Ki Nam Kim

Effects of the interaction between the C677T 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins on homocysteine levels in pregnant women

Objective: The purpose of this study was to investigate the effect of the interaction between the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) genotypes and serum levels of B vitamins on serum homocysteine levels in pregnant women.Design: A cross-sectional study.Setting: Ewha Womans University Hospital, Seoul, Korea.Subjects: A total of 177 normal pregnant women, 24.6±1.1 weeks of gestation, in a 6-month period during 2001–2002.Interventions: Serum vitamin B2, vitamin B6, and homocysteine analyses were conducted using high-performance liquid chromatography methods. Serum folate and vitamin B12 concentrations were determined using a radioimmunoassay kit. MTHFR gene mutation was investigated by the polymerase chain reaction of a genomic DNA fragment.Results: Serum homocysteine was higher in women with the T/T genotype than those with the C/T or C/C genotype of the MTHFR gene (P<0.05). Serum homocysteine was negatively correlated with serum folate in all MTHFR genotypes (P<0.001), and the correlation between the two serum levels was the strongest in the T/T genotype. Serum homocysteine was higher in the subjects with the T/T MTHFR genotype only when the serum folate was below the median level. Explanatory power of B vitamin status as predictors of serum homocysteine levels was more pronounced in the T/T genotypes (68.5%) compared with the C/T (37.9%) or C/C genotypes (20.6%).Conclusions: Serum homocysteine levels in pregnant women varied significantly with MTHFR genotype and the serum B vitamin status. Higher serum folate, vitamin B2, and vitamin B12 concentrations may lessen the MTHFR genotypic effect on serum homocysteine levels.Sponsorship: This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (01-PJ1-PG1-01CH15-0009).

Relationship of Cognitive Function with B Vitamin Status, Homocysteine, and Tissue Factor Pathway Inhibitor in Cognitively Impaired Elderly: A Cross-Sectional Survey

Elevated homocysteine (Hcy) levels have been associated with an increased risk of cognitive impairment and Alzheimers disease (AD). Tissue factor pathway inhibitor (TFPI) has recently emerged as a candidate marker of endothelial damage in AD. We investigated the relationship between plasma levels of folate, vitamin B12, Hcy, and TFPI, as well as cognitive function in 321 [100 each with mild cognitive impairment (MCI) and AD, 121 normal subjects] Korean elderly (mean age 74.8 ± 7.2 years). Plasma folate and vitamin B12 concentrations were analyzed by radioimmunoassay, Hcy by the HPLC-fluorescence method, and TFPI by enzyme-linked immunosorbent assay. Plasma Hcy levels were higher in patients with AD and MCI than those in normal subjects (p < 0.001). The AD group had higher proportions of hyperhomocysteinemic (>15 μM) and folate deficient (<3.0 ng/mL) (p = 0.026) subjects. A multiple regression analysis after adjusting for covariates revealed positive relationships between plasma folate and the MMSE-KC and Boston Naming Test, and between plasma vitamin B12 and the Word List Memory Test in the AD group, but negative associations between plasma Hcy and the Word List Memory and Constructional Recall Tests and between plasma TFPI and the Boston Naming, Word List Recall, and Constructional Recall Tests. In contrast, only plasma folate level was positively associated with the MMSE-KC and Boston Naming Test in the MCI group. No associations were observed in the normal group. These results suggest that plasma folate, vitamin B12, Hcy, and TFPI are associated with cognitive function in cognitively impaired (AD and MCI) elderly and that the association was stronger in patients with AD.

Effects of paternal folate deficiency on the expression of insulin-like growth factor-2 and global DNA methylation in the fetal brain.

SCOPE We examined the effect of paternal folate deficiency on the folate content, the percentage of 5-methycytosine (percentage of 5-mC) in the total DNA, and the protein expression of insulin-like growth factor-2 (IGF-2) in the fetal whole brain. METHODS AND RESULTS Rats were mated after males were fed a folic acid deficient (PD) or folic acid supplemented (PS) diet for 4 weeks, and fetuses were killed on day 20 of gestation. The folate content in the fetal liver was significantly lower in the PD group than in the PS group, whereas it did not differ in the fetal whole brain. The percentage of 5-mC and the protein expression of IGF-2 in the fetal whole brain were both lower in the PD group than in the PS group. There were positive correlations between paternal liver and testis folate content and the percentage of 5-mC and IGF-2 expression in the fetal whole brain. CONCLUSION Our results on the folate content, the percentage of 5-mC, and IGF-2 expression in the fetal whole brain show that paternal folate deficiency at mating can influence fetal brain DNA methylation and IGF-2 expression despite an adequate maternal folate status during the gestational period.

