Minoru Yamakado

International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values

In 1999, the Japan Diabetes Society (JDS) launched the previous version of the diagnostic criteria of diabetes mellitus, in which JDS took initiative in adopting glycated hemoglobin (HbA1c) as an adjunct to the diagnosis of diabetes. In contrast, in 2009 the International Expert Committee composed of the members of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) manifested the recommendation regarding the use of HbA1c in diagnosing diabetes mellitus as an alternative to glucose measurements based on the updated evidence showing that HbA1c has several advantages as a marker of chronic hyperglycemia2–4. The JDS extensively evaluated the usefulness and feasibility of more extended use of HbA1c in the diagnosis of diabetes based on Japanese epidemiological data, and then the ‘Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus’ was published in the Journal of Diabetes Investigation5 and Diabetology International6. The new diagnostic criterion in Japan came into effect on 1 July 2010. According to the new version of the criteria, HbA1c (JDS) ≥6.1% is now considered to indicate a diabetic type, but the previous diagnosis criteria of high plasma glucose (PG) levels to diagnose diabetes mellitus also need to be confirmed. Those are as follows: (i) FPG ≥126 mg/dL (7.0 mmol/L); (ii) 2‐h PG ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or (iii) casual PG ≥200 mg/dL (11.1 mmol/L). If both PG criteria and HbA1c in patients have met the diabetic type, those patients are immediately diagnosed to have diabetes mellitus5,6.

Association Between Serum Uric Acid, Metabolic Syndrome, and Carotid Atherosclerosis in Japanese Individuals

Objective—There are few data available on possible independent association between uric acid and carotid atherosclerosis. Here we first sought to investigate association between uric acid levels and metabolic syndrome in Japanese; second, we assessed whether there is an independent association of uric acid with prevalence of carotid atherosclerosis in individuals subdivided according to gender and metabolic syndrome status. Methods and Results—Cross-sectional data from 8144 individuals who underwent general health screening were analyzed. After adjusting for age, total cholesterol, and smoking status, the odds ratios (95% CI) of sex-specific quartiles of serum uric acid for metabolic syndrome were 1.0, 1.06 (0.60 to 1.87), 2.18 (1.30 to 3.64), and 4.17 (2.56 to 6.79) in women, and 1.0, 0.92 (0.74 to 1.14), 1.52 (1.25 to 1.65), and 1.97 (1.61 to 2.40) in men. After adjusting for age, serum levels, total cholesterol, and smoking status, prevalence of carotid plaque was higher in subjects in the second, third, and fourth quartiles of uric acid level with odds ratios (95% CI) of 1.24 (1.01 to 1.52), 1.37 (1.11 to 1.68), and 1.31 (1.05 to 1.63), respectively, in men without metabolic syndrome but not in men with metabolic syndrome or in women with or without metabolic syndrome. Conclusion—The prevalence of metabolic syndrome showed a graded increase according to serum uric acid values in both genders. In men who did not have metabolic syndrome, uric acid was found to be an independent risk factor for incidence of carotid plaque.

Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima-media thickening.

We investigated the relation between positivity for hepatitis C virus (HCV) and carotid-artery plaque and carotid intima-media thickening by analysing cross-sectional data of individuals undergoing a general health screening test. Of 4784 individuals enrolled, 104 (2.2%) were seropositive for HCV. After adjustment for confounding risk factors, HCV seropositivity was found to be associated with an increased risk of carotid-artery plaque (odds ratio 1.92 [95% CI 1.56-2.38], p=0.002) and carotid intima-media thickening (2.85 [2.28-3.57], p<0.0001). These findings suggest a possible role for chronic hepatitis C in the pathogenesis of carotid arterial remodelling.

