Hideo Tanaka

Long-period accelerometer monitoring shows the role of physical activity in overweight and obesity

CONTEXT:Physical activity (PA) plays an important role in obesity. A new accelerometer has been developed to assess total energy expenditure as well as PA.OBJECTIVE:To investigate the association of PA with overweight and obesity in Japanese men and women, a large cross-sectional study was performed using a single-axis accelerometer.DESIGN, SETTING AND PARTICIPANTS:Population-based cross-sectional study of Japanese 18–84u2009y of age. Height, body weight and PA were measured in 400 male and 388 female Japanese volunteers from 1999 to 2000. The outcome measurements were overweight and obesity, which are defined as a body mass index ≥25u2009kg/m2. PA was measured for 1 to 4 weeks and was then categorized into three activity levels, which were defined as light, moderate and vigorous PA.RESULTS:Prevalence of overweight and obesity was 22.3%. Number of steps and time spent in moderate and vigorous PA per day were lower in overweight and obese individuals. No difference was found in time spent in light PA. Individuals who are in the 4th and 5th quintile of moderate and vigorous PA showed a significantly lower body mass index. When odd ratios (ORs) of overweight and obesity estimated by logistic regression were used as effect measures, overweight and obesity were negatively associated with vigorous PA (ORs=0.91).CONCLUSION:These results indicate that overweight and obese individuals have a lower step rate and are spending less time for moderate to vigorous PA. Participation in vigorous PA is an important predictor of overweight and obesity.

A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population

Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer. Most GWASs to date have been conducted in women of European descent, however, and the contribution of these variants as predictors in Japanese women is unknown. Here, we analyzed 23 genetic variants identified in previous GWASs and conducted a case–control study with 697 case subjects and 1,394 age- and menopausal status-matched controls. We fit conditional regression models with genetic variants and conventional risk factors. In addition, we created a polygenetic risk score, using those variants with a statistically significant association with breast cancer risk, and also evaluated the contribution of these genetic predictors using the c statistic. Eleven single-nucleotide polymorphisms (SNPs) revealed significant associations with breast cancer risk. A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which was an aggregate measure of alleles in seven selected variants, namely FGFR2-rs2981579, TOX3/TNRC9-rs3803662, C6orf97-rs2046210, 8q24-rs13281615, SLC4A7-rs4973768, LSP1-rs38137198, and CASP8-rs10931936. Compared to women with scores of 3 or less, odds ratios (ORs) for women with scores of 4–5, 6–7, 8–9, and 10 or more were 1.33 (95% confidence interval, 1.00–1.80), 1.71 (1.26–2.30), 3.01 (1.97–4.58), and 8.69 (2.75–27.5), respectively (Ptrendxa0=xa01.9xa0×xa010−9). The c statistic for a model including the genetic risk score in addition to the conventional risk factors was 0.6933, versus 0.6652 with the conventional risk factors only (Pxa0=xa01.3xa0×xa010−4). Population-attributable fraction of the risk score was 33.0%. In conclusion, we identified a genetic risk predictor of breast cancer in a Japanese population. Risk models which include a genetic risk score are possibly useful in distinguishing women at high risk of breast cancer from those at low risk, particularly in the context of targeted prevention.

A Prospective Study of Passive Smoking and Risk of Diabetes in a Cohort of Workers: The High-Risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) study

OBJECTIVE—We investigated the impact of active smoking and exposure to passive smoke on the risk of developing diabetes. RESEARCH DESIGN AND METHODS—Data were analyzed from a cohort of participants in the High-Risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP) conducted in Japan from 1999 to 2004. Active and passive smoking status in the workplace was evaluated at baseline. RESULTS—Of 6,498 participants (20.9% women), a total of 229 diabetes cases were reported over a median 3.4 years of follow-up. In the workplace, compared with zero-exposure subjects, the multivariable-adjusted hazard ratios of developing diabetes were 1.81 (95% CI 1.06–3.08, P = 0.028) for present passive subjects and 1.99 (1.29–3.04, P = 0.002) for present active smokers. CONCLUSIONS—In this cohort, exposure to passive smoke in the workplace was associated with an increased risk of diabetes after adjustment for a large number of possible confounders.