Mendelian Randomization Analysis of the Effect of Maternal Homocysteine During Pregnancy, as Represented by Maternal MTHFR C677T Genotype, on Birth Weight

Background We used Mendelian randomization analysis to investigate the causal relationship between maternal homocysteine level, as represented by maternal methylenetetrahydrofolate reductase (MTHFR) C677T genotype, with the birth weight of offspring. Methods We recruited women at 24 to 28 weeks’ gestation who visited Ewha Womans University Hospital for prenatal care during the period from August 2001 to December 2003. A total of 473 newborns with a gestational age of at least 37 weeks were analyzed in this study. We excluded twin births and children of women with a history of gestational diabetes, gestational hypertension, or chronic renal disease. The association of maternal homocysteine concentration with the birth weight of infants was analyzed using 2-stage regression. Results MTHFR C677T genotype showed a dose–response association with homocysteine concentration for each additional T allele (Ptrend < 0.01). Birth weight decreased from 120 to 130 grams as maternal homocysteine level increased, while controlling for confounding factors; however, the association was of marginal significance (P = 0.06). Conclusions Our results suggest an adverse relationship between maternal homocysteine level and birth weight. A reduction in homocysteine levels might positively affect birth outcomes.

Relationship between body-mass index and serum folate concentrations in pregnant women.

The concentration of micronutrients impacts fetal development and pregnancy outcome and has been suggested to be negatively correlated with the body-mass index (BMI). We evaluated the relationship between BMI and the serum folate concentration in 802 and 660 Korean pregnant women in mid- and late pregnancy, respectively, who participated in a multicenter prospective study. There was a significant negative correlation between BMI value and the serum folate concentration at mid- and late pregnancy (P for trend 0.001 and 0.024, respectively). A general linear model confirmed this correlation at both time points after adjusting for gestational age and total folate intake. These findings are important as the serum folate concentration is a rate-limiting factor for placental folate transport to the fetus, and an inadequate folate supply may cause various malformations.

Comparison of dietary food and nutrient intakes by supplement use in pregnant and lactating women in Seoul

This study was performed to compare the dietary food and nutrient intakes according to supplement use in pregnant and lactating women in Seoul. The subjects were composed of 201 pregnant and 104 lactating women, and their dietary food intake was assessed using the 24-h recall method. General information on demographic and socioeconomic factors, as well as health-related behaviors, including the use of dietary supplements, were collected. About 88% and 60% of the pregnant and lactating women took dietary supplements, respectively. The proportion of dietary supplements used was higher in pregnant women with a higher level of education. After adjusting for potential confounders, among the pregnant women, supplement users were found to consume 45% more vegetables, and those among the lactating women were found to consume 96% more beans and 58% more vegetables. The intakes of dietary fiber and β-carotene among supplement users were higher than those of non-users, by 23% and 39%, respectively. Among pregnant women, the proportion of women with an intake of vitamin C (from diet alone) below the estimated average requirements (EAR) was lower among supplement users [users (44%) vs. non-users (68%)], and the proportion of lactating women with intakes of iron (from diet alone) below the EAR was lower among supplement users [usesr (17%) vs. non-users (38%)]. These results suggest that among pregnant and lactating women, those who do not use dietary supplements tend to have a lower intake of healthy foods, such as beans and vegetables, as well as a lower intake of dietary fiber and β-carotene, which are abundant in these foods, and non-users are more likely than users to have inadequate intake of micro-nutrient such as vitamin C and iron.

Effect of paternal folate deficiency on placental folate content and folate receptor α expression in rats

We investigated the effect of paternal folate status on folate content and expression of the folate transporter folate receptor α (FRα) in rat placental tissues. Rats were mated after males were fed a diet containing 0 mg of folic acid/kg of diet (paternal folate-deficient, PD) or 8 mg folic acid/kg of diet (paternal folate-supplemented, PS) for 4 weeks. At 20 days of gestation, the litter size, placental weight, and fetal weight were measured, and placental folate content (n = 8/group) and expression of FRα (n = 10/group) were analyzed by microbiological assay and Western blot analysis, respectively. Although there was no difference observed in litter size or fetal weight, but significant reduction (10%) in the weight of the placenta was observed in the PD group compared to that in the PS group. In the PD group, placental folate content was significantly lower (by 35%), whereas FRα expression was higher (by 130%) compared to the PS group. Our results suggest that paternal folate status plays a critical role in regulating placental folate metabolism and transport.

