Serum coenzyme Q10 and risk of disabling dementia: the Circulatory Risk in Communities Study (CIRCS).

OBJECTIVE: To examine whether coenzyme Q10, a potent antioxidant, is associated with risk of dementia, which has not yet been elucidated. APPROACH AND RESULTS: We performed a case-control study nested in a community-based cohort of approximately 6000 Japanese aged 40-69 years at baseline (1984-1994). Serum coenzyme Q10 was measured in 65 incident cases of disabling dementia with dementia-related behavioral disturbance or cognitive impairment incident between 1999 and 2004, and in 130 age-, sex- and baseline year-matched controls. Serum coenzyme Q10 was inversely associated with dementia: the multivariate odds ratios (95% confidence intervals) were 0.68 (0.26-1.78), 0.92 (0.33-2.56), and 0.23 (0.06-0.86) for individuals with the second, third, and highest quartiles of coenzyme Q10, respectively, as compared with the lowest quartile (P for trend = 0.05). A similar association was found for the coenzyme Q10/total cholesterol ratio: the respective ORs were 0.67 (0.25-1.78), 0.73 (0.28-1.92), and 0.21 (0.05-0.90) (P for trend = 0.04). CONCLUSIONS: Serum coenzyme Q10 levels were inversely associated with risk of disabling dementia.

Relation of serum α- and γ-tocopherol levels to cardiovascular disease-related mortality among Japanese men and women.

BACKGROUND: There is limited evidence regarding the relationship between serum tocopherol levels and cardiovascular disease. METHODS: We conducted a nested case-control study as part of the Japan Collaborative Cohort Study for evaluation of cancer risk (JACC Study). Baseline serum samples were collected from 39 242 participants (age range, 40-79 years) between 1988 and 1990. During the 13-year follow-up, there were 530 stroke deaths (302 ischemic strokes and 210 hemorrhagic strokes) and 211 deaths from coronary heart disease. Controls were matched for sex, age, and area of residence. RESULTS: Serum α-tocopherol level was not associated with any type of cardiovascular death in men; however, in women, it was inversely associated with total stroke mortality and hemorrhagic stroke mortality. The multivariate odds ratio (95% CI) for the highest versus the lowest quintile of serum α-tocopherol levels among women was 0.35 (0.16-0.77; P for trend = 0.009) for total stroke and 0.26 (0.07-0.97; P for trend = 0.048) for hemorrhagic stroke. Serum γ-tocopherol was inversely associated with ischemic stroke mortality in men but positively associated with hemorrhagic stroke mortality in women. The respective multivariate odds ratios (95% CI) for the highest versus the lowest quintile and for a 1-standard deviation increment in γ-tocopherol level were 0.48 (0.22-1.06; P for trend = 0.07) and 0.77 (0.58-1.02), respectively, for ischemic stroke in men and 3.10 (0.95-10.12; P for trend = 0.052) and 1.49 (1.04-2.13) for hemorrhagic stroke in women. CONCLUSIONS: Among women, hemorrhagic stroke mortality was inversely associated with serum α-tocopherol and positively associated with serum γ-tocopherol. These findings are due in part to the antioxidative and antithrombotic activities of these tocopherols.

Validity of brief food frequency questionnaire for estimation of dietary intakes of folate, vitamins B6 and B12, and their associations with plasma homocysteine concentrations.

BACKGROUND: Low nutrient intakes of folate, vitamins B(6) and B(12) have been associated with the risk of chronic diseases and neural tube defects. The aim of this study was to develop a brief food frequency questionnaire (FFQ) for the assessment of these nutrient intakes and to assess its validity. METHODS: We developed a brief FFQ designed specifically for estimating intakes of folate and vitamins B(6) and B(12) and covering 21 food items, and used it to carry out dietary surveys of 579 Japanese men and women. The associations of these vitamin intakes with their serum levels and homocysteine concentrations were examined using multiple linear regression analysis after adjusting for sex, age and cardiovascular risk factors. RESULTS: The Spearman correlation coefficients between vitamin intakes and their serum concentrations were 0.10 for folate, 0.08 for vitamin B(6) and 0.22 for B(12). Changes in plasma homocysteine concentrations associated with a one-standard-deviation increment were -0.03 for dietary folate, -0.03 for dietary vitamin B(6) and -0.03 for dietary vitamin B(12), and were -0.06 for serum folate, -0.03 for serum vitamin B(6) and -0.06 for serum vitamin B(12). CONCLUSION: Positive correlations between dietary intakes estimated from our brief FFQ and serum concentrations for folate and vitamin B(12) as well as negative correlations between dietary intakes and plasma homocysteine concentrations suggest the usefulness of this questionnaire.

