pack‐years were associated with an increased risk; neither gene–gene nor gene–environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population.

Body-Mass Index and Pancreatic Cancer Incidence: A Pooled Analysis of Nine Population-Based Cohort Studies With More Than 340,000 Japanese Subjects

Background A high body mass index (BMI) has been proposed as an important risk factor for pancreatic cancer. However, this association of BMI with pancreatic cancer risk has not been confirmed in Asian populations. Methods We evaluated the association between BMI (either at baseline or during early adulthood) and pancreatic cancer risk by conducting a pooled analysis of nine population-based prospective cohort studies in Japan with more than 340,000 subjects. Summary hazard ratios (HRs) were estimated by pooling study-specific HRs for unified BMI categories with a random-effects model. Results Among Japanese men, being obese at baseline was associated with a higher risk of pancreatic cancer incidence (≥30 kg/m2 compared with 23 to <25 kg/m2, adjusted HR 1.71; 95% confidence interval [CI], 1.03–2.86). A J-shaped association between BMI during early adulthood and pancreatic cancer incidence was seen in men. In contrast, we observed no clear association among women, although there may be a positive linear association between BMI at baseline and the risk of pancreatic cancer (per 1 kg/m2, adjusted HR 1.02; 95% CI, 1.00–1.05). Conclusions Pooling of data from cohort studies with a considerable number of Japanese subjects revealed a significant positive association between obesity and pancreatic cancer risk among men. This information indicates that strategies that effectively prevent obesity among men might lead to a reduced burden of pancreatic cancer, especially in Asian populations.

Body mass index change during adulthood and risk of oesophageal squamous-cell carcinoma in a Japanese population: the Japan Public Health (JPHC)-based prospective study

Background:The influence of body mass index (BMI) change during adulthood on the development of oesophageal squamous-cell carcinoma (ESCC) is unknown.Methods:Based on the Japan Public Health Center-based Prospective Study, we enrolled 103 238 participants from 1990 to 1994. Anthropometric data at age 20 years, baseline, and 5- and/or 10-year follow-up surveys were collected by questionnaire. The effect of BMI change between age 20 years and baseline on ESCC risk was estimated by Cox proportional hazards regression models. The updated BMI was taken into account by fitting a simple linear regression model for each individual, where the slope was incorporated into regressions as a time-varying variable.Results:After excluding the first 5 years of observation, we identified 342 newly diagnosed ESCC cases. An increase in BMI during adulthood was linked with a decreased risk of ESCC development, with each 1% increase per 5 years corresponding to a 15% decrease in ESCC risk (95% confidence interval 9–21%). Identical estimates were obtained from time-dependent models. The importance of BMI change was not modified by gender, smoking, or alcohol drinking but confined to participants assessed as non-overweight at baseline.Conclusions:An increase in BMI during adulthood is associated with a lower risk of developing ESCC among non-overweight subjects.