||Ikezaki H, Fisher VA, Lim E, Ai M, Liu CT, Cupples LA, Nakajima K, Asztalos BF, Furusyo N, Schaefer EJ, Direct versus calculated low-density lipoprotein cholesterol and C reactive protein in cardiovascular disease risk assessment in the Framingham Offspring Study, Clinical Chemistry, 10.1373/clinchem.2019.304600, 65, 9, 1102-1114, 2019.09.
||Ikezaki H, Ai M, Schaefer EJ, Otokozawa S, Asztalos BF, Nakajima K, Zhou Y, Liu CT, Jacques PF, Cupples LA, Furusyo N, Cardiovascular Disease Prevalence and Insulin Resistance in the Kyushu-Okinawa Population Study and the Framingham Offspring Study., Journal of Clinical Lipidology, 10.1016/j.jacl.2017.01.014, 11, 2, 348-356, 2017.03.
||Ikezaki H, Ai M, Schaefer EJ, Otokozawa S, Asztalos BF, Nakajima K, Yanhua Z, Liu CT, Jacques PF, Cupples LA, Furusyo N, Ethnic Differences in Glucose Homeostasis Markers between the Kyushu-Okinawa Population Study and the Framingham Offspring Study., Scientific Reports, 10.1038/srep36725, 6, 36725, 2016.11.
||Ikezaki H, Nomura H, Furusyo N, Ogawa E, Kajiwara E, Takahashi K, Kawano A, Maruyama T, Tanabe Y, Satoh T, Nakamuta M, Kotoh K, Azuma K, Dohmen K, Shimoda S, Hayashi J; Kyushu University Liver Disease Study (KULDS) Group, Efficacy of interferon-beta plus ribavirin combination treatment on the development of hepatocellular., Hepatology Research, 10.1111/hepr.12555, 46, 3, E174-E180, 2016.03.
||Ikezaki H, Furusyo N, Ihara T, Hayashi T, Ura K, Hiramine S, Mitsumoto F, Takayama K, Murata M, Kohzuma T, Ai M, Schaefer EJ, Hayashi J, Glycated Albumin as a diagnostic tool for diabetes in a general Japanese population., Metabolism – Clinical and Experimental, 10.1016/j.metabol.2015.03.003, 64, 6, 698-705, 2015.06.
||Ikezaki H, Furusyo N, Okada K, Ihara T, Hayashi T, Ogawa E, Kainuma M, Murata M, Hayashi J, The utility of urinary myo-inositol as a marker of glucose intolerance., Diabetes Research and Clinical Practice, 10.1016/j.diabres.2013.11.018, 103, 1, 88-96, 2014.01.
||Furusyo N, Ogawa E, Sudoh M, Murata M, Ihara T, Hayashi T, Ikezaki H, Hiramine S, Mukae H, Toyoda K, Taniai H, Okada K, Kainuma M, Kajiwara E, Hayashi J, Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: A randomized trial., Journal of Hepatology, 10.1016/j.jhep.2012.08.003, 57, 6, 1186-1192, 2012.12, Background & Aims: Early menopause in women with chronic hepatitis C virus (HCV) infection is associated with a low likelihood of a sustained virological response (SVR) in conjunction with their antiviral treatment. This is potentially related to their reduced estrogen secretion. The study was done to determine whether selective estrogen receptor modulator administration might improve the efficacy of the current standard of care (SOC) treatment, pegylated interferon (PegIFN) α2a plus ribavirin (RBV), for postmenopausal women. Methods: One hundred and twenty-three postmenopausal women with genotype 1b chronic hepatitis C were randomly assigned to one of two treatment groups: raloxifene hydrochloride (RLX) (60 mg/day) plus SOC (PegIFNα2a 180 μg/week and RBV 600-1000 mg/day) (n = 62) or SOC only (n = 61). Genotyping was performed of the polymorphism in the interleukin-28B (IL28B) gene region (rs8099917) of DNA collected from each patient. Results: One RLX-treated patient discontinued RLX because of a systemic rash following 2 weeks of treatment. Twenty-four weeks after treatment, the SVR rate was significantly higher for RLX plus SOC patients (61.3%) than for SOC only patients (34.4%) (p = 0.0051). Further, the SVR rate was significantly higher for RLX plus SOC patients with IL28B TT (72.5%) than for SOC only patients with IL28B TT (39.2%) (p = 0.0014), but no such relationship was observed in patients carrying the minor IL28B allele. Conclusions: RLX improved the efficacy of SOC in the treatment of postmenopausal women with chronic hepatitis C. RLX shows promise as an adjuvant to the standard antiviral treatment of such patients..
