👤 Atsushi Iwata

Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice. This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting. A real-world observational study with a follow-up period of up to 18 months. A single center in Japan. We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion. Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation. The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8). In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy. Show less

Lecanemab is a monoclonal antibody targeting amyloid-beta protofibrils, indicated for patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease. This study reports interim findings of an ongoing, multicenter, prospective, observational post-marketing study for all patients treated with lecanemab in routine clinical practice in Japan, focusing on amyloid-related imaging abnormalities (ARIAs) and infusion-related reactions primarily observed during up to 28 weeks after treatment initiation. Patients treated with lecanemab at any medical institutions across Japan are included in the study. Data are collected using an electronic data capture system via standardized case report forms (CRFs). Study items included the incidence of ARIA, ARIA-edema or effusion (-E), ARIA-hemorrhage (-H: cerebral microhemorrhages, superficial siderosis, and macrohemorrhage), and infusion-related reactions, reported as adverse drug reactions. As of July 5, 2025, CRFs from 2675 patients were collected, of whom 2672 had data available for the interim analysis. The median age was 76.0 years, and 62.6 % (1672/2672) of patients were diagnosed with MCI. At Week 28, 7.3 % (195/2672) of patients discontinued treatment, with a mean treatment duration of 189.6 ± 34.4 days. Among 2634 patients confirmed to have undergone MRI scans after treatment initiation, ARIA was observed in 7.1 % (188/2634) of patients, ARIA-E in 3.0 % (78/2634), and ARIA-H in 5.2 % (137/2634). Serious ARIA-H (macrohemorrhage) occurred in two patients (0.1 %). Infusion-related reactions were observed in 17.0 % (455/2672), including 0.7 % (18/2672) serious cases. The proportion of patients who experienced ARIA was highest in patients with apolipoprotein E (APOE) ε4 homozygotes. This interim analysis represents one of the largest real-world lecanemab cohorts reported globally to date. Although absolute rates are not directly comparable with those from clinical trials, the trends in ARIA distributions across APOE genotypes and infusion-related reactions were comparable to those observed in clinical trials. Show less

To quantify the Number Needed to Test (NNT) to prevent one ARIA event as a function of A Bayesian simulation study using a Beta-Binomial model to analyze genotype-stratified contingency tables. Data were derived from two published, phase 3 clinical trials: Clarity-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab). Aggregate data from source trials. Simulation of varying treatment discontinuation probability NNT to prevent one ARIA event (any ARIA-E, any ARIA-H, and symptomatic ARIA-E) and the fractional reduction in total ARIA events as a function of NNTs increased (worsened) significantly as The direct safety impact of Show less

Dual-specificity phosphatase 6 (DUSP6) is a phosphatase specific for extracellular signal-regulated kinase (ERK). Dusp6-knockout mice are resistant to diet-induced hepatic steatosis, which appears to be linked to the downregulation of cytochrome P450 4 A (CYP4A); however, its mechanism remains unclear. This study aimed to elucidate how DUSP6 regulates CYP4A11 in human hepatocyte-lineage cells by focusing on forkhead box O1 (FOXO1). HepG2 and HuH-7 cells were challenged with palmitic acid and oleic acid to induce lipid accumulation while manipulating the expression of DUSP6, FOXO1, CYP4A11, ERK, and/or AKT. Lipid accumulation was reduced by DUSP6 knockdown, resulting in decreased CYP4A11 expression despite elevated phosphorylated ERK, AKT, and FOXO1. Inhibition of ERK increased lipid accumulation, while simultaneous inhibition of ERK and AKT decreased it. Knockdown of FOXO1 or induced expression of DUSP6 increased CYP4A11 expression and lipid accumulation, whereas induced expression of FOXO1 decreased them. Chromatin-immunoprecipitation showed that FOXO1 bound to CYP4A11 promoter. Immunoprecipitations revealed that DUSP6 bound to and anchored FOXO1 in the cytoplasm. These results indicate that DUSP6 interferes with FOXO1's repressive activity towards CYP4A11 by sequestering it in the cytoplasm and preventing its nuclear translocation, which ultimately unleashes CYP4A11 and promotes lipid accumulation. Show less

Approximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer (ABC) have PIK3CA alterations, which contributes to endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol 3-kinase inhibitor and degrader, given in combination with fulvestrant, is approved for the treatment of PIK3CA-mutated, HR+, HER2- ABC, based on the SOLAR-1 trial. Aside from PIK3CA, other gene alterations are associated with poor prognosis and limited response to treatment in this patient population. In this retrospective analysis, we performed tissue-based next-generation sequencing of 398 patients (237 PIK3CA-altered, 161 PIK3CA-wild type) from SOLAR-1. Progression-free survival (PFS) correlative analysis was performed in the PIK3CA-altered cohort. PIK3CA-altered and PIK3CA-wild type tumors had distinct genomic profiles. In the PIK3CA-altered cohort, patients who received alpelisib plus fulvestrant had a median PFS (mPFS) of 11.01 months versus 5.55 months for those receiving placebo plus fulvestrant (P=0.0004). Patients in the lowest tumor mutational burden quartile as well as those with FGFR1 or FGFR2 alterations derived greater PFS benefit from alpelisib plus fulvestrant versus placebo plus fulvestrant (18.5 versus 3.22 months; HR 0.38; 95% CI 0.21-0.68. FGFR1 12.71 versus 3.75 months; HR 0.38; 95% CI 0.17-0.81; P=0.32. FGFR2: 9.63 versus 2.78 months; HR 0.31; 95% CI 0.1-0.94; P=0.29); patients with MYC or RAD21 alterations derived limited PFS benefit. Cox and multi-task machine learning models identified lower Eastern Cooperative Oncology Group performance status, prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and PTEN or TP53 alterations among the most deleterious factors for PFS in the PIK3CA-altered cohort. Alpelisib plus fulvestrant provides clinical benefit for patients with PIK3CA-altered, HR+, HER2- ABC across a range of concomitant alterations, including those previously implicated in endocrine therapy or CDK4/6i resistance. Machine learning models identified factors including gene mutations that influenced PFS. Show less

We demonstrated that low-intensity pulsed ultrasound (LIPUS) therapy tended to ameliorate cognitive declines in patients with early Alzheimer's disease (AD) in the pilot trial. Thus, we have started the pivotal trial in a randomized, double-blind, placebo-controlled manner (LIPUS-AD). We here report the clinical characteristics of AD patients enrolled in the trial. The major inclusion criteria included age 50-90 years of both sex, Clinical Dementia Rating (CDR) global score of 0.5∼1.0 and Japanese version of the Mini-Mental State Examination (MMSE-J) score greater than 20 at screening, positive brain Aβ-PET, and no symptomatic brain hemorrhage, infarction, or edema on brain MRI. A total of 231 subjects were finally enrolled. As compared with the pilot trial, they were characterized by older age and higher prevalence of dyslipidemia. They had lower scores of ADAS-J-cog and Modified Hachinski Ischemic Scale (MHIS), while other cognitive scores were comparable with the pilot trial. Use of cholinesterase inhibitors was less as compared with the pilot trial. Clinical characteristics of subjects in the LIPUS-AD trial largely mimic those in the pilot trial, addressing efficacy and safety of the LIPUS therapy in early AD.Clinical Trial Gov. No.: NCT05983575, jRCT No.: jRCT2032230125. Show less

Argyrophilic grain (AG) is a common neurodegenerative accumulation of 4 repeat tau in dendritic spine. Dementia with grain (DG) is defined as AGs with a sole pathological basis for cognitive decline. As with other multifactorial diseases, DG could result from interactions of environmental and genetic factors. However, the genetic basis of DG is largely unknown. To clarify the genetic architecture of DG pathogenesis, we conducted a genome-wide association study (GWAS) with 214 DG cases versus 12,405 controls. We have identified a candidate locus associated with the risk of DG, the SVIL locus on chromosome 10, with genome-wide significance (rs11595141, P = 4.86 Show less