Plasma Free Amino Acid Profiling of Five Types of Cancer Patients and Its Application for Early Detection

Background Recently, rapid advances have been made in metabolomics-based, easy-to-use early cancer detection methods using blood samples. Among metabolites, profiling of plasma free amino acids (PFAAs) is a promising approach because PFAAs link all organ systems and have important roles in metabolism. Furthermore, PFAA profiles are known to be influenced by specific diseases, including cancers. Therefore, the purpose of the present study was to determine the characteristics of the PFAA profiles in cancer patients and the possibility of using this information for early detection. Methods and Findings Plasma samples were collected from approximately 200 patients from multiple institutes, each diagnosed with one of the following five types of cancer: lung, gastric, colorectal, breast, or prostate cancer. Patients were compared to gender- and age- matched controls also used in this study. The PFAA levels were measured using high-performance liquid chromatography (HPLC)–electrospray ionization (ESI)–mass spectrometry (MS). Univariate analysis revealed significant differences in the PFAA profiles between the controls and the patients with any of the five types of cancer listed above, even those with asymptomatic early-stage disease. Furthermore, multivariate analysis clearly discriminated the cancer patients from the controls in terms of the area under the receiver-operator characteristics curve (AUC of ROC >0.75 for each cancer), regardless of cancer stage. Because this study was designed as case-control study, further investigations, including model construction and validation using cohorts with larger sample sizes, are necessary to determine the usefulness of PFAA profiling. Conclusions These findings suggest that PFAA profiling has great potential for improving cancer screening and diagnosis and understanding disease pathogenesis. PFAA profiles can also be used to determine various disease diagnoses from a single blood sample, which involves a relatively simple plasma assay and imposes a lower physical burden on subjects when compared to existing screening methods.

Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences

Interleukin‐6 (IL‐6) may play a role in the pathogenesis of hepatocellular carcinoma (HCC). Recently, it was reported in mouse models that estrogen‐mediated inhibition of IL‐6 production explains the gender disparity in HCC. We conducted a retrospective cohort study to examine whether this hypothesis is applicable to human HCC. We enrolled 330 patients with chronic hepatitis C whose serum samples were collected between January 1994 and December 2002. Serum IL‐6 concentrations were measured and patients were divided into three groups according to IL‐6 levels: low, middle, and high. We evaluated the association between serum IL‐6 levels and the risk of subsequent HCC development, including subgroup analysis on each gender. During the follow‐up period (mean 9.0 yr), HCC developed in 126 patients. The incidence rates differed significantly among the three groups (p = 0.015), increasing in accordance with serum IL‐6 levels. However, unexpectedly, this tendency was significant only in female patients. In a multivariate analysis, higher serum IL‐6 level was an independent risk factor for HCC development in female patients, with a hazard ratio of 1.61. Although female patients showed a weak negative correlation between serum IL‐6 levels and estradiol levels, the lower risk of HCC in female patients cannot be fully explained by estrogen‐mediated inhibition of IL‐6 production. In conclusion, higher serum IL‐6 level was an independent risk factor for HCC development in female but not male chronic hepatitis C patients. Measurement of serum IL‐6 levels may provide useful information for predicting future HCC development in female chronic hepatitis C patients.

Hypertension Is the Most Common Component of Metabolic Syndrome and the Greatest Contributor to Carotid Arteriosclerosis in Apparently Healthy Japanese Individuals

The cluster of metabolic and hemodynamic risk factors known as metabolic syndrome is known to be a risk factor for ischemic cardiovascular diseases and stroke. By analyzing the cross-sectional data from 8,144 individuals (age 19−88 years) who underwent general health screening, we have investigated the prevalence of metabolic syndrome, as diagnosed by modified-National Cholesterol Education Program (NCEP) criteria corresponding to the following five categories: triglycerides ≥150 mg/dl; high density lipoprotein (HDL)-cholesterol <40 mg/dl in men or <50 mg/dl in women; fasting plasma glucose ≥110 mg/dl; systolic/diastolic blood pressure ≥130/85 mmHg; and body mass index >25 kg/m2. We found that the prevalence of metabolic syndrome was 19% in men and 7% in women. After adjustment for age, metabolic syndrome was found to be significantly more prevalent in men than in women, with an odds ratio of 3.08 (95% confidence interval [CI] 2.62−3.61, p<0.0001). Among the five metabolic/hemodynamic risk factor components, hypertension was observed most frequently in individuals with metabolic syndrome, at 85% in men and 87% in women. In addition, multivariate logistic regression analysis adjusted for age, sex, serum total cholesterol levels, and smoking status showed that hypertension possessed the greatest odds ratio (1.43, 95% CI 1.27−1.60) for carotid plaque among the metabolic/hemodynamic risk factors. These data emphasize the importance of controlling blood pressure for reducing the risk of both metabolic syndrome and carotid arteriosclerosis in apparently healthy individuals.

