Serum 5-Methyltetrahydrofolate Status Is Associated with One-Carbon Metabolism-Related Metabolite Concentrations and Enzyme Activity Indicators in Young Women.

Maintaining optimal one-carbon metabolism (OCM) is essential for health and pregnancy. In this cross-sectional study, folate status was assessed based on 5-methyltetrahydrofolate (5-MTHF) levels, and the association between 5-MTHF and OCM-related metabolites was investigated in 227 female Japanese university students aged 18-25 years. The participants were divided into high and low 5-MTHF groups based on their folate status. Serum samples of the participants were collected while they were fasting, and 18 OCM-related metabolites were measured using stable-isotope dilution liquid chromatography-electrospray tandem mass spectrometry. The association between serum 5-MTHF and OCM-related metabolite concentrations was assessed using Spearman's rank correlation coefficient. Serum 5-MTHF concentrations were negatively correlated with total homocysteine (tHcy) concentrations and positively correlated with S-adenosylmethionine (SAM) and total cysteine (tCys) concentrations. Serum 5-MTHF concentrations demonstrated a stronger negative correlation with tHcy/tCys than with tHcy alone. The negative correlation between betaine and tHcy concentrations was stronger in the low 5-MTHF group than in the high 5-MTHF group. The 5-MTHF status could be linked to Hcy flux into the transsulfuration pathway via SAM. Therefore, the tHcy/tCys ratio may be a more sensitive indicator of the 5-MTHF status than tHcy alone. Furthermore, a low 5-MTHF status can enhance Hcy metabolism via betaine.

Determinants of polyunsaturated fatty acid concentrations in erythrocytes of pregnant Japanese women from a birth cohort study: study protocol and baseline findings of an adjunct study of the Japan environment & Children's study.

BACKGROUND: N-3 polyunsaturated fatty acids (n-3 PUFA) may have multiple beneficial effects on the outcome of pregnancy, maternal health and child development. The present study introduced the protocol of a birth cohort study to examine the beneficial effects of n-3 PUFA status in pregnant Japanese women as an adjunct study of the Japan Environment and Children's Study (JECS). METHODS: The JECS participants in the coastal areas of Miyagi Prefecture were further invited to participate in this adjunct study, and 1,878 pregnant women were enrolled prior to delivery. Their n-3 PUFA status was evaluated with fatty acid profiles in erythrocytes of maternal blood collected from 1,623 mothers at 24-30 weeks of gestation and cord blood from 1,505 deliveries. RESULTS: The baseline results, including comprehensive data on the fatty acid status and determinants affecting the PUFA status, were analyzed. In stepwise multivariate analyses, the cord blood docosahexaenoic acid (DHA) level was found to be significantly influenced by the DHA level in maternal blood, the child's sex, and the gestational period. The maternal DHA level was influenced by fish intake, maternal age, and the prepregnancy body mass index. While cord blood eicosapentaenoic acid (EPA) was influenced by maternal EPA, fish intake, and season at birth, additional factors such as maternal education, household income, and smoking habits affected the maternal EPA content. CONCLUSION: Further studies are warranted to clarify the nutritional impacts of n-3 PUFA in pregnant Japanese women of the cohort study.

Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups.

BACKGROUND: The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity. METHODS: Samples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis. RESULTS: rs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (± 3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (± 11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (± 3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289-2.196, p value 0.00013). CONCLUSION: This study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.

Positive natural selection of TRIB2, a novel gene that influences visceral fat accumulation, in East Asia.

Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 × 10(-6) and P = 9.0 × 10(-6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA-associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians.

[Chronological nutrition and prevention of lifestyle-related diseases].