||Ogawa E, Furusyo N, Murata M, Ikezaki H, Ihara T, Hayashi T, Toyoda K, Taniai H, Okada K, Kainuma M, Hayashi J, Insulin resistance undermines the advantages of IL28B polymorphism in the pegylated interferon alpha-2b and ribavirin treatment of chronic hepatitis C patients with genotype 1., Journal of Hepatology, 10.1016/j.jhep.2012.04.027, 57, 3, 534-540, 2012.09, Background & Aims: Recent studies have suggested that insulin resistance exerts a strong influence on chronic hepatitis C virus (HCV) infection. We analyzed pretreatment factors useful for predicting sustained virological response (SVR), especially interleukin (IL) 28B polymorphism and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Methods: This cohort study consisted of 328 chronic hepatitis C patients with HCV genotype 1 who were treated for 48 weeks with pegylated interferon (PegIFN) α-2b and ribavirin (RBV). Genotyping of the polymorphisms in the IL28B gene region (rs8099917) on chromosome 19 was performed on DNA collected from each patient. Results: No significant difference in IL28B genotype distribution was found according to HOMA-IR. Multivariate analysis identified the IL28B TT genotype (OR = 5.97, 95% CI 2.15-16.55, p = 0.0006) and the baseline HOMA-IR (OR = 0.65, 95% CI 0.48-0.87, p = 0.0044) as significant, independent pretreatment predictors of SVR. Receiver operating characteristic analyses to determine the optimal threshold values of HOMA-IR for predicting SVR showed that the areas under the curve (AUC) were high for both IL28B TT (AUC = 0.774, HOMA-IR cut-off value: 2.45) and IL28B TG/GG genotypes (AUC = 0.772, HOMA-IR cut-off value: 1.55). Conclusions: For HCV genotype 1, both IL28B and baseline HOMA-IR are independent pretreatment predictors of SVR in patients treated with PegIFNα-2b and RBV. Insulin resistance undermines the advantages of IL28B polymorphism to obtain SVR..
||Furusyo N, Koga T, Ai M, Otokozawa S, Kohzuma T, Ikezaki H, Schaefer EJ, Hayashi J, Utility of glycated albumin for the diagnosis of diabetes mellitus in a Japanese population study
Results from the Kyushu and Okinawa Population Study (KOPS)., Diabetologia, 10.1007/s00125-011-2310-6, 54, 12, 3028-3036, 2011.12, Aims/hypothesis: Glycated albumin is a measure of the mean plasma glucose concentration over approximately 2-3 weeks. We determined reference values for glycated albumin, and assessed its utility for the diagnosis of type 2 diabetes mellitus in the general population. Methods: We studied 1,575 men and women (mean age, 49.9 years; range, 26-78 years) who participated in a periodic health examination in a suburban Japanese town. HbA 1c and fasting plasma concentrations of glucose (FPG) and glycated albumin were measured. Participants with FPG ≥7.0 mmol/l or HbA 1c ≥6.5% (48 mmol/mol) were diagnosed as having diabetes. In our laboratory, the glycated albumin assay had intra-assay and inter-assay CVs of 1.1% and 1.6%, respectively. Results: Glycated albumin levels were significantly correlated with HbA 1c levels (r=0.766, p<0.001) and FPG (r=0.706, p<0.001). The presence of diabetes was significantly higher in participants with glycated albumin levels between 15.0% and 15.9% (five of 276, 1.81%) than in those with glycated albumin <14% (three of 672, 0.45%) (p=0.037), and was markedly increased in those with a glycated albumin level >16% (58 of 207, 28.0%). Receiver operating characteristic curve analysis indicated that a glycated albumin level of ≥15.5% was optimal for predicting diabetes, with a sensitivity of 83.3% and a specificity of 83.3%. Conclusions/interpretation: There is merit to further investigating the potential for glycated albumin to be used as an alternative measure of dysglycaemia for future research and clinical practice..
