Yoshikuni Kita

Intake of Fish and n3 Fatty Acids and Risk of Coronary Heart Disease Among Japanese The Japan Public Health Center-Based (JPHC) Study Cohort I

Background— Once- or twice-weekly consumption of fish (or a small amount of fish intake) reduces the risk of coronary heart disease and sudden cardiac death in Western countries. It is uncertain whether a high frequency or large amount of fish intake, as is the case in Japan, further reduces the risk. Methods and Results— To examine an association between high intake of fish and n3 polyunsaturated fatty acids and the risk of coronary heart disease, a total of 41 578 Japanese men and women aged 40 to 59 years who were free of prior diagnosis of cardiovascular disease and cancer and who completed a food frequency questionnaire were followed up from 1990–1992 to 2001. After 477 325 person-years of follow-up, 258 incident cases of coronary heart disease (198 definite and 23 probable myocardial infarctions and 37 sudden cardiac deaths) were documented, comprising 196 nonfatal and 62 fatal coronary events. The multivariable hazard ratios (HRs) and 95% confidence intervals in the highest (8 times per week, or median intake=180 g/d) versus lowest (once a week, or median intake=23 g/d) quintiles of fish intake were 0.63 (0.38 to 1.04) for total coronary heart disease, 0.44 (0.24 to 0.81) for definite myocardial infarction, and 1.14 (0.36 to 3.63) for sudden cardiac death. The reduced risk was primarily observed for nonfatal coronary events (HR=0.43 [0.23 to 0.81]) but not for fatal coronary events (HR=1.08 [0.42 to 2.76]). Strong inverse associations existed between dietary intake of n3 fatty acids and risk of definite myocardial infarction (HR=0.35 [0.18 to 0.66]) and nonfatal coronary events (HR=0.33 [0.17 to 0.63]). Conclusions— Compared with a modest fish intake of once a week or ≈20 g/d, a higher intake was associated with substantially reduced risk of coronary heart disease, primarily nonfatal cardiac events, among middle-aged persons.

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 …

Cigarette smoking as a risk factor for stroke death in Japan NIPPON DATA80

Background and Purpose— Some previous Japanese cohort studies failed to show an association between smoking and stroke risk. Because such an association has been noted in other populations, this issue should be re-examined in a recent representative Japanese cohort with a higher total cholesterol level. Methods— A total of 9638 men and women aged 30 years and older without a history of cardiovascular disease (CVD) at baseline in 1980 were followed-up for 14 years. Results— We observed 203 stroke deaths (107 cerebral infarctions, 45 cerebral hemorrhages, and 51 others), 191 heart disease deaths, and 413 CVD deaths. The average serum total cholesterol level was ≈4.91 mmol/L. Cox proportional hazard ratios were calculated adjusting for age, systolic blood pressure, and other conventional risk factors. The hazard ratios for men who smoked 1 to 20 cigarettes/day for all strokes, cerebral infarction, and cerebral hemorrhage were 1.60 (95% CI, 0.91 to 2.79), 2.97 (CI, 1.27 to 6.98), and 0.42 (CI, 0.16 to 1.09), respectively, and for those who smoked ≥21 cigarettes/day, they were 2.17 (CI, 1.09 to 4.30), 3.26 (CI, 1.11 to 9.56), and 0.68 (CI, 0.20 to 2.33), respectively. For women who smoked ≥21 cigarettes/day, the hazard ratio for all strokes was 3.91 (CI, 1.18 to 12.90). For CVD, all heart disease, and ischemic heart disease, the hazard risks of smoking were significant (1.49 to 4.25) for men but not significant for women. Conclusions— Smoking in a cohort with moderate serum total cholesterol level was a potent risk factor for stroke, especially cerebral infarction, for both men and women, and for CVD and ischemic heart disease for men.

Relationship Between Metabolic Risk Factor Clustering and Cardiovascular Mortality Stratified by High Blood Glucose and Obesity NIPPON DATA90, 1990–2000

OBJECTIVE—Metabolic syndrome is diagnosed according to several criteria. Of these, some require glucose intolerance and others require obesity for the diagnosis. We investigated the relationship between metabolic risk factor clustering and cardiovascular disease (CVD) mortality stratified by high blood glucose or obesity. RESEARCH DESIGN AND METHODS—We followed 7,219 Japanese men and women without a history of CVD for 9.6 years. We defined high blood pressure, high blood glucose, high triglycerides, low HDL cholesterol, and obesity as metabolic factors. The multivariate adjusted hazard ratio (HR) for CVD mortality according to the number of clustering metabolic factors was calculated using the Cox proportional hazards model. RESULTS—During follow-up, 173 participants died of CVD. The numbers of metabolic risk factors and CVD mortality were positively correlated (Ptrend = 0.07). The HR was obviously higher among participants with than among those without high blood glucose and clustering of ≥2 other metabolic risk factors (HR 3.67 [95% CI 1.49–9.03]). However, the risk increase was only modest in participants without high blood glucose even if they had ≥2 other metabolic risk factors (1.99 [0.93–4.28]). Conversely, metabolic risk factor clustering was related to CVD mortality irrespective of obesity. CONCLUSIONS—Our findings suggest that glucose tolerance plays an important role in CVD mortality. Because the prevalence of nonobese participants with several metabolic risk factors was quite high and their CVD risk was high, excluding them from the diagnosis of metabolic syndrome because of the absence of obesity might overlook their risk.

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.

Higher stroke incidence in the spring season regardless of conventional risk factors: Takashima Stroke Registry, Japan, 1988-2001.