Lifestyle controls the circadian rhythms produced by clock genes and affects telomere length that regulates healthspan. Biological clocks are classified into oscillatory (clock genes) and hourglass clocks (telomeres). Clock genes align behavioral and biochemical processes with the day/night cycle. Telomeres, the repeated series of DNA sequences that cap the ends of chromosomes, become shorter during cell division. Shortened telomeres have been documented in various pathological states in lifestyle-related diseases, such as atherosclerosis and diabetes. Human activity is driven by NADH and ATP produced from nutrients, and the resulting NAD and AMP play a predominant role in energy regulation. Caloric restriction and proper exercise increase both AMP and NAD, and extend the healthspan. SIRT1, the NAD-dependent deacetylase, attenuates telomere shortening, while PGC-1alpha, a master modulator of gene expression, is phosphorylated by AMP kinase and deacetylated by SIRT1. Prevention of lifestyle related diseases by chronological nutrition is described based on these mechanisms.

Influence of Nutritional Intakes in Japan and the United States on COVID-19 Infection.

The U.S. and Japan are both democratic industrialized societies, but the numbers of COVID-19 cases and deaths per million people in the U.S. (including Japanese Americans) are 12.1-times and 17.4-times higher, respectively, than those in Japan. The aim of this study was to investigate the effects of diet on preventing COVID-19 infection. An analysis of dietary intake and the prevalence of obesity in the populations of both countries was performed, and their effects on COVID-19 infection were examined. Approximately 1.5-times more saturated fat and less eicosapentaenoic acid/docosahexaenoic acid are consumed in the U.S. than in Japan. Compared with food intakes in Japan (100%), those in the U.S. were as follows: beef 396%, sugar and sweeteners 235%, fish 44.3%, rice 11.5%, soybeans 0.5%, and tea 54.7%. The last four of these foods contain functional substances that prevent COVID-19. The prevalence of obesity is 7.4- and 10-times greater in the U.S. than in Japan for males and females, respectively. Mendelian randomization established a causal relationship between obesity and COVID-19 infection. Large differences in nutrient intakes and the prevalence of obesity, but not racial differences, may be partly responsible for differences in the incidence and mortality of COVID-19 between the U.S. and Japan.

Investigation of Maternal Diet and FADS1 Polymorphism Associated with Long-Chain Polyunsaturated Fatty Acid Compositions in Human Milk.

Increasing the amount of long-chain polyunsaturated fatty acids (LCPUFA) in human milk is an important strategy for infant growth and development. We investigated the associations of LCPUFA compositions in human milk with maternal diet (especially fish and shellfish intake), with fatty acid Δ5 desaturase gene (FADS1) polymorphisms, and with gene-diet interactions. The present study was performed as part of an adjunct study of the Japan Environment and Children's Study. The participants were 304 lactating females, who provided human milk 6−7 months after delivery. Fatty acids in human milk were analyzed by gas chromatography, and dietary surveys were conducted using a brief self-administered diet history questionnaire. We also analyzed a single nucleotide polymorphism of FADS1 (rs174547, T/C). There was a significant difference in arachidonic acid (ARA) composition in human milk among the genotype groups, and the values were decreasing in the order of TT > TC > CC. The concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were also different between TT and CC genotype, indicating a tendency for decreasing values in the same order. The composition of ARA showed significant gene−dietary interactions in multiple regression analysis, and the positive correlation between fish and shellfish intake and ARA composition in human milk was significant only in the CC genotype. Moreover, the factor most strongly associated with EPA and DHA composition in human milk was fish and shellfish intake. Therefore, it was suggested that increasing fish and shellfish intake in mothers may increase EPA and DHA composition in human milk, while increasing fish and shellfish intake in CC genotype mothers may lead to increased ARA composition in human milk.

The Body Fat Percentage Rather Than the BMI Is Associated with the CD4 Count among HIV Positive Japanese Individuals.

