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.

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.

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.

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.

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.

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.

[Effects of various ginkgo biloba extracts and proanthocyanidin on hepatic cytochrome P450 activity in rats].

In previous papers, we showed that Ginkgo biloba extract (GBE) induced hepatic cytochrome P450 (CYP) activity, in particular pentoxyresorufin O-dealkylase (PROD; corresponding to CYP2B type) in rats, and that GBE influenced the efficacy of co-administered drugs. In this study, to clarify the nature of the induction, we examined the effects of GBE samples from different sources and some major constituents of GBE on rat hepatic CYP in vitro and in vivo. In the study in vitro, eight GBE samples dose-dependently inhibited PROD activity in microsomes prepared from GBE-treated rats, and the inhibitory ratio correlated well with the content of proanthocyanidin in the GBE samples. Moreover, among six GBE constituents examined, proanthocyanidin markedly inhibited the PROD activity. However, administration of two GBE extracts with different proanthocyanidin contents to rats induced hepatic CYP activity, including PROD, to similar extents, and proanthocyanidin alone did not induce PROD activity. Furthermore, GBE samples extracted with both acetone-water and ethanol-water showed similar induction of CYPs in rats in vivo. These results suggest that most GBE samples available in Japan induce CYPs in rats regardless of the preparation method of the GBE, and that proanthocyanidin is not responsible for the induction. Further studies will be necessary to identify the constituent(s) of GBE involved in the induction of CYPs in vivo.