Association of genetic risk score and chronic kidney disease in a Japanese population.

Chronic kidney disease (CKD) is a public health problem worldwide including Japan. Recent genome-wide association studies have discovered CKD susceptibility variants. We developed a genetic risk score (GRS) based on CKD-associated variants and assessed a possibility that the GRS can improve the discrimination capability for the prevalence of CKD in a Japanese population. The present study consists of 11 283 participants randomly selected from 12 Japan Multi-Institutional Collaborative Cohort Study sites. Individual GRS was constructed combining 18 single-nucleotide polymorphisms identified in a Japanese population. Participants with eGFR <60 mL/min per 1.73 m2 was defined as case (stage 3 CKD or higher) in this study. Logistic regression analysis was used to examine the association between the GRS and CKD risk with adjustment for sex, age, hypertension and type 2 diabetes mellitus. The frequency of individuals with CKD was 8.3%, which was relatively low compared with those previously reported in a Japanese population. The odds ratio of having CKD was 1.120 (95% confidence interval: 1.042-1.203) per 10 GRS increment in the fully adjusted model (P = 0.002). The C-statistic was significantly increased in the model with the GRS, comparing with the model without the GRS (0.720 vs 0.719, Pdifference = 0.008). Increment of the GRS was associated with increased risk of CKD. Additionally, the GRS significantly improved the discriminatory ability of CKD prevalence in a Japanese population; however, the improvement of discriminatory ability brought about by the GRS seemed to be small compared with that of non-genetic CKD risk factors.

Eating rate as risk for body mass index and waist circumference obesity with appropriate confounding factors: a cross-sectional analysis of the Shizuoka-Sakuragaoka J-MICC Study.

BACKGROUND AND OBJECTIVES: The relationship between eating rate (ER) and increased risk of obesity in relation to body mass index (BMI, i.e., total body fat) and waist circumference (WC, i.e., abdominal fat) has not been fully examined. Considering gender differences, we identified unknown confounding factors (CFs) for each risk, and then assessed the two actual obesity risks, adjusting for the CFs. METHODS AND STUDY DESIGN: Using a questionnaire, we collected data for ER (slow, normal as "reference," and fast) and related factors and measured BMI and WC for 3,393 men and 2,495 women. Using multiple logistic regression models, odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated adjusting for both conventional and candidate CFs. RESULTS: The following factors were identified as appropriate CFs, but were differed between the two obesity types: fast food consumption in both genders, sleep duration and restaurants/food service use in men, and family structure and packed lunch in women. In men, actual risks of BMI obesity and WC obesity were negatively associated with slow ER (ORs and 95% CIs; 0.70 and 0.52-0.96, and 0.69 and 0.50-0.96), but positively associated with fast ER (1.48 and 1.25-1.76, and 1.45 and 1.21-1.74). In women, those risks were positively related to fast ER (1.78 and 1.39-2.26, and 1.34 and 1.11-1.61). CONCLUSIONS: For both BMI obesity risk and WC obesity risk, we conclude that slow and fast ER were related to decreased and increased risks when adjusted for appropriate CFs, which differed by gender and the obesity type.

Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. RESULTS: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. CONCLUSION: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

Genome-wide association study for pollinosis identified two novel loci in interleukin (IL)-1B in a Japanese population.

The number of pollinosis patients in Japan has significantly increased over the past 20 years. The majority of genome-wide association studies (GWAS) on pollinosis have been conducted in subjects of European descent, with few studies in Japanese populations. The aim of our GWAS was to identify genetic loci associated with self-reported pollinosis in a Japanese population and to understand its molecular background using a combination of single nucleotide polymorphisms (SNPs) and gene- and pathway-based analyses. A total of 731 and 560 individuals who were recruited as participants of the Japan Multi-Institutional Collaborative Cohort Study participated in the discovery and replication phases, respectively. The phenotype of pollinosis was based on the information from a self-administered questionnaire. In the single-SNP analysis, four SNPs (rs11975199, rs11979076, rs11979422, and rs12669708) reached suggestive significance level (P < 1 × 10-4) and had effects in the same direction in both phases of the study. The pathway-based analysis identified two suggestive pathways (nucleotide-binding oligomerization domain -like receptor and tumor necrosis factor signaling pathways). Both rs1143633 and rs3917368 in the interleukin-1B gene showed associations in the retrace (from pathway to gene and SNP) analysis. We performed single-SNP, gene, and pathway analysis and shed light on the molecular mechanisms underlying pollinosis in a Japanese population.