Maintenance of the cluster of differentiation 4 (CD4) positive lymphocyte count (CD4 count) is important for human immunodeficiency virus (HIV) positive individuals. Although a higher body mass index (BMI) is shown to be associated with a higher CD4 count, BMI itself does not reflect body composition. Therefore, we examined the association of body weight, body composition and the CD4 count, and determined the optimal ranges of CD4 count associated factors in Japanese HIV positive individuals. This cross-sectional study included 338 male patients treated with antiretroviral therapy for ≥12 months. Multiple logistic regression analysis was used to identify factors significantly associated with a CD4 count of ≥500 cells (mm3)-1. The cutoff values of factors for a CD4 ≥ 500 cells (mm3)-1 and cardiovascular disease risk were obtained by receiver operating characteristic curves. Age, body fat percentage (BF%), nadir CD4 count, duration of antiretroviral therapy (ART), years since the HIV-positive diagnosis and cholesterol intake showed significant associations with the CD4 count. The cutoff value of BF% for a CD4 ≥ 500 cells (mm3)-1 and lower cardiovascular disease risk were ≥25.1% and ≤25.5%, respectively. The BF%, but not the BMI, was associated with CD4 count. For the management of HIV positive individuals, 25% appears to be the optimal BF% when considering the balance between CD4 count management and cardiovascular disease risk.

High prevalence of an anti-hypertriglyceridemic variant of the MLXIPL gene in Central Asia.

MLXIPL is a transcription factor integral to the regulation of glycolysis and lipogenesis in the liver. Common variants of the MLXIPL gene (MLXIPL) are known to influence plasma triglyceride levels in people of European descent. As MLXIPL has a key role in energy storage, genetic variations of the MLXIPL may be relevant to physiological adaptations to nutritional stresses that have occurred during the evolution of modern humans. In the present study, we assessed the phenotypic consequences of the Q241H variant of MLXIPL in populations of Asian and Oceanian origin and also surveyed the prevalence of Q241H variant in populations worldwide. Multiple linear regression models based on 2373 individuals of Asian origin showed that the H allele was significantly associated with decreased concentrations of plasma triglycerides (P=0.0003). Direct genotyping of 1455 individuals from Africa, Asia and Oceania showed that the triglyceride-lowering H allele was found at quite low frequencies (0.00-0.16) in most of the populations examined. The exceptions were some Central Asian populations, including Mongolians, Tibetans and Uyghurs, which exhibited much higher frequencies of the H allele (0.21-0.26). The high prevalence of the H allele in Central Asia implies that the Q241H variant of MLXIPL might have been significant for utilization of carbohydrates and fats in the common ancestors of these populations, who successfully adapted to the environment of Central Asia by relying on nomadic livestock herding.

Associations of umbilical cord fatty acid profiles and desaturase enzyme indices with birth weight for gestational age in Japanese infants.

Long-chain polyunsaturated fatty acids (LCPUFAs) required for infant development are produced by Δ6 desaturase (D6D) and Δ5 desaturase (D5D). The D6D index and D5D index are calculated based on their respective precursor/product ratios. The D5D and D6D indices are related to obesity and lifestyle-related diseases. The aim of the present study was to examine the associations of umbilical cord fatty acid profiles, D6D index, and D5D index in appropriate for gestational age (AGA), small for gestational age (SGA), and large for gestational age (LGA) infants. This was a nested case-control study, and the relationship between case and control maternal blood and umbilical cord blood fatty acid compositions was examined. Cases were small for gestational age (SGA; n = 55) and large for gestational age (LGA; n = 149) infants, whereas controls were appropriate for gestational age (AGA; n = 204) infants. Fatty acid profiles in maternal blood and umbilical cord plasma were analyzed by gas-liquid chromatography. The D6D index was calculated as dihomo-γ-linolenic acid (DGLA 20: 3 n-6) / linoleic acid (18: 2 n - 6), and the D5D index was calculated as arachidonic acid (20: 4 n - 6) / DGLA (20: 3 n - 6). Statistical analysis of umbilical cord blood fatty acids was performed with multiple comparisons. SGA infants showed high umbilical cord values for α-linolenic acid and DHA and lower values for DGLA compared to AGA infants. SGA infants showed a higher D5D index but a lower D6D index than AGA infants. LGA infants showed high values for α-linolenic acid and DGLA and lower values for arachidonic acid than AGA infants. LGA infants showed a high D6D index and a low D5D index relative to AGA infants. No significant differences in maternal blood fatty acid profiles, the D6D index, and D5D index desaturase activities were found among the three groups. There were differences in umbilical cord fatty acid profiles and D6D and D5D indices among AGA, SGA, and LGA infants, but further study is needed.