Serum vitamin C concentration and hs-CRP level in middle-aged Japanese men and women.

OBJECTIVE: To examine the association between concentrations of serum vitamin C, a contributive factor to prevention of cardiovascular disease and levels of hs-CRP, a risk factor for cardiovascular disease, in population-based samples of middle-aged men and women. DESIGN: A cross-sectional study. METHODS AND RESULTS: The subjects were 778 men and 1404 women, aged 40-69 years, who participated in a cardiovascular risk survey in Kyowa, Ibaraki prefecture in 2002 as part of the Circulatory Risk in Communities Study (CIRCS). Inverse associations between serum vitamin C concentrations and hs-CRP levels were established for both men and women. Multivariable-adjusted mean values of hs-CRP for the lowest to highest quintiles of vitamin C levels were 0.75, 0.65, 0.61, 0.61 and 0.47 mg/L (P for trend <0.001) for men, and 0.56, 0.51, 0.49, 0.41 and 0.41 mg/L (P for trend <0.001) for women. The inverse association between vitamin C and hs-CRP was stronger for non-smoking men and women, non-overweight women and postmenopausal women. CONCLUSIONS: Serum vitamin C concentrations were found to be inversely associated with hs-CRP levels in both men and women, primarily among non-smokers, non-overweight women and postmenopausal women. The respective roles of serum vitamin C and hs-CRP levels in the development of cardiovascular disease thus warrant further investigation.

Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: The JACC study.

Evidence for association between serum total homocysteine (tHcy) level and cardiovascular disease is limited in Asian populations. We conducted a nested case-control study under JACC Study. A total of 39,242 subjects aged 40-79 years provided serum samples at baseline surveys between 1988 and 1990. Control subjects were selected by matching for sex, age, community and year of serum storage. Serum tHcy levels were measured by high-performance liquid chromatography. During the 10-year follow-up, there were 444 deaths due to total cardiovascular disease, including 310 total stroke (131 hemorrhage and 101 ischemic strokes) and 134 coronary heart diseases. The risks of mortality from ischemic stroke, coronary heart disease, and total cardiovascular disease were significantly higher in individuals with the highest serum tHcy quartile (>or=15.3micromol/L) than in those with the lowest quartile (<10.5micromol/L); the respective multivariable odds ratios (95% CI) were 4.35 (1.12-16.9), 3.40 (1.17-9.86), and 1.68 (1.02-2.77). The multivariable odds ratios associated with a 5-micromol/L increase in tHcy were 1.49 (1.01-2.18), 2.01 (1.21-3.35), and 1.15 (1.00-1.32), respectively. High serum tHcy levels were associated with increased mortality from ischemic stroke, coronary heart disease and total cardiovascular disease among Japanese.

Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese.

BACKGROUND: To date, no prospective studies have examined the association between serum homocysteine levels and the risk of stroke and stroke subtypes in Asian populations. METHODS AND RESULTS: A prospective, nested, case-control study of Japanese subjects 40 to 85 years of age was conducted by using frozen serum samples from 11 846 participants in cardiovascular risk surveys collected from 1984 to 1995 for one community and 1989 to 1995 for the other two communities. By the end of 2000, we identified 150 incident strokes, the subtypes of which were confirmed by imaging studies. Three control subjects per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Serum total homocysteine levels were measured by high-performance liquid chromatography. Compared with control subjects, total (n=150), hemorrhagic (n=52), and ischemic (n=98) strokes had higher geometric mean values of total homocysteine and higher proportions of homocysteine > or =11.0 micromol/L. The multivariate odds ratios (95% CI) for highest (> or =11.0 micromol/L) versus lowest quartiles (<7.0 micromol/L) of homocysteine after adjustment for body mass index, smoking, alcohol intake, hypertension, serum total cholesterol, and other cardiovascular risk factors were 2.99 (1.51 to 5.93) for total stroke, 3.89 (1.60 to 9.46) for ischemic stroke, 3.36 (1.27 to 8.90) for lacunar infarction, and 1.63 (0.44 to 6.00) for hemorrhagic stroke. The respective multivariate odds ratios associated with a 5-micromol/L increase in homocysteine were 1.40 (1.09 to 1.80), 1.52 (1.07 to 2.14), 1.48 (1.01 to 2.18), and 1.10 (0.76 to 1.59). The excess risk of total and ischemic strokes did not vary significantly according to sex, age, smoking status, or hypertensive status. CONCLUSIONS: High total homocysteine concentrations were associated with the increased risk of total stroke, more specifically ischemic stroke and lacunar infarction, among Japanese men and women.