Inter- and intra-individual variations in seasonal and daily stabilities of the human gut microbiota in Japanese.

Relationships between human gut microbiota, dietary habits, and health/diseases are the subject of epidemiological and clinical studies. However, the temporal stability and variability of the bacterial community in fecal samples remain unclear. In this study, middle-aged Japanese male and female volunteers (n = 5 each) without disease were recruited from the Sakura Diet Study. Fecal samples and lifestyle information were collected in every quarter and at each defecation for 7 continuous days. Next-generation sequencing of 16S rDNA and hierarchical clustering showed no time trend and intra-individual differences in both fecal sample sets. Significant inter-individual variations in seasonal and daily fecal sample sets were detected for 24 and 23 out of 39 selected dominant genera (>0.1% of the total human gut microbiota; occupation rate >85%), respectively. Intra- to inter-individual variance ratios in 26 and 35 genera were significantly <1.0 for seasonal and daily stabilities. Seasonal variation in fermented milk consumption might be associated with Bifidobacterium composition, but not with Lactobacillus. For most of the dominant genera in the human gut microbiota, inter-individual variations were significantly larger than intra-individual variations. Further studies are warranted to determine the contributions of human gut microbiota to nutritional metabolism, health promotion, and prevention/development of diseases.

Evaluation of cyanocobalamin in multivitamin tablets and their Standard Reference Material 3280 by HPLC with visible detection.

As a part of the development of an alternative to microbiological assay for vitamin B12, we performed a quantitative analysis of cyanocobalamin (CN-cbl) in a National Institute of Standards and Technology Standard Reference Material (SRM 3280) by HPLC. Using this method, the observed value (4.64 microg/g) of CN-cbl in SRM 3280 was found to be in good agreement with the certified value (4.80 microg/g). The accuracy was over 95%, with a corresponding measurement precision value of 5%. To evaluate the applicability of the method on commercial multivitamin tablets, the method was applied to a variety of these samples. The present method has a good accuracy and precision to evaluate CN-cbl with respect to all of the examined tablets.

Some Japanese mothers do not follow package instructions of infant formula: a web-based analytical cross-sectional study.

BACKGROUND: Not following the infant formula package instruction endangers infant health. Although infant formula misuse has been reported abroad, its incidence in Japan remains unknown. Furthermore, it is reasonable to assume that experience in childcare reduces the likelihood of making mistakes in using infant formula. This study aimed to examine the association between compliance with infant formula package instruction and childcare experience in Tokyo and surrounding prefectures in Japan. METHODS: Using a web-based questionnaire, mothers with infants were analyzed cross-sectionally and surveyed regarding their infants' nutrition and formula preparation methods in August 2021. Compliance with the infant formula package was determined according to (a) using unlabeled infant formula, (b) preparing infant formula without reading package instructions, (c) giving formula to children ≥ 2 h after preparing, and (d) adding other ingredients to the formula bottle. The association between the misuse of infant formula and childcare experience was examined by grouping the participants by infant age (< 6 months and ≥ 6 months), and by comparing first-born child status with later-born. Of the 333 mothers with infants, 3 were excluded due to out-of-scope responses, and 330 were included in the analysis. RESULTS: The major sources of information on infant feeding methods among the participants were obstetric facilities (92.1%), internet (36.1%), and family (20.9%). The proportions of participants using infant formulas not labeled as "infant formula," such as follow-up milk, not preparing at prescribed concentrations, feeding infant formulas > 2 h after preparation, and adding additional ingredients to the bottle were 7.9%, 4.1%, 23.1%, and 15.9%, respectively, which suggest the misuse of infant formula. These four answers did not differ significantly between mothers of children aged < 6 months and ≥ 6 months or between those with first-born and later-born children. CONCLUSION: This study suggested that some Japanese mothers do not follow package instructions of infant formula in Japan. The misuse of infant formula may not be related to the length of time spent in childcare or the presence or absence of childcare experience. Providing appropriate information on the correct use of infant formula to all caregivers, regardless of their parenting experience, is required.

