Haruo Mikami

Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of environmental tobacco smoke and lung cancer: A case‐control study in Japanese nonsmoking women

Genetic backgrounds may modify the association of environmental tobacco smoke (ETS) with lung cancer risk. Polymorphisms of both the activating and detoxifying enzymes, cytochrome P4501A1 (CYP1A1) and glutathione‐S‐transferase M1 (GSTM1), may be important as genetic factors. We conducted a multicenter case‐control study in Japanese nonsmoking women. Cases were women aged 30–89 years and newly diagnosed as having lung cancer from November 1997 to March 2001 in 4 study areas. We also recruited age‐matched (5‐year strata) and hospital‐matched nonsmoking controls. A total of 158 cases and 259 hospital controls supplied blood for genotyping. Detailed information on ETS exposure from husbands and that in other situations and on potential confounders was collected by interview. Odds ratios (ORs) were estimated by using conditional logistic models. We found no increase in the risk of lung cancer for CYP1A1 Msp I genotypes. For the GSTM1 null genotype vs. nonnull genotype, the OR was 1.37 [95% confidence interval (CI) 0.90–2.09], which indicated a somewhat increased risk for the GSTM1 null genotype. A gene‐environment interaction was suggested, with combined GSTM1 null genotype and high‐dose ETS exposure (≥40 pack‐years by husbands) conferring significantly higher risk (OR = 2.27, 95% CI 1.13–4.57) compared to the GSTM1 nonnull genotype and low‐dose ETS exposure (<40 pack‐years). Our results do not support a major role of Msp I polymorphism of the CYP1A1 gene as a risk factor for lung cancer among nonsmoking women. In contrast, the GSTM1 null genotype posed an increased, although not significant, risk among them. Additional studies are warranted to confirm the ETS‐GSTM1 polymorphism interaction suggested in our present study.

Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study

BackgroundThe aim of this study was to explore the associations between common potential functional promoter polymorphisms in pro-/anti-inflammatory cytokine genes and kidney function/chronic kidney disease (CKD) prevalence in a large Japanese population.MethodsA total of 3,323 subjects aged 35-69 were genotyped for all 10 single nucleotide polymorphisms (SNPs) in the promoter regions of candidate genes with minor allele frequencies of > 0.100 in Japanese populations. The estimated glomerular filtration rate (eGFR) and CKD prevalence (eGFR < 60 ml/min/1.73 m2) of the subjects were compared among the genotypes.ResultsA higher eGFR and lower prevalence of CKD were observed for the homozygous variants of IL4 -33CC (high IL-4 [anti-inflammatory cytokine]-producing genotype) and IL6 -572GG (low IL-6 [pro-inflammatory cytokine]-producing genotype). Subjects with IL4 CC + IL6 GG showed the highest mean eGFR (79.1 ml/min/1.73 m2) and lowest CKD prevalence (0.0%), while subjects carrying IL4 TT + IL6 CC showed the lowest mean eGFR (73.4 ml/min/1.73 m2) and highest CKD prevalence (17.9%).ConclusionsThe functional promoter polymorphisms IL4 T-33C (rs2070874) and IL6 C-572G (rs1800796), which are the only SNPs that affect the IL-4 and IL-6 levels in Japanese subjects, were associated with kidney function and CKD prevalence in a large Japanese population.

Reproductive and menstrual factors and thyroid cancer among Japanese women: the Japan Collaborative Cohort Study.

AIM Thyroid cancer is more frequent in women than in men, suggesting the potential role of reproductive and menstrual factors in this cancer. To investigate the association with these factors, we examined 37,986 women involved in the Japan Collaborative Cohort (JACC) Study from 1988 to 1997. METHODS Reproductive and menstrual factors were assessed with a self-administered questionnaire at baseline. Hazard ratios (HR) and 95% confidence intervals (95% CI) of thyroid cancer incidence were estimated using Cox proportional hazards regression. RESULTS Eighty-six new cases of thyroid cancer were recorded during 379,281 person-years of follow-up. Overall incidence rate was 22.7 per 100,000 person-years, with a diagnosed peak of 38.2 per 100,000 at 55-59 years old. Multivariate HRs of 0.56 (95% CI 0.25-1.24) and 0.52 (95% CI 0.24-1.16) were observed for women who had experienced pregnancy or a live birth, respectively, but without statistical significance. Further, we saw no associations with other factors, such as age at menarche, age at menopause, age at first birth, or hormone use. CONCLUSIONS There was no significant association between thyroid cancer and reproductive and menstrual factors in the present study. Additional cohort studies should further examine this possible relationship among Japanese women.

Number of children and all-cause mortality risk: results from the Japan Collaborative Cohort Study.

BACKGROUND The mean total birth rate of the world had been gradually decreasing, with the rate in Japan now at its lowest level internationally. From a public health perspective, it is important to determine the impact of the number of children on all-cause mortality. METHODS A total of 96,311 individuals from the Japan Collaborative Cohort Study were followed from 1988-90 for an average of 14.4 years. Hazard ratios (HRs) with a 95% confidence interval were calculated from proportional hazard models to estimate the risk of all-cause mortality according to the number of children. RESULTS As of 2006, a total of 18,807 deaths had occurred. Both childless men and women showed higher all-cause mortality risks than those with two children (HR: 1.17 in men and 1.29 in women). Those with one child also showed higher risks (1.13 and 1.16, respectively). Having four or more children among men and five or more children among women also posed a risk (1.16 in men with four children and 1.22 in women with five or more children), showing a U-shaped association between the number of children and all-cause mortality risk. The risk of having only one child seemed evident with the decrease in age among both men and women, while the risk of having many children was apparent with the increase in age. CONCLUSION We found a U-shaped association between the number of children and all-cause mortality among both men and women, with the lowest risk among those with two children.