||Hiroaki Ikezaki, Elise Lim, L Adrienne Cupples, Ching-Ti Liu, Bela F Asztalos, Ernst J Schaefer, Small Dense Low-Density Lipoprotein Cholesterol Is the Most Atherogenic Lipoprotein Parameter in the Prospective Framingham Offspring Study., Journal of the American Heart Association, 10.1161/JAHA.120.019140, 10, 5, e019140, 2021.02, Background Elevated plasma levels of direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein (LDL) triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and lipoprotein(a) have all been associated with incident atherosclerotic cardiovascular disease (ASCVD). Our goal was to assess which parameters were most strongly associated with ASCVD risk. Methods and Results Plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol, direct LDL-C, sdLDL-C, LDL triglycerides, remnant lipoprotein particle cholesterol, triglyceride-rich lipoprotein cholesterol, and lipoprotein(a) were measured using standardized automated analysis (coefficients of variation, <5.0%) in samples from 3094 fasting subjects free of ASCVD. Of these subjects, 20.2% developed ASCVD over 16 years. On univariate analysis, all ASCVD risk factors were significantly associated with incident ASCVD, as well as the following specialized lipoprotein parameters: sdLDL-C, LDL triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and direct LDL-C. Only sdLDL-C, direct LDL-C, and lipoprotein(a) were significant on multivariate analysis and net reclassification after adjustment for standard risk factors (age, sex, hypertension, diabetes mellitus, smoking, total cholesterol, and high-density lipoprotein cholesterol). Using the pooled cohort equation, many specialized lipoprotein parameters individually added significant information, but no parameter added significant information once sdLDL-C (hazard ratio, 1.42; P<0.0001) was in the model. These results for sdLDL-C were confirmed by adjusted discordance analysis versus calculated non-high-density lipoprotein cholesterol, in contrast to LDL triglycerides. Conclusions sdLDL-C, direct LDL-C, and lipoprotein(a) all contributed significantly to ASCVD risk on multivariate analysis, but no parameter added significant risk information to the pooled cohort equation once sdLDL-C was in the model. Our data indicate that small dense LDL is the most atherogenic lipoprotein parameter..
||Hiroaki Ikezaki, Norihiro Furusyo, Yuya Yokota, Masumi Ai, Bela F Asztalos, Masayuki Murata, Jun Hayashi, Ernst J Schaefer, Small Dense Low-Density Lipoprotein Cholesterol and Carotid Intimal Medial Thickness Progression., Journal of atherosclerosis and thrombosis, 10.5551/jat.54130, 27, 10, 1108-1122, 2020.10, AIM: The association between small dense low-density lipoprotein cholesterol (sdLDL-C) levels and carotid intimal medial thickness (cIMT) progression has not been evaluated fully. We assessed specialized lipoproteins, including sdLDL-C, with regard to cIMT progression in a prospective observational study in Japan. METHODS: Plasma total cholesterol, direct LDL-C, sdLDL-C, LDL-triglycerides (LDL-TG), high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, triglycerides, Lp(a), and adiponectin were measured in 2,030 men and women (median age 59 years, free of cardiovascular disease (CVD) and off cholesterol lowering medication). At both baseline and after a five-year follow-up, cIMT was assessed. Univariate, multivariate regression, and least square analyses were performed to examine the relationships between direct LDL-C, sdLDL-C, and other lipoproteins with cIMT progression. RESULTS: The median cIMT at baseline was 0.63 mm and five-year progression was 0.18 mm. After adjustment for standard CVD risk factors, including age, gender, systolic blood pressure, total cholesterol, HDL-C, smoking, diabetes, and hypertension treatment, only direct LDL-C, sdLDL-C, and the sdLDL-C/LDL-C ratio were associated with cIMT progression. Even in subjects with direct LDL-C ＜100 mg/dL, who were considered at low CVD risk, elevated sdLDL-C were associated with cIMT progression (P for trend=0.009) in a model with established CVD risk factors, although the sdLDL-C/LDL-C ratio did not. Those correlations did not change by including triglycerides as a controlling factor or excluding premenopausal women from the analyzed population. CONCLUSIONS: Small dense LDL-C has a stronger relationship with cIMT progression than LDL-C does; therefore, measuring sdLDL-C may allow for the formulation of optimal therapy for CVD prevention..