Independent relationships of daily life activity and leisure-time exercise with metabolic syndrome and its traits in the general Japanese population.

PURPOSE: This study aimed to investigate independent relationships of daily non-exercise life activity and leisure-time exercise volume and intensity with the prevalence of metabolic syndrome and its traits in Japanese adults. METHODS: Data of 24,625 eligible subjects (12,709 men, 11,916 women) who participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were analyzed. Information about lifestyle characteristics was obtained from a questionnaire. Logistic regression analyses were performed to evaluate the independent associations of daily life activity as well as leisure-time exercise volume and intensity with the prevalence of metabolic syndrome and its traits by sex. RESULTS: Male subjects with higher daily life activity as well as with higher leisure-time exercise volume had a lower prevalence of metabolic syndrome, independently with each other. Female subjects with higher daily life activity also had a lower prevalence of metabolic syndrome. Particularly, male and female subjects with the highest daily life activity quartile showed considerably low odds ratios of 0.66 (95% CI, 0.53-0.81) and 0.64 (0.52-0.79), respectively, for low HDL-cholesterol even after the adjustment for BMI compared with the first quartile. Meanwhile, male subjects with the higher leisure-time exercise showed a quite lower prevalence of elevated triglycerides. Higher moderate-intensity exercise was more intensely associated with a lower prevalence of metabolic syndrome and some of its traits in both sexes. CONCLUSIONS: Our results suggest that higher daily life activity and higher moderate-intensity exercise may be independently associated with a lower risk of metabolic syndrome in Japanese adults.

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals.

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.

Genome-wide association meta-analysis and Mendelian randomization analysis confirm the influence of ALDH2 on sleep durationin the Japanese population.

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.

Association of exposure level to passive smoking with hypertension among lifetime nonsmokers in Japan: a cross-sectional study.

Brief exposure to passive smoking immediately elevates blood pressure. However, little is known about the association between exposure to passive smoking and chronic hypertension. We aimed to examine this association in a cross-sectional study, after controlling multiple potential confounders.Participants included 32,098 lifetime nonsmokers (7,216 men and 24,882 women) enrolled in the Japan Multi-Institutional Collaborative Cohort Study. Passive smoking was assessed using a self-administered questionnaire. The single question about exposure to passive smoking had five response options: "sometimes or almost never," "almost every day, 2 hours/day or less," "almost every day, 2 to 4 hours/day," "almost every day, 4 to 6 hours/day," and "almost every day, 6 hours/day or longer." Hypertension was defined as any of the following: systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or use of antihypertensive medication. Multivariate-adjusted odds ratio (OR) and 95% confidence interval (CI) for hypertension were estimated by exposure level to passive smoking using unconditional logistic regression models.The multivariate-adjusted OR for hypertension in those exposed almost every day was 1.11 (95% CI: 1.03-1.20) compared with those exposed sometimes or almost never. The OR for a 1-hour per day increase in exposure was 1.03 (95% CI: 1.01-1.06, Pfor trend = .006). This association was stronger in men than in women; the ORs were 1.08 (95% CI: 1.01-1.15, Pfor trend = .036) and 1.03 (95% CI: 1.00-1.05, Pfor trend = .055), respectively.Our findings suggest importance of tobacco smoke control for preventing hypertension.

A genome-wide association study in the Japanese population identifies the 12q24 locus for habitual coffee consumption: The J-MICC Study.