Non-invasive measurement of brachial-ankle pulse wave velocity is associated with serum C-reactive protein but not with alpha-tocopherol in Japanese middle-aged male workers.

Pulse wave velocity (PWV) is an indicator of arterial stiffness, especially in the aorta, and a marker for vascular damage. We examined the association of brachial-ankle PWV (baPWV) with serum alpha-tocopherol and C-reactive protein (CRP) levels in addition to the traditional risk factors. Study subjects were 178 Japanese male workers aged 50-59 without past histories of cardiovascular diseases. The relation of baPWV with serum alpha-tocopherol and CRP levels was cross-sectionally analyzed after adjusting for other cardiovascular risk factors. The arithmetic mean of serum alpha-tocopherol was 38.9 micromol/l, and the geometric mean of serum CRP was 0.47 mg/l. Multiple linear regression analysis indicated that serum CRP levels were associated with an elevation of baPWV, in addition to age, systolic blood pressure and heart rate. However, serum alpha-tocopherol, serum lipids (triglyceride, low and high density lipoprotein cholesterol), fasting plasma glucose, body mass index, smoking and alcohol drinking did not significantly correlate to baPWV. Multivariate-adjusted means of baPWV according to serum CRP quartile were 1,431, 1,436, 1,507 and 1,508 cm/s (p = 0.033). The serum CRP level might be an important marker for arterial stiffness in Japanese middle-aged males. However, no relation was observed between alpha-tocopherol and baPWV.

Validity of the self-administered food frequency questionnaire used in the 5-year follow-up survey for the JPHC Study to assess folate, vitamin B6 and B12 intake: comparison with dietary records and blood level.

To validate a self-administered food frequency questionnaire (FFQ) for the estimation of dietary intake of folate, vitamins B6 and B12, we compared measures of these vitamins by the FFQ and plasma concentrations among 87 male volunteers aged 40-89 years in the Japan Public Health Center-based prospective study (JPHC Study). No men used folate, vitamins B6 or B12 as supplements. There was a moderate association between energy-adjusted dietary intake and plasma concentration for folate and vitamin B6. The Spearman correlation coefficient was 0.26 and 0.23, respectively, in the total samples. These correlation coefficients were slightly higher when men in the Ishikawa PHC area were excluded from the analysis; the correlation coefficient was 0.29 for folate and 0.26 for vitamin B6. No significant correlation was found between dietary vitamin B12 intake and serum B12 concentration; the correlation coefficient was 0.06 in the total sample and 0.15 when the Ishikawa men were excluded from the analysis. In conclusion, we found that the FFQ used for the 5-year follow-up survey of JPHC Study could reasonably rank individuals by dietary intake of folate and vitamin B6, but not vitamin B12, among Japanese community-dwelling population samples.

Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism.

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the [gaaa](n) repeat ("S" denotes [gaaa](n)=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, [gaaa](n), -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0+/-0.6 micro g/ml) and higher HDL cholesterol levels (55.1+/-12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the [gaaa](n) repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the [gaaa](n) repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.

Effects of serum B vitamins on elevated plasma homocysteine levels associated with the mutation of methylenetetrahydrofolate reductase gene in Japanese.

High plasma homocysteine, a risk factor for atherosclerosis, is frequently caused by a common mutation in the gene for the enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR), C677T (alanine to valine substitution) or low intake of B vitamins that affect the remethylation or transsulfuration pathways in homocysteine metabolism. However, the interaction of the C677T mutation and B vitamins other than folate has not been well elucidated. We conducted a cross-sectional survey of 324 men and 641 women who participated in a 1996 health examination under a hypothesis that high nutritional status of folate, vitamin B12 and vitamin B6 expressed as high serum levels, may compensate for the hyperhomocysteinemia associated with homozygosity for the C677T mutation, but not for having the mutation per se. Age-adjusted plasma homocysteine levels were higher for both men and women with the homozygous genotype for the mutation than those who were heterozygous or had no mutation. Elevated homocysteine levels in homozygous genotype was attenuated among persons with higher serum levels of vitamin B12 and folate, but not vitamin B6, and among persons with the combination of lower folate and higher vitamin B12 and of higher folate and higher vitamin B12, split by the median. These findings suggest that elevated homocysteine levels among Japanese with the homozygous genotype for the MTHFR gene mutation can be modified efficiently by dietary supplement of vitamin B12 as well as folate.