Naoyuki Takashima

Cardiovascular Disease and Risk Factors in Asia A Selected Review

Cardiovascular disease (CVD) prevention in Asia is an important issue for world health, because half of the world’s population lives in Asia. Asian countries and regions such as Japan, the Republic of Korea, the People’s Republic of China, Hong Kong, Taiwan, and the Kingdom of Thailand have greater mortality and morbidity from stroke than from coronary heart disease (CHD), whereas the opposite is true in Western countries.1 The reasons why this specific situation is observed in countries with rapid and early-phase westernization, such as Japan and South Korea, are very interesting. The Seven Countries Study conducted by Keys et al2 in 1957 found that Japanese populations had lower fat intake, lower serum total cholesterol, and lower CHD than populations in the United States and Scandinavia, in spite of higher smoking rates. The serum total cholesterol level in Japan has increased rapidly since World War II in accordance with an increase in dietary fat intake from 10% of total energy intake per capita per day to 25%.1,2 Despite this increase, the specific characteristic of lower CHD incidence and mortality than that in Western countries has persisted.3,4 Whether Japanese people and certain other Asian populations have different risk factors for CHD than Western populations has been a subject of discussion for quite some time. In this article, we discuss the existence of higher stroke rates and lower CHD rates in Asian countries than in Western countries and the respective risk factors for this on the basis of extensive reviews of cohort studies. We also discuss whether these risk factors differ from those of Western countries. Along with this, we examine the relationship between serum total cholesterol and total stroke and its subtypes. We also address the emerging problems and important issues for CVD prevention in Asia. An extensive …

Brachial–ankle pulse wave velocity predicts all-cause mortality in the general population: findings from the Takashima study, Japan

Brachial–ankle pulse wave velocity (baPWV) is a relatively new non-invasive measure of arterial stiffness obtained using an automated system. We assessed the relationship between baPWV and 6.5-year overall mortality from the Takashima cohort study. The baPWV was measured in 2642 participants at baseline. When participants were divided into tertiles, all-cause mortality increased significantly as baPWV increased (P<0.001). Participants in the highest baPWV tertile showed an increased risk of all-cause mortality evidenced by a multivariable adjusted hazard ratio of 6.8 (95% confidence interval: 1.4–32.8) as compared with the lowest tertile. The present study demonstrated that increased baPWV is an independent predictor of all-cause mortality in the Japanese population.

Common Variants in the ATP2B1 Gene Are Associated With Susceptibility to Hypertension: The Japanese Millennium Genome Project

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10−5; allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10−11). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10−4). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10−18). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10−7) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.

Ischemic Stroke Subtypes in a Japanese Population Takashima Stroke Registry, 1988–2004

Background and Purpose— Population-based information on the epidemiology of ischemic stroke (IS) subtypes is scant. In this study, we characterized IS subtypes in terms of incidence, time trend, and risk factor profiles in a community-based population. Methods— We obtained data from the Takashima Stroke Registry on approximately 55 000 residents of Takashima County in central Japan and calculated age-adjusted stroke incidence rates for different IS subtypes. We determined the incidence time trend by calculating the average annual change across years and also compared risk factors between subtypes. Results— There were 1389 first-ever ischemic strokes registered during 1988 to 2004. Lacunar infarction was the most frequent etiology (54.1%) followed by cardioembolic infarction (22.9%). Age-adjusted incidence rates for different IS subtypes were lacunar, 77.1; cardioembolic, 31.5; and nonlacunar, 29.7/105 person-years. The average annual change was not significant for the IS subtypes except for nonlacunar infarction, which showed a decreasing trend. Risk factor analysis showed that patients with lacunar infarctions were younger and less likely to have a history of transient ischemic attack or a drinking habit than patients with nonlacunar infarctions. Conclusion— Lacunar infarct was the most common IS subtype in our population. We found no significant change in the incidence of subtypes during the study, except a decrease in nonlacunar infarction.