A variant of the CLOCK gene and related haplotypes are associated with the prevalence of type 2 diabetes in the Japanese population

Circadian rhythm disruptions can cause various health disorders. The present study evaluated associations between single nucleotide polymorphisms in the core circadian gene clock circadian regulator (CLOCK) and the prevalence of type 2 diabetes (T2D) in the Japanese population.

Variant of the clock circadian regulator (CLOCK) gene and related haplotypes are associated with the prevalence of type 2 diabetes in the Japanese population.

Circadian rhythm disruptions can cause various health disorders. The present study evaluated associations between single nucleotide polymorphisms in the core circadian gene clock circadian regulator (CLOCK) and the prevalence of type 2 diabetes (T2D) in the Japanese population.

Detailed analysis of Japanese population substructure with a focus on the Southwest Islands of Japan

Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating FST among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study.

Prospective study of transfusion history and thyroid cancer incidence among females in Japan

A link between hepatitis C virus (HCV) infection and thyroid cancer was recently reported in a series of case‐control studies in southern Italy. A prospective study could reinforce these findings. However, cohort studies that began before 1990 rarely assessed serological HCV infection. In addition, thyroid cancer is rare and generally has a good prognosis. Therefore, incidence outcome data are required, rather than mortality data, to evaluate the risk of thyroid cancer. Blood transfusion history might be a possible substitute measure to evaluate the cancer risks associated with HCV infection because blood transfusions were the major HCV transmission route in Japan until 1992. The purpose of our study was therefore to examine the association between transfusion history and thyroid cancer. A baseline survey of members of the JACC Study was conducted from 1988 until 1990, which involved 110,792 participants from 45 areas throughout Japan. Data were collected from a total of 37,983 women with no history of cancer at the baseline (337,906 person‐years) and 79 cases of thyroid cancer were identified among this group. A history of blood transfusion marginally increased the risk of thyroid cancer [risk ratio (RR) = 1.77, 95% confidence interval (CI) = 0.95–3.30], and a history of transfusion and/or liver disease significantly increased the thyroid cancer risk (RR = 1.84, 95% CI = 1.07–3.16). These results indirectly support an association between HCV and thyroid cancer. In addition, our data reveal an association between blood transfusion and thyroid cancer, which might be facilitated by transfusion‐associated immunomodulation.

Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: A cross-sectional analysis of the Japan Multi-institutional Collaborative Cohort Study.

AIMS Brain-muscle-Arnt-like protein-1 (BMAL1) and BMAL2 genes are essential components of the circadian clock, and are considered to be involved in glucose homeostasis. We examined whether single nucleotide polymorphisms (SNPs) of BMAL1 and BMAL2 were associated with the prevalence of type 2 diabetes (T2DM) in the general Japanese population. METHODS We studied 2467 subjects (1232 men and 1235 women, 35-69 years old), including 105 men and 57 women with T2DM, from the participants of the Japan Multi-institutional Collaborative Cohort Study. The association between SNPs in the BMAL1 (rs11022775 and rs2290035) and BMAL2 (rs7958822) genes and T2DM were analyzed by multiple logistic regression after adjustment for potential confounders. Analysis was also performed after stratification by body mass index (≥25 kg/m(2) and <25 kg/m(2)) to investigate an interaction between genotypes and obesity. RESULTS The A/G and A/A genotypes of BMAL2 rs7958822 showed significantly higher adjusted odds ratios (OR) for T2DM than the G/G genotype among obese men (OR=2.2, 95% confidence intervals [CI] 1.1, 4.6, P for interaction=0.0495) and obese women (OR=2.7, 95% CI 1.1, 6.7, P for interaction=0.199). There were no significant associations between BMAL1 rs11022775 or rs2290035 genotypes and T2DM. CONCLUSIONS To the best of our knowledge, this is the first study to show the significant association between BMAL2 rs7958822 genotype and T2DM among obese subjects.

Effect of the PPARG2 Pro12Ala polymorphism and clinical risk factors for diabetes mellitus on HbA1c in the Japanese general population.

Background Although the peroxisome proliferator-activated receptor-γ2 (PPARG2) Pro12Ala gene variant is associated with diabetes mellitus, the associations and interactions of this polymorphism and known clinical risk factors with glycated hemoglobin (HbA1c) remain poorly understood. We investigated if carrying the Ala allele was inversely associated with HbA1c level and examined possible interactions. Methods This cross-sectional analysis used data collected from 1281 men and 1356 women aged 40 to 69 years who completed the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. PPARG2 polymorphism was determined by multiplex polymerase chain reaction (PCR)-based Invader assay. Multiple linear regression and ANCOVA were used to control for confounding variables (age, body mass index [BMI], energy intake, alcohol, smoking, physical activity, and family history of diabetes) and examine possible interactions. Results After adjustment, the Ala allele was significantly inversely associated with HbA1c in women but not in men. Older age, BMI, and family history of diabetes were associated with higher HbA1c in both sexes. When stratified by PPARG2 genotype, these associations were observed in subjects with the Pro12Pro genotype but not in Ala allele carriers. A significant interaction of genotype and BMI on HbA1c was observed in women. Older age, BMI, and family history of diabetes were significantly associated with high-normal HbA1c (≥5.7% NGSP), whereas PPARG2 polymorphism was not. Conclusions Although PPARG2 Pro12Ala polymorphism might attenuate associations between known risk factors and HbA1c level, it had a small effect on high-normal HbA1c, as compared with clinical risk factors, in the general population.