Published papers

Background: An early repolarization pattern, characterized by an elevation of the QRS-ST junction (J-point) on 12-lead electrocardiography (ECG) is associated with cardiac and sudden death. However, little is known about the prognostic significance of J-point elevation for various disease-specific cardiovascular outcomes, including coronary artery disease (CAD). Methods and Results: To investigate the association between the presence of J-point elevation ≥0.1 mV and various disease-specific cardiovascular outcomes, we conducted a 15-year prospective study in a representative general Japanese population of 7,630 individuals (41% men, mean age 52.4 years) who participated in the National Survey of Circulatory Disorders. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. J-point elevation was present in 264 individuals (3.5%) and was associated with an increased risk of cardiac death (adjusted HR, 2.54; 95% confidence interval [CI] 1.40-4.58; P=0.002) and death from CAD (adjusted HR, 4.66; 95% CI 2.30-9.46; P<0.001). In a subgroup analysis by age, the association between J-point elevation and cardiovascular outcomes was more remarkable in middle-aged (<60 years) than in older individuals (≥60 years) (all P for interaction <0.05). Conclusions: J-point elevation on standard 12-lead ECG was an independent predictor of cardiac death and death from CAD in a representative sample of the general Japanese population, particularly among the middle-aged.

The relationship between alcohol consumption and the risk for cardiovascular disease (CVD) is U-shaped, whereas alcohol drinking is linearly associated with blood pressure, and the CVD risk also increases linearly according to blood pressure level. Accordingly, we investigated the net effect of alcohol consumption and hypertension on CVD and its subtypes in this study. A 13-year prospective study of 2336 Japanese men who were free from CVD was performed; ex-drinkers were excluded. The participants were divided into eight groups classified by the combination of the presence of hypertension (systolic/diastolic blood pressure ≥140/90 mm Hg) and alcohol consumption (never-, current-(light, moderate and heavy) drinkers). Multivariate-adjusted hazard ratios (HRs) for the incidence of CVD, coronary artery disease (CAD) and stroke due to the combination of hypertension and alcohol consumption were calculated and compared with non-hypertensive never-drinkers. The HRs for CVD and its subtypes were higher in hypertensives than those in non-hypertensives; in hypertensives without medication for hypertension, the relationship between alcohol consumption and the risks for CVD and CAD was U-shaped, with the highest and most significant increase in never-drinkers. The risk for total stroke was the highest in heavy-drinkers, which was significant. In non-hypertensives, there was no evident increase or decrease in the HRs for CVD and its subtypes in drinkers. Accordingly, controlling blood pressure is important to prevent CVD. In hypertensives, heavy drinking should be avoided to prevent CVD, although light-to-moderate drinking could be protective for CAD. Furthermore, in non-hypertensives, drinkers may need to continuously monitor their blood pressure. © 2013 The Japanese Society of Hypertension All rights reserved.

Regulator of G-protein signaling 2 (RGS2) is a key molecule in signal pathways of vasoactive peptides, such as angiotensin II and endothelin 1, and is believed to have an important role in the pathophysiology of atherosclerosis. We have previously reported that common polymorphisms of RGS2 are associated with hypertension in Japanese. In this study, we studied whether the three previously identified common polymorphisms of RGS2 (638AG, 1026TA and 1891-1892delTC) could be implicated in carotid atherosclerosis in Japanese patients with hypertension (459 men and 382 woman) and in a Japanese general population (814 men and 956 woman). We assessed two criteria for carotid atherosclerosis: maximal intima-media thickness (M-IMT) and mean-IMT. When subjects with atherosclerotic lesions were defined as having mean-IMT1.0 mm, multivariate logistic regression analysis performed after adjusting for confounding factors showed a significant association of the three common polymorphisms, 638AG (AA versus AGGG: odds ratio (OR), 1.55; 95% confidence interval (CI), 1.105-2.185; P0.0113 only for the general population), 1026TA (TT versus TAAA: OR, 1.42; 95% CI, 1.027-1.972; P0.034 for hypertensive subjects and OR, 1.56; 95% CI, 1.129-2.151; P0.0071 for the general population), and 1891-1892delTC (II versus IDDD: OR, 1.44; 95% CI, 1.043-2.008; P0.028 for hypertensive subjects, OR, 1.32; 95% CI 1.002-1.742; P0.048 for the total general population and OR 1.59; 95% CI 1.155-2.207; P0.0047 for the general population), with carotid atherosclerosis. When atherosclerosis was defined as M-IMT 1.0 mm, the values of M-IMT were also significantly different between the three genotypes in the three common polymorphisms. Taken together, these data suggest that genetic polymorphisms in RGS2 are associated with intima-media thickening of carotid artery in humans. © 2011 The Japanese Society of Hypertension All rights reserved.