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) confer cardio-renal protection, and recent work implicates enhanced branched-chain amino acid (BCAA) catabolism as a potential mechanism in the heart. Whether SGLT2i also promotes renal BCAA catabolism is largely unknown. We hypothesized that SGLT2i enhances renal BCAA catabolism independently of glycemic effects. We conducted a prospective, single-center, open-label, nonrandomized, controlled clinical study in patients with type 2 diabetes stably treated with insulin, who were assigned to dapagliflozin (5 mg/day with dose-reduced insulin; n=8/9 completed) or insulin dose-up (n=5/8 completed). At 12 weeks, changes in urinary and plasma metabolites and short-chain acylcarnitines related to BCAA catabolism were quantified. To explore mechanisms, 10-week-old db/db mice received luseogliflozin (10 mg/kg/day, p.o.) or insulin glargine (10 U/day, s.c.) for 4 weeks; renal histology, mRNA and protein expression of key enzymes involved in BCAA catabolism, including branched-chain aminotransferase 2 (BCAT2), branched-chain ketoacid dehydrogenase (BCKDH), and BCKD kinase (BCKDK), were assessed. Dapagliflozin treatment induced greater increases in urinary excretion of three BCAA-derived metabolites-3-hydroxypropionic acid, C5-OH carnitine, and 3-hydroxybutyric acid-compared with insulin at comparable glycemic levels. In contrast, C4 carnitine (an earlier metabolite in valine catabolism) rose more with insulin. No corresponding between-group differences were detected in plasma metabolites. In db/db mice, luseogliflozin attenuated glomerular mesangial expansion and tubular epithelial atrophy, and reduced Col1a1 mRNA and TGF-β1 protein, compared with glargine at comparable glycemic levels. Luseogliflozin decreased the phosphorylated (inactive) form of the BCKDH E1α subunit (p-BCKDHA/BCKDHA) and lowered BCKDK protein. mRNA expression of amino acid transporters and BCAT2 expression was unchanged. Across complementary human and mouse studies, SGLT2 inhibition was suggested to enhance renal BCAA catabolism compared with insulin at comparable glycemic levels. In humans, increases in urinary BCAA-derived downstream metabolites without corresponding changes in plasma support a kidney-localized metabolic effect. In mice, SGLT2 inhibitor improved renal histopathology, and reduced phosphorylation-mediated inactivation of BCKDH. These findings provide mechanistic, translational evidence that SGLT2i modulate BCAA flux independently of glucose lowering, suggesting BCAA catabolism as a therapeutic axis in diabetic kidney disease. https://rctportal.mhlw.go.jp/en/detail?trial_id=UMIN000052955, identifier UMIN000052955. Show less

Limited evidence exists on the role of lipoprotein(a) [Lp(a)] in the progression of atherosclerotic coronary plaques as assessed by intravascular imaging modality, particularly under low-density lipoprotein cholesterol (LDL-C) lowering therapy. In this study, we aimed to evaluate the clinical significance of Lp(a) as a residual risk factor for coronary plaque progression, using serial intravascular ultrasound (IVUS) in statin-treated patients with coronary artery disease (CAD). This observational cohort study included statin-treated patients from two clinical prospective trials (the ENTERPRISE trial and Extended-ESTABLISH trial) in which coronary plaques were assessed using serial grayscale IVUS at baseline and at 6-12 months follow-up. The primary endpoints were defined as absolute changes in normalized total atheroma volume (TAV Show less

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). This study used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant down-regulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with that in WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared with WT and Dusp6-haploinsufficiency mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, down-regulation of CYP4A, and up-regulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK. Show less

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD. Show less

In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported. We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed. A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group. Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.). Show less