Coffee is one of the most widely consumed beverages worldwide, and its role in human health has received much attention. Although genome-wide association studies (GWASs) have investigated genetic variants associated with coffee consumption in European populations, no such study has yet been conducted in an Asian population. Here, we conducted a GWAS to identify common genetic variations that affected coffee consumption in a Japanese population of 11,261 participants recruited as a part of the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. Coffee consumption was collected using a self-administered questionnaire, and converted from categories to cups/day. In the discovery stage (n = 6,312), we found 2 independent loci (12q24.12-13 and 5q33.3) that met suggestive significance (P < 1 × 10-6). In the replication stage (n = 4,949), the lead variant for the 12q24.12-13 locus (rs2074356) was significantly associated with habitual coffee consumption (P = 2.2 × 10-6), whereas the lead variant for the 5q33.3 locus (rs1957553) was not (P = 0.53). A meta-analysis of the discovery and replication populations, and the combined analysis using all subjects, revealed that rs2074356 achieved genome-wide significance (P = 2.2 × 10-16 for a meta-analysis). These findings indicate that the 12q24.12-13 locus is associated with coffee consumption among a Japanese population.

Genomewide Association Study of Leisure-Time Exercise Behavior in Japanese Adults.

PURPOSE: Although several genetic factors may play a role in leisure-time exercise behavior, there is currently no evidence of a significant genomewide association, and candidate gene replication studies have produced inconsistent results. METHODS: We conducted a two-stage genomewide association study and candidate single-nucleotide polymorphisms (SNP) association study on leisure-time exercise behavior using 13,980 discovery samples from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, and 2036 replication samples from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center-2 study. Leisure-time physical activity was measured using a self-administered questionnaire that inquired about the type, frequency and duration of exercise. Participants with ≥4 MET·h·wk of leisure-time physical activity were defined as exhibiting leisure-time exercise behavior. Association testing using mixed linear regression models was performed on the discovery and replication samples, after which the results were combined in a meta-analysis. In addition, we tested six candidate genetic variants derived from previous genomewide association study. RESULTS: We found that one novel SNP (rs10252228) located in the intergenic region between NPSR1 and DPY19L1 was significantly associated with leisure-time exercise behavior in discovery samples. This association was also significant in replication samples (combined P value by meta-analysis = 2.2 × 10). Several SNP linked with rs10252228 were significantly associated with gene expression of DPY19L1 and DP19L2P1 in skeletal muscle, heart, whole blood, and the nervous system. Among the candidate SNP, rs12612420 in DNAPTP6 demonstrated nominal significance in discovery samples but not in replication samples. CONCLUSIONS: We identified a novel genetic variant associated with regular leisure-time exercise behavior. Further functional studies are required to validate the role of these variants in exercise behavior.

Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-analysis of 11 randomized controlled trials.

BACKGROUND: Clinical trials have reported the cholesterol-lowering effects of soy protein intake, but the components responsible are not known. OBJECTIVE: This meta-analysis was primarily conducted to evaluate the precise effects of soy isoflavones on lipid profiles. The effects of soy protein that contains enriched and depleted isoflavones were also examined. DESIGN: PUBMED was searched for English-language reports of randomized controlled trials published from 1990 to 2006 that described the effects of soy protein intake in humans. Eleven studies were selected for the meta-analysis. RESULTS: Soy isoflavones significantly decreased serum total cholesterol by 0.10 mmol/L (3.9 mg/dL or 1.77%; P = 0.02) and LDL cholesterol by 0.13 mmol/L (5.0 mg/dL or 3.58%; P < 0.0001); no significant changes in HDL cholesterol and triacylglycerol were found. Isoflavone-depleted soy protein significantly decreased LDL cholesterol by 0.10 mmol/L (3.9 mg/dL or 2.77%; P = 0.03). Soy protein that contained enriched isoflavones significantly decreased LDL cholesterol by 0.18 mmol/L (7.0 mg/dL or 4.98%; P < 0.0001) and significantly increased HDL cholesterol by 0.04 mmol/L (1.6 mg/dL or 3.00%; P = 0.05). The reductions in LDL cholesterol were larger in the hypercholesterolemic subcategory than in the normocholesterolemic subcategory, but no significant linear correlations were observed between reductions and the starting values. No significant linear correlations were found between reductions in LDL cholesterol and soy protein ingestion or isoflavone intakes. CONCLUSIONS: Soy isoflavones significantly reduced serum total and LDL cholesterol but did not change HDL cholesterol and triacylglycerol. Soy protein that contained enriched or depleted isoflavones also significantly improved lipid profiles. Reductions in LDL cholesterol were larger in hypercholesterolemic than in normocholesterolemic subjects.