Polymorphism of CYP11B2 Determines Salt Sensitivity in Japanese

Aldosterone plays essential roles in body fluid and electrolyte homeostasis and blood pressure. However, the association between polymorphisms in the CYP11B2 gene and hypertension is controversial. We resequenced CYP11B1 and CYP11B2 and identified 35 polymorphisms in this region. We performed association studies between the plasma aldosterone concentration and 13 polymorphisms in this region in 1443 subjects. The subjects were all obtained from the Suita Cohort Study. Multiple regression analysis indicated that aldosterone levels were determined by renin activity, age, total cholesterol, and hematocrit. Residuals of the aldosterone levels after adjusting for these confounding factors were nominally associated with the T(−344)C (P=0.0026), C(595)T (P=0.0180), −(4837)C (P=0.0310), and G(4936)A (P=0.0498) polymorphisms. Only the T(−344)C polymorphism was significantly associated with the aldosterone level after a correction for multiple testing (Bonferroni). A significant interaction was observed between the T(−344)C polymorphism and renin activity in determining aldosterone levels. Moreover, a significant interaction was observed in 2063 subjects between urinary sodium excretion, which reflects sodium intake, and the T(−344)C polymorphism in determining systolic blood pressure. Only subjects with the TT genotype showed a positive correlation between urinary sodium excretion and systolic blood pressure. In vitro experiments confirmed the functional significance of this T(−344)C polymorphism in terms of angiotensin II reactivity. Thus, the T(−344)C polymorphism in CYP11B2 appears to affect salt sensitivity in Japanese and to have clinical significance.

Long-term risk of BP values above normal for cardiovascular mortality: a 24-year observation of Japanese aged 30 to 92 years.

Objective: In Western populations, blood pressure (BP) measured at baseline has been reported to predict long-term (over 20 years) risk of mortality from cardiovascular diseases (CVDs). However, corresponding evidence is scarce in Asia where stroke is dominant. We investigated the association between baseline BP and 24-year mortality risk due to CVD, in a representative Japanese general population. Methods: We followed up a nationwide sample of 8592 Japanese, aged 30 years or above without a history of CVD and antihypertensive medication at baseline, for 24 years. Hazard ratios for CVD mortality in BP categories defined according to JCN7 criteria were estimated using Cox model adjusted for potential confounding factors with normal BP treated as the reference category. Results: We observed 689 CVD deaths. Hazard ratios for CVD mortality were progressively and significantly increased from the category of prehypertension. Population-attributable fraction (PAF) demonstrated that 43 and 48% of CVD and stroke deaths were explained by non-normal BP at baseline. Hazard ratios and PAF were remarkably higher in younger participants (aged 30–59 years) than those in the elderly (aged 60 years or above). Particularly, in younger men, 81% of CVD deaths were explained by non-normal BP. In sensitivity analysis, participants with antihypertensive medication showed the highest hazard ratio for CVD morality compared with the other categories. Conclusions: BP levels above normal at baseline retained significant relative and absolute risks of CVD and stroke mortality during 24 years. Long-lasting burden of non-normal BP particularly in younger individuals suggests the importance of primary prevention of high BP from younger generation.

Dietary salt intake and blood pressure in a representative Japanese population: baseline analyses of NIPPON DATA80.