We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD. Show less

Mesenchymal stem cells (MSC) can differentiate into chondrocytes. Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed during chondrogenic differentiation and can be produced by MSC. EBI3 is also a subunit of interleukin (IL)-27 and IL-35, and it accumulates in the endoplasmic reticulum (ER) when its partners, such as IL-27 p28 and IL-35 p35, are insufficient. ER stress induced by protein accumulation is responsible for chondrogenic differentiation. However, the role of EBI3 and its relevance to the ER stress in chondrogenic differentiation of MSC have never been addressed. Here, we demonstrate that EBI3 protein is expressed in the early stage of chondrogenic differentiation of MSC. Additionally, knockdown, overexpression, or induction of EBI3 through IL-1β inhibits chondrogenesis. We show that EBI3 localizes and accumulates in the ER of MSC after overexpression or induction by IL-1β and TNF-α, whereas ER stress inhibitor 4-phenylbutyric acid decreases its accumulation in MSC. Moreover, EBI3 modulates ER stress sensor inositol-requiring enzyme 1 α (IRE1α) after induced by IL-1β, and MSC-like cells coexpress EBI3 and IRE1α in rheumatoid arthritis (RA) synovial tissue. Altogether, these data demonstrate that intracellular EBI3 commits to chondrogenic differentiation by regulating ER stress sensor IRE1α. Show less

Craniofacial structures change dynamically in morphology during development through the coordinated regulation of various cellular molecules. However, it remains unclear how these complex mechanisms are regulated in a spatiotemporal manner. Here we applied natural cubic splines to model gene and microRNA (miRNA) expression from embryonic day (E) 10.5 to E14.5 in the proximal and distal regions of the maxillary processes to identify spatiotemporal patterns of gene and miRNA expression, followed by constructing corresponding regulatory networks. Three major groups of differentially expressed genes (DEGs) were identified, including 3,927 temporal, 314 spatial, and 494 spatiotemporal DEGs. Unsupervised clustering further resolved these spatiotemporal DEGs into 8 clusters with distinct expression patterns. Interestingly, we found 2 clusters of differentially expressed miRNAs: 1 had 80 miRNAs monotonically decreasing and the other had 97 increasing across developmental stages. To evaluate the phenotypic relevance of these DEGs during craniofacial development, we integrated data from the CleftGeneDB database and constructed the regulatory networks of genes related to orofacial clefts. Our analysis revealed 2 hub miRNAs, mmu-miR-325-3p and mmu-miR-384-5p, that repressed cleft-related genes Show less

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene are responsible for several severe forms of craniosynostotic disorders, such as Apert and Crouzon syndromes. Patients with craniosynostotic disorders caused by a mutation in Fgfr2 present with several clinical symptoms, including hypersalivation. Here we used a transgenic mouse model of Apert syndrome (Fgfr2 Fgfr2 The number of ducts and acini in Fgfr2 These results suggested that increased FGFR1 signaling and apoptosis in the submandibular glands of Fgfr2 Show less

Biallelic CLN3 gene variants have been found in either juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or isolated retinal dystrophy. It has been reported that most JNCL patients carry a common 1.02-kb deletion variant homozygously. Clinical characteristics of patients with biallelic CLN3 missense variants are not well elucidated. We described a 26-year-old Japanese male patient with isolated retinal dystrophy. Whole-exome sequencing (WES) and transmission electron microscopy (TEM) were performed. Whole-exome sequencing identified a novel homozygous CLN3 missense variant [c.482C>T; p.(Ser161Leu)]. Ophthalmoscopy revealed retinal degeneration and macular atrophy, and later attenuated retinal vessels. Severely reduced responses were observed in both rod and cone electroretinograms. In TEM of the patient's lymphocytes, fingerprint profiles, which are specific findings in CLN3-associated JNCL, were observed in 16/624 (2.56%) lymphocytes of the patient, who has never exhibited neurological signs during the 13-year follow-up period. Our results indicated that this novel CLN3 missense variant is associated with teenage-onset isolated retinal dystrophy. This is the first report of any patient with CLN3-associated disorder in the Japanese population. Although fingerprint profiles have never been reported in CLN3-associated isolated retinal dystrophy, these profiles were observed, albeit infrequently, suggesting that frequency of the fingerprint profiles might depend on variant types. Show less