Vulnerability of folate in plasma and bone marrow to total body irradiation in mice.

PURPOSE: To examine how folate status in a body is influenced by oxidative stress. MATERIAL AND METHODS: Mice were given total body irradiation (TBI) by X-ray, and changes in the concentration of folate were compared to those in vitamins C and E. RESULTS: In a time-dependent study, folate in plasma and bone marrow decreased from 5 h until 120 h post-TBI at 3 Gy. Folate in plasma and bone marrow decreased in a dose-dependent manner at 24 h. Marked decreases of vitamins C and E were also detected in bone marrow, but not in plasma even at 10 Gy of TBI. The susceptibility of plasma folate by irradiation was confirmed by an in vitro exposure study. Neither vitamins C and E nor folate were decreased in the liver by TBI. CONCLUSION: It is suggested that folate is vulnerable to oxidative stress, and folate may need to be evaluated, particularly for TBI or radiotherapy.

Bilobalide in Ginkgo biloba extract is a major substance inducing hepatic CYPs.

In a search for substances related to the marked induction of hepatic cytochrome P450 (CYP) by ginkgo biloba extract (GBE), mice were given either GBE (1000 mg kg(-1)) or fractions of GBE for 5 days. The content and activity of CYPs were induced markedly by a bilobalide-rich fraction, but not by flavonoid-rich fractions. The level of induction by the bilobalide-rich fraction was almost the same as that induced by the unfractionated GBE, suggesting that bilobalide is largely responsible for the CYPs induction. To confirm these findings, mice were given various doses of bilobalide (10.5, 21 and 42 mg kg(-1)), or GBE (1000 mg kg(-1), containing bilobalide at 42 mg kg(-1)). Treatment with bilobalide induced CYPs markedly and in a dose-dependent manner, and the level of induction was quite similar between bilobalide (42 mg kg(-1)) and GBE. Treatment with GBE and with bilobalide greatly induced pentoxyresorufin O-dealkylase activity. These findings indicate that bilobalide is the major substance in GBE that induces hepatic CYPs.

Actual Daily Intakes of Tea Catechins and Thier Estimation According to Four Season 3 Day Weighed Dietary Records and a Short Food Frequency Questionnaire among Japanese Men and Women

Background: Tea catechins are considered to be important preventive factors of cancer on several organs; however, the relationships of the actual daily intakes (ADIs) on the preventive effects have not been adequately addressed. We measured the ADIs of tea catechins as annual averages derived from every their ingested cups recorded by each subject, and the estimation models were established considering tea origin. Methods: Fifty-nine Japanese men and women completed four season 3 day weighed dietary records (WDRs) and a food frequency questionnaire (FFQ), and samples of green, oolong and black teas, ingested during a total 12 days were collected for the analysis. The ADIs of the total and composed catechins of all tea samples were measured by a high-performance liquid chromatography. The estimation models for the ADIs (R2: coefficient of determination) based on the WDRs and FFQ were established with multiple regression analysis using appropriate confounding factors. Results: The ADIs of total catechins and epigallocatechin gallate (EGCg) were 110 and 21.4 mg/day in men and 157 and 34.7 mg/day in women, respectively. The total catechins ADIs were positively associated with green tea consumption based on WDRs and FFQ (adjusted R2 =0.421 and 0.341 for men and 0.346 and 0.238 for women, p<0.05 for all, respectively). Likewise, the EGCg ADIs were associated with green tea intake derived from WDRs and FFQ, respectively. Conclusions: We revealed the ADIs of total catechins and EGCg as annual averages could establish their estimation models. These provide reference information to clarify their relationships with cancer risks.

Genetic Variants of RAMP2 and CLR are Associated with Stroke.