A single nucleotide polymorphism in the FADS1/FADS2 gene is associated with plasma lipid profiles in two genetically similar Asian ethnic groups with distinctive differences in lifestyle.

Recent genome-wide association studies (GWASs) showed that single nucleotide polymorphisms (SNPs) in FADS1/FADS2 were associated with plasma lipid concentrations in populations with European ancestry. We investigated the associations between the SNPs in FADS1/FADS2 and plasma concentrations of triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in two Asian groups, i.e., Japanese and Mongolians. The genotype of rs174547 (T/C), found to be associated with triglyceride and HDL-C concentrations in the GWAS, was determined in 21,004 Japanese and 1,203 Mongolian individuals. Genotype-phenotype association was assessed by using multiple linear regression models, assuming an additive model of inheritance. The copy number of the rs174547 C allele was significantly associated with increased triglyceride levels (P = 1.5 x 10(-6)) and decreased HDL-C levels (P = 0.03) in the Japanese population. On the other hand, in the Mongolian population, the rs174547 C allele copy number was strongly associated with decreased LDL-C levels (P = 2.6 x 10(-6)), but was not associated with triglyceride and HDL-C levels. The linkage disequilibrium pattern and haplotype structures of SNPs around the FADS1/FADS2 locus showed no marked dissimilarity between Japanese and Mongolian individuals. The present data indicate that the FADS1/FADS2 locus can be added to the growing list of loci involved in polygenic dyslipidemia in Asians. Furthermore, the variable effects of FADS1/FADS2 on plasma lipid profiles in Asians may result from differences in the dietary intake of polyunsaturated fatty acids, which serve as substrates for enzymes encoded by FADS1/FADS2.

ATP synthase: from single molecule to human bioenergetics.

ATP synthase (F(o)F(1)) consists of an ATP-driven motor (F(1)) and a H(+)-driven motor (F(o)), which rotate in opposite directions. F(o)F(1) reconstituted into a lipid membrane is capable of ATP synthesis driven by H(+) flux. As the basic structures of F(1) (alpha(3)beta(3)gammadeltaepsilon) and F(o) (ab(2)c(10)) are ubiquitous, stable thermophilic F(o)F(1) (TF(o)F(1)) has been used to elucidate molecular mechanisms, while human F(1)F(o) (HF(1)F(o)) has been used to study biomedical significance. Among F(1)s, only thermophilic F(1) (TF(1)) can be analyzed simultaneously by reconstitution, crystallography, mutagenesis and nanotechnology for torque-driven ATP synthesis using elastic coupling mechanisms. In contrast to the single operon of TF(o)F(1), HF(o)F(1) is encoded by both nuclear DNA with introns and mitochondrial DNA. The regulatory mechanism, tissue specificity and physiopathology of HF(o)F(1) were elucidated by proteomics, RNA interference, cytoplasts and transgenic mice. The ATP synthesized daily by HF(o)F(1) is in the order of tens of kilograms, and is primarily controlled by the brain in response to fluctuations in activity.

Associations of erythrocyte fatty acid compositions with FADS1 gene polymorphism in Japanese mothers and infants.