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα Show less

Obesity, a risk factor for all-cause and cardiovascular mortality, is a major health concerns among middle-aged men. The aim of this study was to investigate a possible association of dietary habits and obesity related single nucleotide polymorphisms (SNPs) with obesity and metabolic abnormalities. We conducted a retrospective cohort study using annual health examination data of 5112 male workers, obtained between 2007 and 2011. Average dietary energy was estimated using electronically collected meal purchase data from cafeteria. We examined 8 SNPs related to obesity: GHRL rs696217, PPARG rs1175544, ADIPOQ rs2241766, ADIPOQ rs1501299, PPARD rs2016520, APOA5 rs662799, BRAP rs3782886, and ITGB2 rs235326. We also examined whether SNPs that were shown to associate with obesity affect other metabolic abnormalities such as blood pressure (BP), glucose, and lipid profile. Average dietary energy significantly associated with increased abdominal circumference (AC) and body mass index (BMI). The odds ratios (ORs) of overweight and obesity also increased. The major allele of rs696217 significantly increased BMI and an increased OR with obesity, while the minor allele of rs3782886 was associated with significantly decreased AC and the decreased ORs with overweight and obesity. The minor allele of rs3782886 was also associated with significantly decreased systolic BP (SBP), triglyceride (TG), high-density lipoprotein (HDL), and fasting blood sugar (FBS), while rs696217 was not associated with other metabolic abnormalities. Average dietary energy in lunch, rs3782886, and rs696217 were associated with obesity, and rs3782886 was associated with other metabolic abnormalities. Show less

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10 Show less

Several single nucleotide polymorphisms (SNPs) have been implicated in the predisposition to chronic kidney disease (CKD). Atherosclerotic disease is deeply involved in the incidence of CKD; however, whether SNPs related to arteriosclerosis are involved in CKD remains unclear. This study aimed to identify SNPs associated with CKD and to examine whether risk allele accumulation is associated with CKD. We conducted a cross-sectional study using data of 4814 male workers to examine the association between estimated glomerular filtration rate (eGFR) and 59 candidate polymorphisms (17 CKD, 42 atherosclerotic diseases). We defined the genetic risk score (GRS) as the total number of risk alleles that showed a significant association in this analysis and examined the relationship with CKD (eGFR < 60 ml/min/1.73m2). Multivariate logistic regression, discrimination by area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), and category-free net reclassification improvement (cNRI) were evaluated. In total, 432 participants were categorized as having CKD. We found eight candidate SNPs with P value < 0.05 (CX3CR1 rs3732379, SHROOM3 rs17319721, MTP rs1800591, PIP5K1B rs4744712, APOA5 rs662799, BRAP rs3782886, SPATA5L1 rs2467853, and MCP1 rs1024611) in the multivariate linear regression adjusted for age, body mass index, systolic blood pressure, and fasting blood glucose. Among these eight SNPs, BRAP rs3782886 and SPATA5L1 rs2467853 were significantly associated with eGFR (false discovery rate < 0.05). GRS was significantly associated with CKD (odds ratio, 1.17; 95% confidence interval, 1.09-1.26). C-statisics improved from 0.775 to 0.780 but showed no statistical significance. However, adding GRS significantly improved IDI and cNRI (0.0057, P = 0.0028, and 0.212, P < 0.001, respectively). After adjustment for clinical factors, kidney function was associated with BRAP rs3782886 and SPATA5L1 rs2467853 and the GRS for CKD that we developed was associated CKD. Show less

We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes. We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis. All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10(-4), binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037-1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10(-4), adjusted for sex, age and BMI). ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population. Show less