||Hiroaki Ikezaki, Norihiro Furusyo, Paul F Jacques, Motohiro Shimizu, Masayuki Murata, Ernst J Schaefer, Yoshihisa Urita, Jun Hayashi, Higher dietary cholesterol and ω-3 fatty acid intakes are associated with a lower success rate of Helicobacter pylori eradication therapy in Japan., The American journal of clinical nutrition, 10.3945/ajcn.116.144873, 106, 2, 581-588, 2017.08, Background:Helicobacter pylori infection is a known risk factor for duodenal ulcers, gastritis, and gastric cancer. The eradication of H. pylori is successful in treating these disorders; however, the success rate of eradication therapy is declining. There may be an interaction with nutrient intake to account for this decline.Objective: We investigated the influence of food and nutrient intake on H. pylori eradication therapy.Design: In this study, 4014 subjects underwent endoscopy, were tested for serum antibodies to H. pylori (2046 positive; 51.0%), and had their food intake assessed with the use of a food-frequency questionnaire (FFQ). Of the positive subjects, endoscopies showed that 389 (19.0%) had gastritis and/or duodenal ulcers and were also positive for a 13C-urea breath test (UBT). These 389 subjects received 1-wk H. pylori eradication therapy with lansoprazole, amoxicillin, and clarithromycin and a second UBT 8 wk after treatment. Complete demographic characteristics, serum lipid, insulin, glycated hemoglobin, C-reactive protein (CRP), and creatinine concentrations as well as complete FFQs were available for 352 subjects. Multivariate logistic regression analyses were performed to determine factors that were associated with successful H. pylori eradication therapy.Results: The success rate of eradication therapy was 60.4% (235 of 389). Factors associated with the failure of eradication therapy included increased age (P = 0.02), higher CRP concentrations (P < 0.01), higher dietary cholesterol (P < 0.01) or egg intake (P < 0.01), higher ω-3 (n-3) fatty acid (P = 0.02) or fish intake (P = 0.01), and higher vitamin D intake (P = 0.02). Moreover, the higher vitamin D intake was strongly linked to higher fish intake. A limitation of the study is that we did not assess the antibiotic resistance of H. pyloriConclusions: Our results indicate that higher egg and fish intake may be negatively correlated with successful H. pylori eradication therapy in H. pylori-positive subjects with gastritis and/or duodenal ulcers..
||Hiroaki Ikezaki, Norihiro Furusyo, Ryoko Nakashima, Makiko Umemoto, Ken Yamamoto, Yuji Matsumoto, Azusa Ohta, Sho Yamasaki, Satoshi Hiramine, Koji Takayama, Eiichi Ogawa, Kazuhiro Toyoda, Masayuki Murata, Nobuyuki Shimono, Jun Hayashi, Kyushu and Okinawa Population Study (KOPS): a large prospective cohort study in Japan., BMJ open, 10.1136/bmjopen-2021-053763, 11, 12, e053763, 2021.12, PURPOSE: The Kyushu and Okinawa Population Study (KOPS) was established to investigate gene-environmental interactions in non-communicable diseases in Japan. Besides collecting blood samples and anthropometric measurements, we also obtained medical histories, psychological status and lifestyle habits, including physical activities and dietary patterns. PARTICIPANTS: KOPS is a community-based prospective cohort study and consists of participants from four southwestern areas in Japan. Baseline surveys were conducted between 2004 and 2007 (wave 1), and 2009 and 2012 (wave 2) at the sites of municipality-based health check-ups. A total of 17 077 participants were included, comprising 10 697 participants of wave 1 and 6380 participants of wave 2; the median age in both groups was 61 years. Among them, 3006 individuals participated in both wave 1 and wave 2 surveys. FINDINGS TO DATE: We have focused on either risk or confounding factors for non-communicable diseases. We have assessed the clinical utility of the newly developed biomarkers for impaired glucose tolerance, such as urinary myo-inositol and glycated albumin, and atherosclerosis, such as small dense low-density lipoprotein cholesterol. We have conducted an international collaborative study with Framingham Offspring Study to investigate ethnic differences in impaired glucose tolerance and cardiovascular diseases. We have found that insulin resistance and deficiency might account for the ethnic differences in impaired glucose tolerance and cardiovascular disease risks. As gene-environmental interaction analyses, we found a synergic effect of interleukin 28B single nucleotide polymorphisms (SNPs) and gender on the spontaneous elimination of hepatitis C, and a beneficial interaction of SNPs of high-density lipoprotein cholesterol and gender on the impact of physical activity. In addition, we reported eight novel loci contributing to the development and severity of coronary artery disease from a large genome-wide association study. FUTURE PLANS: We plan to investigate further the clinical utility of the newly developed biomarkers and the gene-environmental interactions using prospective data..