Long-chain polyunsaturated fatty acids (LC-PUFAs) are involved in the fetal growth in utero, and are essential for the development of visual and cognitive functions during infancy. The purpose of this study was to examine the associations of erythrocyte fatty acid compositions with FADS1 gene polymorphism in Japanese mothers and infants. The subjects were 383 mothers who participated in an adjunct birth cohort study of the Japan Environment and Children's Study (JECS). In maternal FADS1 SNP genotypes, the precursor fatty acids composition of the Δ5 desaturase in the maternal blood showed significant differences in levels among the groups, and showed increasing values in the order of TT < TC < CC genotype groups. On the other hand, many product fatty acids levels were significantly reduced in the order of TT > TC > CC genotype groups, and DHA levels were significantly lower in the CC genotype group relative to the other groups. Likewise, the relationship between fetal genotype group and fatty acid composition in cord blood was very similar to the maternal relationship. These results indicate the maternal and fetal blood fatty acid compositions are strongly influenced by the FADS1 genotypes. With respect to the cord blood DHA composition, the levels in the fetal CC genotype group showed a trend toward lower values in the maternal CC genotype group pair (p = 0.066) compared to the maternal TC genotype group pair. However, in the fetal TT and TC genotype groups (p = 0.131, p = 0.729, respectively), the maternal genotype did not have a significant effect. The DHA composition was more influenced by the maternal genotype in the fetal CC genotype group than in the fetal TT and TC genotype groups. It was shown that DHA transport via the placenta from the mother might be promoted in the fetal CC genotype compared to the other fetal genotype groups. In conclusion, differences in the FADS1 SNP genotypes of pregnant women and their children may greatly affect the supply of LC-PUFAs. Further studies on the involvement of the FADS1 polymorphisms and the fetal LC-PUFA levels in the fetal growth and development are warranted.

Relationships between docosahexaenoic acid compositions of maternal and umbilical cord erythrocytes in pregnant Japanese women.

Previous reports have shown that the transfer of docosahexaenoic acid (DHA) from mother to fetus during pregnancy is important for development of the child's nervous and visual functions. The amount of DHA passing through the placenta varies depending on the relative DHA compositions of the erythrocytes in the maternal blood and the umbilical cord. Prior research has reported that if the DHA composition of the maternal erythrocytes is over 5.6 g%, DHA in the erythrocytes of the child undergoes bioattenuation, whereas it undergoes biomagnification if the maternal erythrocyte composition is lower than 5.6 g%. The relationship between DHA levels in maternal erythrocytes during pregnancy and in umbilical cord erythrocytes at delivery was assessed in Japanese pregnant women. This study was performed as an adjunct study of the Japan Environment and Children's Study. DHA compositions of maternal erythrocytes at 24-30 weeks of pregnancy and of umbilical cord erythrocytes at delivery were determined in 1368 mother-infant pairs. Median DHA values were 7.41% in the maternal erythrocytes and 6.84% in the umbilical cord erythrocytes, indicating significantly lower levels in the umbilical cord. When DHA composition in maternal erythrocytes was lower than 6.6%, DHA was theoretically higher in umbilical cord erythrocytes than in maternal erythrocytes. Conversely, when DHA composition in maternal erythrocytes was higher than 6.6%, DHA in umbilical cord erythrocytes was theoretically lower than in maternal erythrocytes. We therefore consider that there is a turning point of around 6% in the DHA composition of maternal and umbilical cord blood that is exchanged between mother and fetus: if the composition in the maternal blood is higher, then bioattenuation in DHA transfer from the maternal circulation to the umbilical cord occurs, while if it is lower, then biomagnification occurs. This corroborates the findings of previous research.

Levels of plasma insulin, leptin and adiponectin, and activities of key enzymes in carbohydrate metabolism in skeletal muscle and liver in fasted ICR mice fed dietary n-3 polyunsaturated fatty acids.