Background And Purpose- Light-to-moderate alcohol consumption is associated with reduced risk for cardiovascular disease, whereas high serum γ-glutamyltransferase (GGT) level is associated with cardiovascular disease. However, whether light-to-moderate alcohol drinking is still related to reduced risk of cardiovascular disease irrespective of GGT level is uncertain. Methods- We performed a 12.5-year cohort study of 2336 men (excluding exdrinkers) who were free from cardiovascular disease. They were classified into 4 groups according to alcohol consumption: never, and current light, moderate, or heavy drinker. The multivariate-adjusted hazard ratios of alcohol consumption for incidence of coronary artery disease, total stroke, and ischemic stroke compared with those of never drinkers were assessed with stratification by GGT median (32 IU/L). Results- In participants with GGT >32 IU/L, the hazard ratios of all current drinkers for total and ischemic stroke were higher than those of never drinkers. However, in all current drinkers with GGT ≤32 IU/L, the multivariate-adjusted hazard ratios for total and ischemic stroke were lower than in never drinkers. Conclusions- In men with above GGT median, alcohol drinking even with light-to-moderate consumption could be a risk factor for ischemic stroke. © 2011 American Heart Association, Inc.

Aim: Previous studies suggest that klotho gene polymorphisms may be associated with atherosclerosis, but did not assess the relationship between klotho gene polymorphisms and atherosclerosis parameters such as carotid artery intima-media thickness (IMT). Here, we studied whether klotho single nucleotide polymorphisms (SNP) were associated with carotid atherosclerosis. Methods: All subjects were Japanese. Eight-hundred and fifty-three patients with hypertension (465 men and 388 women) in the outpatient clinic and 1783 subjects from the general population (821 men and 962 women) attending health check-ups were analyzed in the present study. We measured mean IMT of the common carotid artery to evaluate carotid atherosclerosis. Four single nucleotide polymorphisms (SNP) (rs7323281; intron1, rs5644481; exon4, rs3752472; exon3, rs650439; intron4) of klotho were selected as representative SNP in haplotype blocks. Results: Multivariate logistic regression analysis adjusted by confounding factors showed a significant association of rs650439 with carotid atherosclerosis in hypertensive patients (TT vs TA vs AA, P < 0.01; TT + TA vs AA, P < 0.01). By ancova considering confounding factors, rs650439 was also significantly associated with mean IMT (TT + TA vs AA, P = 0.04) in the hypertensive population. However, there was no significant association between klotho SNP and carotid IMT in the general population. Compared to the general population, the subject group with hypertensive patients clearly had more atherosclerosis risk factors. Conclusion: Only in hypertensive patients was klotho rs650439 strongly associated with mean IMT thickening of the common carotid artery. Therefore, klotho SNP (rs650439) may influence on the progression of carotid atherosclerosis in patients with hypertension. © 2010 Japan Geriatrics Society.