Impact of Multiple Alcohol Dehydrogenase Gene Polymorphisms on Risk of Upper Aerodigestive Tract Cancers in a Japanese Population

Alcohol intake is positively associated with the risk of upper aerodigestive tract (UAT) cancer. The genes that encode alcohol-metabolizing enzymes, primarily alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH), are polymorphic. In Caucasians, significant associations between polymorphisms in ADH1B (rs1229984) and ADH1C (rs698 and rs1693482), and UAT cancer have been observed, despite strong linkage disequilibrium among them. Moreover, UAT cancer was significantly associated with rs1573496 in ADH7, and not with rs1984362 in ADH4. However, little evidence is available concerning ADH4 or ADH7 polymorphisms in Asian populations. We conducted a matched case-control study to clarify the role of ADH polymorphisms in a Japanese population. Cases and controls were 585 patients with UAT cancer and 1,170 noncancer outpatients. Genotyping for ADHs and ALDH2 was done using TaqMan assays. Associations between polymorphisms and UAT cancer were assessed by odds ratios and 95% confidence intervals using conditional logistic regression models that adjusted for age, sex, smoking, drinking, and ALDH2. Adjusted odds ratios were significant for rs4148887 and rs3805322 in ADH4, rs1229984 in ADH1B, rs698 and rs1693482 in ADH1C, and rs284787, rs1154460, and rs3737482 in ADH7. We also observed that ADH7 rs3737482 and ADH4 rs4148887 had independently and statistically significant effects on UAT cancer. The magnitude of effect of these ADH polymorphisms was greater in subjects who were heavy drinkers, heavy smokers, and had esophageal cancer. These findings show that multiple ADH gene polymorphisms were associated with UAT cancer in this Japanese population. Further studies in various ethnicities are required. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3097–102)

Comparison between self‐reported facial flushing after alcohol consumption and ALDH2 Glu504Lys polymorphism for risk of upper aerodigestive tract cancer in a Japanese population

Some Japanese exhibit facial flushing after drinking alcohol. Facial flushing was considered to be caused by acetaldehydemia. The concentration of blood acetaldehyde was concerned with the catalytic activity of acetaldehyde dehydrogenase (ALDH). Acetaldehyde dehydrogenase (ALDH)‐2 polymorphism (rs671, Glu504Lys) was known to be associated with upper aerodigestive tract (UAT) cancer due to modulation of ALDH2 enzyme activity. It remains controversial whether facial flushing is useful in predicting UAT cancer risk as a surrogate marker of ALDH2 polymorphism. We conducted a case–control study to assess the risk of UAT cancer and facial flushing and ALDH2 polymorphism. Cases and controls were 585 UAT cancer patients and matched 1170 noncancer outpatients of Aichi Cancer Center Hospital. Information on facial flushing and other lifestyle factors was collected via a self‐administered questionnaire. Association between facial flushing, polymorphism, and UAT cancer was assessed by odds ratios and 95% confidence intervals by using conditional logistic regression models. The facial flushing had no significant association with UAT cancer, although ALDH2 Lys allele was significantly associated with UAT cancer. No significant interaction between facial flushing and alcohol consumption was observed in this study, whereas ALDH2 Lys allele had significant association with UAT cancer. The misclassification between facial flushing and ALDH2 genotype was observed in 18% of controls with ALDH2 Glu/Glu genotype and in 16% of controls with ALDH2 Glu/Lys genotype. Facial flushing was less useful to predict UAT cancer risk than genotyping ALDH2 polymorphism. (Cancer Sci 2010)

FGFR2 intronic polymorphisms interact with reproductive risk factors of breast cancer: Results of a case control study in Japan

Recently, 2 genome‐wide association studies demonstrated that single nucleotide polymorphisms (SNPs) of the fibroblast growth factor receptor 2 (FGFR2) gene at intron 2 are significantly associated with the risk of female breast cancer. As the next step, it is necessary to evaluate the interaction between these SNPs and known risk factors of breast cancer because such an evaluation could elucidate mechanisms of carcinogenesis and lead to preventive advances. We conducted a case‐control study of 456 newly and histologically diagnosed breast cancer cases and 912 age‐ and menopausal status‐matched noncancer controls. The impact of 5 FGFR2 intronic SNPs on the risk of breast cancer and the interactions between these SNPs and various known risk factors of breast cancer were evaluated in both pre and postmenopausal women. We observed a statistically significant association between 4 SNPs and breast cancer risk and these 4 SNPs were in strong linkage disequilibrium in the Japanese population. rs2420946 was associated with a population‐attributable risk of 17.7%. We found that FGFR2 polymorphisms interact with family history of breast cancer (interaction p = 0.003) and reproductive risk factors, namely, age at menarche (interaction p = 0.019) and parity (interaction p = 0.026). Of note, a significant association between body mass index (BMI) ≥ 25 and FGFR2 polymorphism was observed among postmenopausal women (trend p = 0.012), but not among premenopausal women. In contrast, BMI < 25 had no significant association with this polymorphism regardless of menopausal status. These findings suggest that FGFR2 intronic SNPs affect the reproductive hormone‐related pathway and contribute to the development of female breast cancer in the Japanese population.