Background The relationship between dietary salt intake and blood pressure (BP) has been rarely investigated in a large population of Japanese. The characteristics of nutrients intake and foods intake in Japanese people with high salt intake have also not investigated well. Methods Data of 10 422 participants (4585 men and 5837 women) aged 30 or older who participated in both the National Survey on Circulatory Disorders and National Nutrition Survey in Japan conducted in 1980 were used. The nutrition surveys were performed with weighing record method for three consecutive days to each household. BP and intakes of nutrients and foods were compared by the quintiles of estimated individual salt intake per day. Analyses of covariance were used to calculate multivariate-adjusted mean BP values by the quintiles. Results Participants with higher salt intake showed higher intakes of soy beans/legume, fruit, other vegetables, and fish/shellfish. Intakes of protein, potassium, calcium, iron, magnesium, and fiber were higher in higher quintiles of salt intake. In men, adjusted systolic BPs were higher in the higher salt intake quintiles; there was 4.3 mm Hg difference in multivariate-adjusted systolic BP between the lowest quintile (mean salt intake 8.7 g/day) and the highest quintile (mean salt intake 23.5 g/day) (P < 0.001). In women, adjusted mean systolic BPs were not statistically different among the quintile of salt intake. Conclusions A positive relationship of dietary salt intake to BP was observed, especially in men, in this large-scale representative Japanese population.

Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: A 24-year follow-up of NIPPON DATA80

BACKGROUND Dietary intake of long-chain n-3 PUFA (LCn3FA) among Japanese is generally higher than that in Western populations. However, little is known whether an inverse association of LCn3FA with cardiovascular disease (CVD) risk exists in a population with higher LCn3FA intake. OBJECTIVE To investigate the association between LCn3FA intake and the long-term risk of CVDs in a Japanese general population. METHODS We followed-up a total of 9190 individuals (56.2% women, mean age 50.0 years) randomly selected from 300 areas across Japan and free from CVDs at baseline. Dietary LCn3FA intake was estimated using household weighed food records. Cox models were used to calculate multivariate-adjusted hazard ratios (HR) and confidence intervals (CI) according to sex specific quartiles of LCn3FA intake. RESULTS During 24-year follow-up (192,897 person-years), 879 cardiovascular deaths were observed. The median daily intake of LCn3FA was 0.37% kcal (0.86 g/day). Adjusted HR for CVD mortality was lower in the highest quartile of LCn3FA intake (HR 0.80; 95% CI 0.66-0.96) compared with the lowest quartile, and the trend was statistically significant (P = 0.038). The similar but statistically non-significant trends were observed for coronary heart disease death and stroke death. In analyses by age groups, the inverse associations of LCn3FA intake with the risk of total CVD death and stroke death were significant in younger individuals (30-59 years at baseline). CONCLUSION LCn3FA intake was inversely and independently associated the long-term risk of total CVD mortality in a representative sample of Japanese with high LCn3FA intake.

Genome-Wide Association Meta-analysis Identifies Novel Variants Associated With Fasting Plasma Glucose in East Asians

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.

Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study

BackgroundThe aim of this study was to explore the associations between common potential functional promoter polymorphisms in pro-/anti-inflammatory cytokine genes and kidney function/chronic kidney disease (CKD) prevalence in a large Japanese population.MethodsA total of 3,323 subjects aged 35-69 were genotyped for all 10 single nucleotide polymorphisms (SNPs) in the promoter regions of candidate genes with minor allele frequencies of > 0.100 in Japanese populations. The estimated glomerular filtration rate (eGFR) and CKD prevalence (eGFR < 60 ml/min/1.73 m2) of the subjects were compared among the genotypes.ResultsA higher eGFR and lower prevalence of CKD were observed for the homozygous variants of IL4 -33CC (high IL-4 [anti-inflammatory cytokine]-producing genotype) and IL6 -572GG (low IL-6 [pro-inflammatory cytokine]-producing genotype). Subjects with IL4 CC + IL6 GG showed the highest mean eGFR (79.1 ml/min/1.73 m2) and lowest CKD prevalence (0.0%), while subjects carrying IL4 TT + IL6 CC showed the lowest mean eGFR (73.4 ml/min/1.73 m2) and highest CKD prevalence (17.9%).ConclusionsThe functional promoter polymorphisms IL4 T-33C (rs2070874) and IL6 C-572G (rs1800796), which are the only SNPs that affect the IL-4 and IL-6 levels in Japanese subjects, were associated with kidney function and CKD prevalence in a large Japanese population.