Background: Recent genome-wide association studies have identified several genetic variants as susceptibility loci for serum uric acid (UA) levels. We also identified a common nonsense mutation, W258X, responsible for renal hypouricemia. Here, we investigated clinical implications of these genetic variants by cross-sectional and longitudinal genetic epidemiological analysis. Methods: The study enrolled 5,165 Japanese subjects aged 64 ± 12 years from the general population. Clinical parameters were obtained from the personal health records, evaluated at medical checkups. Results: Serum UA levels were significantly different between the SLC22A12 rs11231825 (CC/CT/TT: 4.5 ± 1.6, 5.0 ± 1.4, 5.3 ± 1.4 mg/dl; p = 7.6 × 10 -20), SLC2A9 rs1014290 (TT/TG/GG: 4.9 ± 1.4, 5.1 ± 1.4, 5.3 ± 1.4 mg/dl; p = 3.1 × 10-11) and ABCG2 rs2231142 (TT/TG/GG: 5.3 ± 1.5, 5.2 ± 1.4, 5.1 ± 1.4 mg/dl; p = 2.0 × 10-5) genotypes. During 9.4 years of follow-up, 87 new cases of hyperuricemia were diagnosed. Multiple logistic regression analysis identified the accumulation of risk alleles as a significant determinant of future development of hyperuricemia (OR = 7.94; 95% CI: 1.97-53.6). In contrast, subjects with nonsense mutation predominantly showed lower UA levels (XX/XW/WW: 1.3 ± 1.7, 3.6 ± 1.0, 5.2 ± 1.4 mg/dl; p = 9.3 × 10-82). However, these subjects showed significantly reduced renal function (β = -0.111; p < 0.001) independently of possible covariates. Conclusion: Accumulation of risk genotypes was an independent risk factor for future development of hyperuricemia. Genetically developed hypouricemia was an independent risk factor for decreased renal function. Copyright © 2010 S. Karger AG, Basel.

Background: The association between single nucleotide polymorphisms (SNPs) at 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) and low-density lipoprotein-cholesterol (LDL-C) levels has been well replicated in genome-wide association studies (GWAS) of white populations. Recently, the common intronic SNP of HMGCR (rs3846662) has been reported to be a functional variant, influencing the alternative splicing of exon 13. The aim of this study was to examine the association between rs3846662 of HMGCR and the level of LDL-C in Japanese. Methods and Results: Significant differences in LDL-C levels were observed among the genotypes of rs3846662 (P=0.0002 (n=2,686) and P=0.004 (n=2,110)) for the Suita and Ehime samples, respectively. The G allele of rs3846662 was associated with higher LDL-C levels (ß, 3.56; P=4.91×10-5). Consistent with this observation, the risk G allele at rs3846662 was more prevalent in subjects with myocardial infarction (MI) (n=701) than in subjects without MI (n=3,118); 0.559 and 0.511 in MI cases and controls, respectively (nominal P=0.0038). The odds ratio adjusted for age, sex, diabetes, hypertension, and drinking and smoking habits was 1.15 (95% confidence interval 1.04-1.28; P=0.0075). Conclusions: The previously reported association of rs3846662 with LDL-C levels was replicated in the present Suita and Ehime samples. The LDL-associated SNP, rs3846662, appears to confer susceptibility to MI in Japanese.

Aim: In animals, dietary energy restriction is reported to increase longevity, whereas in humans, all cohort studies from Western countries have not shown an association between the low energy intake and longevity. We examined the association between total energy intake and longevity in Japan where dietary pattern is different from that in the West. Methods: A total of 7,704 Japanese aged 30–69 years were followed from 1980 to 2009. Participants were divided into the quintiles of total energy (kcal/day. based on data collected from the National Nutrition Survey. Hazard ratios and 95% confidence intervals (CIs. were derived through the use of Cox proportional hazards models to compare the risk of death across and between the quintiles. Results: There was a significant association between increased energy intake and all-cause mortality risk in only men (P for linear trend=0.008). In cause-specific analysis, compared with the lowest quintile, there was rise in coronary heart disease (CHD. mortality among men (HR; 2.63, 95%CI; 0.95–7.28, P for linear trend 0.016. and women (HR; 2.91, 95%CI; 1.02–8.29, P for linear trend 0.032. and cancer mortality among men (HR; 1.50, 95%CI; 0.999–2.24, P for linear trend 0.038. in the top quintile. Conclusion: We observed significant associations of high energy intake with all-cause and cancer mortality among men and with CHD mortality among men and women. Further studies are needed to confirm the benefits of caloric restriction.