The aim of this study was to clarify the mechanisms related to plasma glucose concentration in mice fed a diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs). Male Crlj:CD-1 (ICR) mice were fed experimental diets containing 6% lard (LD), 6% fish oil (FO) or 4.1% lard plus 1.5% docosahexaenoic acid ethyl ester and 0.4% eicosapentaenoic acid ethyl ester (DE) for 12 weeks. There were no marked differences in plasma glucose and insulin concentration changes on glucose tolerance test between the three dietary groups. At the end of the feeding trial, plasma glucose concentration was significantly lower in fasted mice in the FO group than in those in the LD group (P<.005). Plasma adiponectin concentration was significantly higher in the FO group than in the LD group (P<.05). Hexokinase, phosphofructokinase, glucose-6-phosphate dehydrogenase and glycerophosphate dehydrogenase activities in skeletal muscle tended to be lower in the FO group than in the LD group, while there were no differences in glucokinase and phosphofructokinase activities in liver between the three dietary groups. However, hepatic glycerophosphate dehydrogenase activity was 53-fold and 4.2-fold higher in the FO group than in the LD and DE groups, respectively (P<.0005 and P<.05, respectively). These results suggest that the reduction in plasma glucose concentration in mice fed n-3 PUFAs is mainly caused by acceleration of glucose uptake and glycerol synthesis in the liver rather than in the skeletal muscle.

Vitamin C activity of dehydroascorbic acid in humans--association between changes in the blood vitamin C concentration or urinary excretion after oral loading.

We performed oral loading of AsA or DAsA (1 mmol) in subjects who had consumed a diet low in vitamin C (C) (C< or =5 mg/d) for 3 d before loading, and measured urinary and blood vitamin C. Since the crossover method was used, the same experiment was repeated after an interval of about 1 mo in each subject. The results of the experiment including a total of 17 subjects for 2005 and 2006, were as follows. (1) There were marked individual differences in urinary C excretion. (2) The C level in 24-h urine after C loading did not differ between the two orally administered C forms (AsA and DAsA). (3) C excretion between 0 and 3 h after C loading was significantly higher (p<0.05) for the DAsA group, while those between 3 and 6, 6 and 9, 9 and 12, and 12 and 24 h after C loading were significantly higher (p<0.05 or p<0.01) for the AsA group. (4) The blood C concentration and the increase in C 1 h after C loading were significantly higher (p<0.05 and p<0.01, respectively) in the DAsA than in the AsA group. (5) Evaluation of the association between C metabolism and the single nucleotide polymorphisms of glutathione S-transferase P (GSTP) 1-1 showed a lower urinary C excretion and a significantly lower C level in 24-h urine (p<0.05) after AsA loading, and a significantly lower urinary C excretion between 0 and 3 h after DAsA loading (p<0.05) for the GA heterozygotes than for the AA homozygotes. Considering the activity of C as DAsA in humans, based on urinary and blood C levels after a single loading of C, the utilization of DAsA is equivalent to that of AsA, although the metabolic turnover time is different. The involvement of polymorphisms in the xenobiotic metabolizing enzyme, GSTP1-1, in C metabolism, particularly urinary C excretion, was also clarified. This demonstrates the necessity of considering gene polymorphisms in determining individual C requirements. An abstract of this paper was reported by the Vitamin C Research Committee (Ochanomizu University) in 2007.

The concentrations of blood sugar and HbA1c are significantly higher in g/g homozygotes of adiponectin t45g polymorphism than in heterozygotes and wild types.