AIM: Stroke is associated closely with vascular homeostasis, and several complex processes and interacting pathways, which involve various genetic and environmental factors, contribute to the risk of stroke. Although adrenomedullin (ADM) has a number of physiological and vasoprotective functions, there are few studies of the ADM receptor system in humans. The ADM receptor comprises a calcitonin-receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs). We analyzed single nucleotide polymorphisms (SNPs) in the RAMP2 and CLR genes to determine their association with stroke in the light of gene-environment interactions. METHODS: Using cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study in the baseline surveys, 14,087 participants from 12 research areas were genotyped. We conducted a hypothesis-based association between stroke prevalence and SNPs in the RAMP2 and CLR genes based on data abstracted from two SNPs in RAMP2 and 369 SNPs in CLR. We selected five SNPs from among the CLR variants (rs77035639, rs3815524, rs75380157, rs574603859, and rs147565266) and one RAMP2 SNP (rs753152), which were associated with stroke, for analysis. RESULTS: Five of the SNPs (rs77035639, rs3815524, rs75380157, rs147565266, and rs753152) showed no significant association with obesity, ischemic heart disease, hypertension, dyslipidemia, and diabetes. In the logistic regression analysis, rs574603859 had a lower odds ratio (0.238; 95% confidence interval, 0.076-0.745, adjusted for age, sex, and research area) and the other SNPs had higher odds ratios for association with stroke. CONCLUSIONS: This was the first study to investigate the relationships between ADM receptor genes (RAMP2 and CLR) and stroke in the light of gene-environment interactions in human.

Selective protection of curcumin against carbon tetrachloride-induced inactivation of hepatic cytochrome P450 isozymes in rats.

We investigated the effects of curcumin, a major antioxidant constituent of turmeric, on hepatic cytochrome P450 (CYP) activity in rats. Wistar rats received curcumin-containing diets (0.05, 0.5 and 5 g/kg diet) with or without injection of carbon tetrachloride (CCl(4)). The hepatic CYP content and activities of six CYP isozymes remained unchanged by curcumin treatment, except for the group treated with the extremely high dose (5 g/kg). This suggested that daily dose of curcumin does not cause CYP-mediated interaction with co-administered drugs. Chronic CCl(4) injection drastically decreased CYP activity, especially CYP2E1 activity, which is involved in the bioactivation of CCl(4), thereby producing reactive free radicals. Treatment with curcumin at 0.5 g/kg alleviated the CCl(4)-induced inactivation of CYPs 1A, 2B, 2C and 3A isozymes, except for CYP2E1. The lack of effect of curcumin on CYP2E1 damage might be related to suicidal radical production by CYP2E1 on the same enzyme. It is speculated that curcumin inhibited CCl(4)-induced secondary hepatic CYPs damage through its antioxidant properties. Our results demonstrated that CYP isozyme inactivation in rat liver caused by CCl(4) was inhibited by curcumin. Dietary intake of curcumin may protect against CCl(4)-induced hepatic CYP inactivation via its antioxidant properties, without inducing hepatic CYPs.

Low folate status increases chromosomal damage by X-ray irradiation.

PURPOSE: To examine how folate status influences chromosomal damage following X-ray irradiation. MATERIAL AND METHODS: In an animal study, mice were fed either a low, basal, or high folic acid diet (0, 2, or 40 mg/kg diet, respectively) for 4 weeks, and then given total body irradiation (TBI) at 0.5 Gy. In a human study, subjects were supplemented with folic acid (800 microg/day) for 2 weeks and their peripheral blood was irradiated at 0.5 Gy in vitro. Chromosomal damage was determined by micronucleus assay. RESULTS: In an animal study, TBI-induced chromosomal damage was higher and folate concentration was lower in the bone marrow of the low folic acid group compared to the other two diet groups. The chromosomal damage and folate concentration were comparable between the basal and high folic acid groups. TBI administered to mice decreased folate in the plasma, erythrocyte and bone marrow. In a human study, supplementation with folic acid increased plasma folate, but did not influence either plasma homocysteine or X-ray-induced chromosomal damage in lymphocytes. CONCLUSION: Low folate status increases susceptibility to X-ray-induced chromosomal damage, but excessive folic acid supplementation under normal conditions yields no further protection due to folate saturation in the target tissue.