Background: Plasma concentration of n-3 polyunsaturated fatty acids (PUFAs) has been reported to be associated with renal function in Western populations. However, few studies have investigated the association between serum long-chain n-3 and n-6 PUFA profiles and renal function in a Japanese population with high marine-derived longchain n-3 PUFA intake. Methods: A cross-sectional study was performed in 549 Japanese rural community-dwellers aged 40 to 64 years. In adjusted analysis of covariance, we assessed the relationship between estimated glomerular filtration rate (eGFR) and tertiles of serum long-chain n-3 and n-6 PUFA profiles ([eicosapentaenoic acid {EPA} + docosahexaenoic acid {DHA}]:arachidonic acid [AA]). GFR was estimated by Japanese specific equations using serum creatinine and cystatin C (eGFRcre and eGFRcys). Using multivariate-adjusted linear regression models, we also assessed the relationships between eGFRs and several n-3 and n-6 PUFAs, which have been suggested to be associated with renal function. Results: In all participants, higher dietary fish intake as assessed by a semi-quantitative questionnaire was associated with higher serum value of (EPA+DHA):AA. Participants in the higher (EPA+DHA):AA tertiles had nonsignificantly higher eGFRcre and significantly higher eGFRcys (P = 0.016). In addition, eGFRcys in T2+T3 of (EPA+DHA):AA was significantly higher than that in T1 (adjusted mean eGFRcys, T1: 87 ml/min/1.73m2, T2+T3: 91 ml/min/1.73m2; P < 0.01). Among the PUFAs, only (EPA+DHA) was significantly associated with eGFRcys. Conclusions: Serum (EPA+DHA):AA, which reflects an individual's fish intake, might be associated with eGFRcys in Japanese community-dwellers.

© 2019 National Lipid Association Background: Branched-chain amino acids (BCAAs) play a key role in energy homeostasis. Objective: We aimed to investigate the association between plasma BCAA levels and dyslipidemia in the Japanese population without diabetes mellitus. Methods: This cross-sectional study included 4952 participants without diabetes mellitus, enrolled in the Tsuruoka Metabolomic Cohort Study. Plasma BCAA levels were measured by capillary electrophoresis–mass spectrometry. Correlations between lipid and BCAA profiles were evaluated by sex-stratified multiple linear regression analyses, after adjusting for confounders. Logistic regression was used to identify associations between BCAAs and metabolic dyslipidemia (MD) defined as triglyceride levels ≥150 mg/dL, high-density lipoprotein cholesterol levels ≤40 mg/dL for men and ≤50 mg/dL for women, or low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dL. Results: In both sexes, the levels of individual BCAAs and the total BCAA levels correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels. Valine, leucine, and total BCAA levels were weakly and positively correlated with LDL-C levels. Increased BCAA levels showed positive associations with MD. However, associations between BCAAs and elevated LDL-C levels were unclear. Furthermore, the associations between BCAA levels and MD regardless of fasting blood sugar (FBS) levels (high or low). Although valine, leucine, and total BCAA levels were weakly associated with elevated LDL-C levels in the high-FBS group, no such association was observed in the low-FBS group. Conclusions: BCAAs might be associated with MD independently of the FBS level and might play an important role in lipid metabolism and dyslipidemia.

© 2019, Japanese Circulation Society. All rights reserved. Background: Several cohort studies have demonstrated an association between socioeconomic status (SES) and health outcomes in Japan. As long-term employment is common in Japan, the size of the company may be related to cardiovascular disease (CVD) mortality risk. We examined the association of employment conditions with CVD mortality risk among working-age Japanese men (30–59 years, n=2,091). Methods and Results: We used 20-year follow-up data from NIPPON DATA90, for which baseline data were obtained from the 4th National Survey on Circulatory Disorders in 1990. Participants were classified into 4 groups: 3 strata for indefinite-term employees according to company size (large company/public office, moderate-sized, or small), and the self-employed/administrator group. Multivariable-adjusted hazard ratios (HRs) were adjusted for age, lifestyle, and CVD risk factors. Smokers were more common, habitual exercise was less common, and the average systolic blood pressure was higher among indefinite-term employees of small companies compared with employees at large companies/public offices. There was no significant difference in the total CVD mortality risk between indefinite-term employees and self-employed/administrator participants. The age-adjusted HR (95% confidence interval) for total CVD using indefinite-term employees of large companies/public office as a reference was 2.53 (1.12, 5.69) for employees of small companies. Conclusions: Working as an indefinite-term employee at a small company in Japan was significantly associated with elevated risk of CVD mortality among Japanese men.