Adiponectin (Ad) is reported to reduce insulin resistance in metabolic syndrome. The relation between the polymorphism of Ad (t45 g), biochemical indices including Ad and insulin concentrations, and food intake was examined, since the g/g homozygotes are known to be diabetes-prone. Subjects were 45 women (68.87 +/- 7.74 years old) who received preventive intervention in our nutrition clinic. Their food intake was estimated by the three day dietary record, and the blood was taken for genetic and biochemical analyses. Polymerase chain reaction and RFLP of Ad-DNA revealed the wild type (t/t = 51%), heterozygotes (t/g = 41%) and mutant homozygotes (g/g = 9%). Concentrations of total and high molecular weight Ad (12-18mers, HMW-Ad) were determined by ELISA. The project was approved by the ethics committee of our university and by the written agreement of the subject. Serum insulin concentration was negatively correlated with HMW-Ad (y = -0.802 + 11.7, P = .006), but not correlated with total Ad. HMW-Ad in the g/g homozygotes (1.18 +/- 1.28 microg/ml) was significantly (P = .024) lower than that in both wild type (t/t, 4.07 +/- 2.96 microg/ml) and heterozygotes (t/g, 2.23 +/- 1.90 microg/ml). The concentrations of fasting plasma glucose (average = 157.5 +/- 49.4 mg/dl) and HbAlc (average = 7.3 +/- 1.7%) in g/g were significantly (P < .001, in any combination) higher than those in both t/t and t/g. HMW-Ad were negatively correlated with intakes of both carbohydrate (group I food of Ministry of Health, Welfare and Labor) and sugar. The intakes of carbohydrate and sugar were not different among t/t, t/g and g/g groups. Although g/g homozygotes are diabetes prone, improvement of the insulin resistance by restricting the intakes of both carbohydrate-rich foods and cane sugar may be easier in g/g than in t/g and t/t.

Relationship between genetic polymorphism, serum folate and homocysteine in Alzheimer's disease.

In order to prevent Alzheimer disease (AD), relationship between single nucleotide polymorphisms (SNPs) of methylene tetrahydrofolate reductase (MTHFR) and folate-homocysteine metabolism was studied. Subjects were 10 males and 42 females (87.9 +/- 7.7 years old) in the special nursing homes for the elderly. Their average care level was 4.2 +/- 0.9, and average cognitive ability estimated by MMSE was 6.9 +/-7.3. Dietary intake was measured by weighing method. Concentrations of serum folate and total serum homocysteine (tHcy), and genetic polymorphisms were determined. The daily nutrient intake was as follows: total energy 2.7 kcal/kg; protein, 1.0 g/kg; folic acid, 7.3 microg/kg; vitamin B12, 0.11 microg/kg. Compared with control elderly persons, serum folate was very low (4.5 ng/ml, control = 10.1 ng/ml) and serum homocysteine was very high (21.4 micromol/L, control = 10.2 microg/L), despite having an adequate folate intake (342 microg/day, mainly polyglutamyl folate). The frequency of TT homozygote of MTHFR was higher (21.1%) in Alzheimer patients than that in control (15%). TT homozygotes showed the lowest serum folate (3.5 ng/ml, 35% of control), the highest serum homocysteine 25 micromol/L, 250% of control and the lowest MMSE score (5) among all the genotypes. The bioavailability of polyglutamyl folate may be impaired in the subjects, even when their total folate intake was sufficient. The early prevention of Alzheimer's disease by monoglutamyl folate intake (400 mcg per day) is recommended especially in TT homozygote of MTHFR.

Genetic polymorphisms of xenobiotic enzymes affect human vitamin C excretion.

This study describes the effect of gene polymorphisms on the metabolism of vitamin C. An oral loading of 1 mmol ascorbic acid (176 mg) or dehydroascorbic (174 mg) was given to 17 healthy females volunteers who had consumed a low vitamin C diet (vitamin C < 5 mg/day) for 3 days before loading. The urinary total vitamin C was determined. The urinary excretion of vitamin C (VC) was compared between ascorbic acid (AsA) and dehydroascorbic acid (DAsA), and the 24 hour total VC excretion was same. However gene polymorphisms of glutathione S-transferases P1 (GSTP1) showed the effect on that excretion. GSTP1 is one of xenobiotic enzymes in VC metabolism. The VC excretions in 24 hour after VC loading were greater (P < .01) in AA homozygotes of GSTP1 (46.7 +/- 18.1 mg) than GA heterozygotes (28.2 +/- 14.0 mg). On the single oral administration, the type of polymorphisms of GSTP1 has stronger effect on VC metabolism than the form of VC, DAsA and AsA. This study showed that determination of nutrient requirement needs to be considered with personal genotype.