Background and Purpose— Seasonal variation in stroke incidence was examined using 14-year stroke registration data in a Japanese population. We also examined if this variation was modified by conventional stroke risk factors hypertension, diabetes mellitus, drinking, and smoking. Methods— Data were obtained from the Takashima Stroke Registry, which covers a stable population of ≈55 000 in Takashima County in central Japan. There were 1665 (men, 893; women, 772) registered first-ever stroke cases during 1988 to 2001. The average age of stroke onset for men and women patients was 69.4 and 74.2 years, respectively. Incidence rates (per 100 000 person-years) and 95% CI were calculated by gender, age, and stroke subtype for winter, spring, summer, and autumn. After stratifying patients by their risk factor history, the OR (with 95% CI) of having a stroke in autumn, winter, and spring were calculated, with summer serving as a reference. Results— Among the seasons, stroke incidence per 100 000 person-years was highest in the spring (231.3; 95% CI, 211.1 to 251.5). Spring incidence was highest in both men (240.8; 95% CI, 211.5 to 270.2) and women (222.1; 95% CI, 194.4 to 249.9), and in subjects younger than 65 years (72.6; 95% CI, 60.0 to 85.3) and 65 years or older (875.9; 95% CI, 787.5 to 964.3). Among stroke subtypes, spring incidence was highest for cerebral infarction (154.7; 95% CI, 138.2 to 171.2) and cerebral hemorrhage (53.7; 95% CI, 44.0 to 63.4). The spring excess in stroke incidence was observed regardless of the presence or absence of the risk factor histories. Conclusions— Stroke incidence appears to be highest in the spring among a Japanese population regardless of conventional risk factor history. Factors that explain this excess need further investigation.

Egg consumption, serum total cholesterol concentrations and coronary heart disease incidence: Japan Public Health Center-based prospective study

Limited egg consumption is often recommended to reduce serum cholesterol concentration for the prevention of CHD. We examined the association of egg consumption and total cholesterol concentration with the risk of CHD. A total of 90 735 subjects (19 856 men and 21 408 women, aged 40-59 years in cohort I; 23 463 men and 26 008 women, aged 40-69 years in cohort II) were followed from 1990-4 to the end of 2001 under the Japan Public Health Center-based prospective study. Total cholesterol was obtained in 36 % of the subjects. Men and women were combined for the analyses. The subjects were categorised into four groups according to egg consumption. Subjects with total cholesterol >or=2200 mg/l were less frequent in frequent egg consumption groups in both cohorts (trend P<0.0001). Subjects with <1 d/week of egg consumption were more likely to avoid a cholesterol-rich diet. Egg consumption was not associated with the risk of CHD, although total cholesterol was significantly related to the risk of CHD. The multivariate hazard ratio of CHD in subjects with total cholesterol >or=2400 v. <1800 mg/l was 2.17 (95 % CI 1.22, 3.85; trend P=0.0018). In conclusion, eating eggs more frequently, up to almost daily, was not associated with an increase in CHD incidence for middle-aged Japanese men and women. Subjects with hypercholesterolaemia were less frequently in frequent egg consumption groups, probably because they avoided eating eggs.

Relationship between metabolic risk factor clustering and cardiovascular mortality stratified by high blood glucose and obesity: NIPPON DATA90, 1990-99

OBJECTIVE—Metabolic syndrome is diagnosed according to several criteria. Of these, some require glucose intolerance and others require obesity for the diagnosis. We investigated the relationship between metabolic risk factor clustering and cardiovascular disease (CVD) mortality stratified by high blood glucose or obesity. RESEARCH DESIGN AND METHODS—We followed 7,219 Japanese men and women without a history of CVD for 9.6 years. We defined high blood pressure, high blood glucose, high triglycerides, low HDL cholesterol, and obesity as metabolic factors. The multivariate adjusted hazard ratio (HR) for CVD mortality according to the number of clustering metabolic factors was calculated using the Cox proportional hazards model. RESULTS—During follow-up, 173 participants died of CVD. The numbers of metabolic risk factors and CVD mortality were positively correlated (Ptrend = 0.07). The HR was obviously higher among participants with than among those without high blood glucose and clustering of ≥2 other metabolic risk factors (HR 3.67 [95% CI 1.49–9.03]). However, the risk increase was only modest in participants without high blood glucose even if they had ≥2 other metabolic risk factors (1.99 [0.93–4.28]). Conversely, metabolic risk factor clustering was related to CVD mortality irrespective of obesity. CONCLUSIONS—Our findings suggest that glucose tolerance plays an important role in CVD mortality. Because the prevalence of nonobese participants with several metabolic risk factors was quite high and their CVD risk was high, excluding them from the diagnosis of metabolic syndrome because of the absence of obesity might overlook their risk.

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.

Identification of Hypertension-Susceptibility Genes and Pathways by a Systemic Multiple Candidate Gene Approach: The Millennium Genome Project for Hypertension

A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p<0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein–related positive genes (GNI2, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n=9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene–gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension (χ2=9.93, p=0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061–1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension (p=0.0052). Furthermore, the high-risk genotype was associated with a significantly higher systolic blood pressure (133.08±19.46 vs. 132.25±19.19 mmHg, p=0.04) and diastolic blood pressure (79.65±11.49 vs. 79.01±11.32 mmHg, p=0.019) in the total population. In conclusion, a systemic multiple candidate gene approach can be used to identify not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene–gene interactions to predispose to hypertension.