ABO blood group alleles and the risk of pancreatic cancer in a Japanese population

Several studies have investigated a possible association between the ABO blood group and the risk of pancreatic cancer (PC), but this association has not been fully evaluated in Asian populations. The present study aimed to assess the impact of genotype‐derived ABO blood types, particularly ABO alleles, on the risk of PC in a Japanese population. We conducted a case–control study using 185 PC and 1465 control patients who visited Aichi Cancer Center in Nagoya, Japan. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, all participants’ two ABO alleles were inferred. The impact of ABO blood type on PC risk was examined by multivariate analysis, with adjustment for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). An increased risk of PC was observed with the addition of any non‐O allele (trend Pu2003=u20030.012). Compared with subjects with the OO genotype, those with AO and BB genotypes had significantly increased OR of 1.67 (CI, 1.08–2.57) and 3.28 (CI, 1.38–7.80), respectively. Consistent with earlier reports showing a higher risk of PC for individuals with the non‐O blood type, the previously reported protective allele (T) for rs505922 was found to be strongly correlated (r2u2003=u20030.96) with the O allele. In conclusion, this case–control study showed a statistically significant association between ABO blood group and PC risk in a Japanese population. Further studies are necessary to define the mechanisms by which the ABO gene or closely linked genetic variants influence PC risk. (Cancer Sci 2011; 102: 1076–1080)

Association between an 8q24 locus and the risk of colorectal cancer in Japanese.

BackgroundA genome-wide association study (GWAS), which assessed multiple ethnicities, reported an association between single nucleotide polymorphisms in the 8q24 region and colorectal cancer risk. Although the association with the identified loci was strong, information on its impact in combination with lifestyle factors is limited.MethodsWe conducted a case-control study in 481 patients with colorectal cancer (CRC) and 962 sex-age matched non-cancer controls. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Two 8q24 loci, rs6983267 and rs10090154, were assessed by the TaqMan method. Associations were then assessed by multivariate logistic regression models that considered potential confounders.ResultsWe found an increased risk of CRC with rs6983267 but not with rs10090154. An allelic OR was 1.22 (1.04-1.44, p for trend = 0.014), which remained significant after adjustment for confounders (OR = 1.25). No statistically significant interaction with potential confounding factors was observed.ConclusionThe polymorphism rs6983267 showed a significant association with CRC in a Japanese population. Further investigation of the biological mechanism of this association is warranted.

Selected Polymorphisms of Base Excision Repair Genes and Pancreatic Cancer Risk in Japanese

Background Although several reports have described a possible association between DNA repair genes and pancreatic cancer (PC) in smokers, this association has not been fully evaluated in an Asian population. We assessed the impact of genetic polymorphisms in the base excision repair (BER) pathway on PC risk among Japanese. Methods This case-control study compared the frequency of 5 single-nucleotide polymorphisms (SNPs) of BER genes, namely rs1052133 in OGG1, rs1799782 and rs25487 in XRCC1, rs1130409 in APE1, and rs1136410 in PARP1. SNPs were investigated using the TaqMan assay in 185 PC cases and 1465 controls. Associations of PC risk with genetic polymorphisms and gene–environment interaction were examined with an unconditional logistic regression model. Exposure to risk factors was assessed from the results of a self-administered questionnaire. We also performed haplotype-based analysis. Results We observed that the minor allele of rs25487 in XRCC1 was significantly associated with PC risk in the per-allele model (odds ratio = 1.29, CI = 1.01–1.65; trend P = 0.043). Haplotype analysis of XRCC1 also showed a statistically significant association with PC risk. No statistically significant interaction between XRCC1 polymorphisms and smoking status was seen. Conclusions Our findings suggest that XRCC1 polymorphisms affect PC risk in Japanese.

Association between vitamin D and calcium intake and breast cancer risk according to menopausal status and receptor status in Japan

Although several studies have investigated the possible association between elevated vitamin D and calcium intake and low breast cancer risk, findings have been inconsistent. We conducted a case‐control study to clarify the association between vitamin D and calcium intake and breast cancer risk among pre‐ and post‐ menopausal women in Japan. We also investigated whether these effects were modified by tumor receptor status, specifically estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor‐2 (HER2) status. We examined 1803 breast cancer patients and 3606 age‐ and menopausal status‐matched noncancer controls. Among cases, 713 were assessed for ER, PR, and HER2 status. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional or unconditional logistic models adjusted for potential confounders. A significant inverse association was observed between vitamin D and calcium intake and breast cancer risk among all subjects, with top quartile ORs of 0.76 (95% CI, 0.63–0.90; trend Pu2003=u20030.001) and 0.83 (95% CI, 0.69–0.99; trend Pu2003=u20030.038), respectively. In analyses stratified by menopausal status, a significant association between risk and vitamin D was observed only among premenopausal women (trend Pu2003<u20030.001), whereas that between risk and calcium intake was seen only among postmenopausal women (trend Pu2003=u20030.022). Heterogeneity by menopausal status for these associations was statistically significant. This association was modified by tumor receptor status. These findings suggest that the protective effects of vitamin D and calcium intake against breast cancer risk may differ by menopausal status and receptor status.