Possibility of multivariate function composed of plasma amino acid profiles as a novel screening index for non-small cell lung cancer: a case control study

BackgroundThe amino-acid balance in cancer patients often differs from that in healthy individuals, because of metabolic changes. This study investigated the use of plasma amino-acid profiles as a novel marker for screening non-small-cell lung cancer (NSCLC) patients.MethodsThe amino-acid concentrations in venous blood samples from pre-treatment NSCLC patients (n = 141), and age-matched, gender-matched, and smoking status-matched controls (n = 423), were measured using liquid chromatography and mass spectrometry. The resultant study data set was subjected to multiple logistic regression analysis to identify amino acids related with NSCLC and construct the criteria for discriminating NSCLC patients from controls. A test data set derived from 162 patients and 3,917 controls was used to validate the stability of the constructed criteria.ResultsThe plasma amino-acid profiles significantly differed between the NSCLC patients and the controls. The obtained model (including alanine, valine, isoleucine, histidine, tryptophan and ornithine concentrations) performed well, with an area under the curve of the receiver-operator characteristic curve (ROC_AUC) of >0.8, and allowed NSCLC patients and controls to be discriminated regardless of disease stage or histological type.ConclusionsThis study shows that plasma amino acid profiling will be a potential screening tool for NSCLC.

Novel, Objective, Multivariate Biomarkers Composed of Plasma Amino Acid Profiles for the Diagnosis and Assessment of Inflammatory Bowel Disease

Background Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram). Methodology and Principal Findings We measured fasting plasma aminograms in 387 IBD patients (Crohns disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898–0.983) and 0.894 (95%CI: 0.853–0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853–0.935) and 0.849 (95%CI: 0.770–0.928), and correlated with clinical disease activity indexes for CD (rs = 0.592, 95%CI: 0.385–0.742, p<0.001) or UC (rs = 0.598, 95%CI: 0.452–0.713, p<0.001), respectively. Conclusions and Significance In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.

Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10−4) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10−10; FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10−8) and 3p11.2 (rs2055109; P = 3.94 × 10−8). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10−7). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.

Absolute value of visceral fat area measured on computed tomography scans and obesity-related cardiovascular risk factors in large-scale Japanese general population (the VACATION-J study)

Abstract Background. The management of cardiovascular risk factors is important for prevention of atherosclerotic cardiovascular diseases (ACVD). Visceral fat accumulation plays an important role in the clustering of cardiovascular risk factors, leading to ACVD. The present study investigated the gender- and age-specific relationship between obesity-related cardiovascular risk factor accumulation and computed tomography (CT)-measured fat distribution in a large-scale Japanese general population. Methods and results. Fat distribution was measured on CT scans in 12,443 subjects (males/females = 10,080/2,363), who underwent medical health check-up at 9 centers in Japan. The investigated obesity-related cardiovascular risk factors were hyperglycemia, dyslipidemia, and elevated blood pressure. Visceral fat area (VFA) for all males and old females showed almost symmetric distribution, while that of young females showed skewed distribution with a marked left shift. Only a small proportion of young females had large visceral fat and cardiovascular risk accumulation. The mean number of risk factors exceeded 1.0 at around 100 cm2 for VFA in all groups, irrespective of gender, age (cut-off age 55), and BMI (cut-off BMI 25 kg/m2). Conclusions. In this large-scale Japan-wide general population study, an absolute VFA value of about 100 cm2 equated with obesity-related cardiovascular risk factor accumulation, irrespective of gender, age, and BMI. Clinical trial registration information. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000002780&language=E.