Background: Homogeneous assays for low-density lipoprotein-cholesterol (LDL-C) have good precision and are pretreatment-free procedures. However, their accuracies have been questioned, especially in diseased subjects. In this study, we aimed to verify whether LDL-C levels determined by homogeneous assays [LDL-C (H)] agree with those determined by a beta-quantification method [LDL-C (BQ)] in fresh clinical samples. Methods: We determined LDL-C levels in 49 non-diseased and 124 diseased subjects whose triglyceride (TG) levels were less than 11.29 mmol/L (1000 mg/dL) using 12 homogeneous assays and a BQ method simultaneously. Results: In total, 30.6% of non-diseased subjects and 46.0% of diseased subjects were in the postprandial state. The maximum inter- and intra-assay CVs were 1.8% and 1.5%, and 8 reagents had a CV of 1.0% or less. The mean bias ranged from -0.5% to 1.8% for non-diseased subjects and from -0.7% to 1.6% for diseased subjects. For non-diseased subjects, all but one reagent achieved the National Cholesterol Education Program (NCEP) total error requirement in more than 90% of samples. However, for diseased subjects, the number of reagents that met this requirement was low. With some reagents, LDL-C (H) was higher than LDL-C (BQ), especially in subjects with hypertriglyceridemia. While for other reagents, the difference between the two methods was not associated with hypertriglyceridemia except for type I (n = 2) and type III hyperlipidemia (n = 1). Postprandial sampling was not the main factor for discordant results. Conclusions: LDL-C (H) agrees with LDL-C (BQ) in non-diseased subjects, but exhibits positive bias for subjects with hypertriglyceridemia in diseased subjects for some reagents. © 2012 Elsevier Ireland Ltd.

BACKGROUND: A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. METHODS AND RESULTS: Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. CONCLUSIONS: We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations. © 2012 American Heart Association, Inc.

Aim: The autosomal recessive hypercholesterolemia (ARH) gene is located on chromosome 1p35 and encodes a 308-amino acid protein containing a phosphotyrosine-binding domain. Several researchers have identified mutations of ARH that cause autosomal recessive hypercholesterolemia; however, it remains unknown whether this gene is involved in common hypercholesterolemia. Methods and Results: We searched for polymorphisms of the ARH gene by denaturing high-performance liquid chromatography and direct sequencing. We identified 18 single nucleotide polymorphisms of the gene, including 9 novel polymorphisms, and determined 2 haplotype blocks. No association was observed between common hypercholesterolemia and any polymorphisms or haplotypes of the ARH gene; however, we newly identified a rare Thr56Met missense mutation located in the phosphotyrosine-binding domain, which is the functional domain responsible for cholesterol metabolism. Among 1,800 Japanese individuals enrolled in the Suita study, only 4 were heterozygous for Thr56Met and all had hypercholesterolemia. The total cholesterol level and low-density lipoprotein cholesterol level of diabetic patients with the Thr56Met missense mutation was 276.3 ± 13.8 mg/dL and 185.3 ± 7.37 mg/dL, respectively. Conclusions: Because the Thr56Met missense mutation occurs in an orthologously conserved functional domain and all subjects with the mutation had hypercholesterolemia resembling familiar hypercholesterolemia, it may be a cause of familial hypercholesterolemia.

Background: Large-scale genome-wide association studies (GWAS) have been successful in identifying genes that contribute to common diseases and phenotypes. A GWAS of hypertension-related phenotypes in a Japanese population was conducted in the current study. Methods and Results: A total of 936 participants were recruited from the Suita Study and a GWAS with 538,732 single nucleotide polymorphisms (SNP) was performed. The phenotypes included were systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), waist-to-hip ratio (WHR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma brain natriuretic peptide (BNP) concentration and alcohol consumption (AC). The SNP exceeding the genome-wide significance level were subjected to subsequent association studies using samples available from the Suita Study and Nomura Study. There is no master gene in the Japanese population that profoundly affects SBP, DBP, BMI, WHR, PRA and PAC. AC was influenced by the functional polymorphism in ALDH2, which affected BP levels in men. The BNP concentration was influenced by a polymorphism in the 3' region of the gene encoding for BNP. However, this polymorphism did not influence blood pressure (BP). Six SNP were identified to be associated with hypertension in both the Suita and Nomura studies. Conclusions: Although several candidate SNP relevant to hypertension and those influencing AC and BNP were identified, our middle-sized GWAS indicated that there is no master gene in Japanese people that profoundly affects BP-related phenotypes.