Relationship among Plasma Homocysteine, Folate, Vitamin B12 and Nutrient Intake and Neurocognitive Function in the Elderly

This study examined the relationship among plasma homocysteine, folate, and vitamin B12 levels and neurocognitive function in 118 community-dwelling elderly subjects (mean age, 75.1 ± 6.7 years). The Mini-Mental State Examination (MMSE-KC) was used to screen and assess neurocognitive function in the participants. Dietary intake data including the use of dietary supplements were obtained using the 24-hour recall method by well-trained interviewers. Plasma folate and vitamin B12 concentrations were analyzed by radioimmunoassay, and homocysteine was assessed by a high performance liquid chromatography-fluorescence method. The proportions of participants with suboptimal levels of plasma folate (＜ 3 ng/mL), vitamin B12 (＜ 221 pmol/mL), and homocysteine (＞ 15 μmol/L) were 16.1%, 5.9%, and 21.2%, respectively. A multiple regression analysis showed that plasma homocysteine was negatively associated with plasma folate and vitamin B12 levels. The MMSE-KC test scores were significantly associated with plasma homocysteine and fo late, but not with vitamin B12, after adjusting for age, gender, body mass index, living with spouse, education, current smoking, energy intake, and chronic diseases such as hypertension, diabetes, thyroid disease, dyslipidemia, stroke, and cardiovascular disease. A general linear model adjusted for covariates revealed that MMSE-KC test scores increased from the lowest to the highest quartiles of vitamin B1, vitamin B2, vitamin B6, vitamin B12, and vitamin C intake (p for trend = 0.012, 0.039, 0.014, 0.046, 0.026, respectively). These results indicate that the problem of folate inadequacy and hyperhomocysteinemia are highly prevalent among community-dwelling elderly people and that dietary intake of the B vitamins and vitamin C is positively associated with cognitive function scores. (Korean J Nutr 2011; 44(6): 498 ~ 506)

Folate nutrition is related to neuropsychological functions in the elderly

We investigated the nutritional state of B vitamins and the neuropsychological functions in 25 subjects, aged 63.1 ± 6.3 years, residing in rural areas of Korea. Nutritional states of thiamin, riboflavin, and pyridoxine were assessed enzymatically in the erythrocytes, and folate concentrations were measured microbiologically in the plasma and erythrocytes. A battery of composite neuropsychological test was administered to the subjects. Plasma folate was correlated with the total intelligence score (p=0.049). Folate levels in the erythrocytes were correlated with the performance intelligence scores such as block design (p=0.017) and picture arrangement (p=0.016). The red cell folate was correlated with memory scores such as general memory (p=0.009) and delayed recall (p=0.000). Although it did not reach statistical significance, verbal memory (p=0.053) was highly correlated with the red cell folate. The red cell folate was also correlated positively with the percent of conceptual level response number score (p=0.029), and negatively with the grooved pegboard test score for the non-dominant hand (p=0.010). Fine motor coordination was also influenced by folate nutrition, as finger tapping scores in both hands were significantly correlated with red cell folate (dominant hand; p=0.026, non-dominant hand; p=0.004). Other B vitamins such as thiamin, riboflavin, and vitamin B6 were not as strongly correlated with neuropsychological function test scores as folate was. These results suggest that folate nutrition influences neuropsychological function test scores significantly in humans. Further studies are needed to explore the relationship between folate or other vitamin B nutrition and neuropsychological functions and the implications thereof.

Relationship between Milk and Calcium Intake and Lipid Metabolism in Female Patients with Type 2 Diabetes

Purpose This study was conducted to determine the association between intake of milk and dairy products as well as calcium and biomarkers related to lipid metabolism in Korean female patients with type 2 diabetes. Materials and Methods A cohort of 509 female subjects (mean age: 59.0 years; range: 35-80 years) was recruited from Huhs Diabetes Clinic in Seoul between 2005 and 2010. Dietary intake was assessed using a validated food-frequency questionnaire. Subjects were divided into three groups on the basis of their daily intake of milk and dairy products [<50 g/day (0<50 g/day), 50-200 g/day, and >200 g/day (>200-1201 g/day)] and then further divided into two groups according to their daily calcium intake: below and above the estimated average requirement (EAR). Results After adjustment for age, body mass index, energy intake, exercise, use of nutritional supplements and cholesterol medication, the level of serum high-density lipoprotein (HDL)-cholesterol was significantly higher in subjects with milk and dairy products consumption of >200 g/day than in subjects in the other two groups. Those subjects with a milk and dairy products consumption of >200 g/day had significantly higher levels of apolipoprotein A-1 and a significantly lower atherogenic index than the other two groups. Patients with a calcium intake above the EAR exhibited a significantly greater serum HDL-cholesterol level than those with a calcium intake below the EAR. Conclusion Milk and dairy products, good sources of calcium, play a positive role in lipid profiles in female patients with type 2 diabetes.