Although many single nucleotide polymorphisms (SNPs) have been identified to be associated with metabolic syndrome (MetS), there was only a slight improvement in the ability to predict future MetS by the simply addition of SNPs to clinical risk markers. To improve the ability to predict future MetS, combinational effects, such as SNP-SNP interaction, SNP-environment interaction, and SNP-clinical parameter (SNP × CP) interaction should be also considered. We performed a case-control study to explore novel SNP × CP interactions as risk markers for MetS based on health check-up data of Japanese male employees. We selected 99 SNPs that were previously reported to be associated with MetS and components of MetS; subsequently, we genotyped these SNPs from 360 cases and 1983 control subjects. First, we performed logistic regression analyses to assess the association of each SNP with MetS. Of these SNPs, five SNPs were significantly associated with MetS (P < 0.05): LRP2 rs2544390, rs1800592 between UCP1 and TBC1D9, APOA5 rs662799, VWF rs7965413, and rs1411766 between MYO16 and IRS2. Furthermore, we performed multiple logistic regression analyses, including an SNP term, a CP term, and an SNP × CP interaction term for each CP and SNP that was significantly associated with MetS. We identified a novel SNP × CP interaction between rs7965413 and platelet count that was significantly associated with MetS [SNP term: odds ratio (OR) = 0.78, P = 0.004; SNP × CP interaction term: OR = 1.33, P = 0.001]. This association of the SNP × CP interaction with MetS remained nominally significant in multiple logistic regression analysis after adjustment for either the number of MetS components or MetS components excluding obesity. Our results reveal new insight into platelet count as a risk marker for MetS. Show less

In a mice study, insulin suppressed apolipoprotein A-V (apoA-V) gene expression in a dose dependent manner. Thus, we investigated the association between apoA-V levels and dyslipidemias in obese children with hyperinsulinemia. The subjects were 17 obese children (15 male, 2 female) aged 11.8 ± 2.4 years. Total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), triglyceride (TG), apoA-V and insulin levels were determined. Obese children with hyperinsulinemia had greater percent overweight, higher TG level, lower HDLC level and lower apoA-V level than those without hyperinsulinemia. In simple regression analysis, apoA-V level correlated negatively with TG (r = -0.613, p = 0.0152) and insulin levels (r = -0.566, p = 0.0279), and positively correlated with HDLC (r = 0.811, p = 0.0002). In stepwise regression analysis, insulin level emerged as the independent determinant of TG level after apoA-V level was taken into account, whereas apoA-V emerged as the independent determinant of HDLC level after adjusting for insulin level. Insulin may be a potent regulator of serum apoA-V level in obesity, and apoA-V level may partly contribute to the development of obesity-associated dyslipidemia. Show less

The aim of the present study was to explore the role of variations with modest effects (previously identified by a large-scale meta-analysis in European populations) in the genetic background of type 2 diabetes (T2D) and diabetes-related traits in a Japanese population. We enrolled 2632 Japanese subjects with T2D and 2050 non-diabetic subjects. We analyzed nine single-nucleotide polymorphisms (SNPs), including rs340874 (PROX1), rs4607517 (GCK), rs2191349 (DGKB-TMEM195), rs7034200 (GLIS3), rs10885122 (ADRA2A), rs174550 (FADS1), rs11605924 (CRY2), rs10830963 (MTNR1B) and rs35767 (IGF1). rs340874 (PROX1) and rs174550 (FADS1) were significantly associated with T2D (P=0.0078, OR: 1.12; and P=0.0071, OR: 1.12, respectively). Subjects with more risk alleles related to nine SNPs had an increased risk of T2D (P=0.0017), as well as a higher fasting plasma glucose level (P=0.018), higher HbA(1c) level (P=0.013) and lower HOMA-β (P=0.033) compared with subjects who had fewer risk alleles. We identified a significant association of a SNP of FADS1 and a SNP near PROX1 with T2D in a Japanese population. The present findings suggest that inclusion of SNPs with a tendency to increase the disease risk captured more of the genetic background of T2D than that revealed by only assessing significant SNPs. Show less

Many gene variants are involved in the susceptibility to schizophrenia and some of them are expected to be associated with other human characters. Recently reported meta-analysis of genetic associations revealed nucleotide variants in synaptic vesicular transport/Golgi apparatus genes with schizophrenia. In this study, we selected the dymeclin gene (DYM) as a candidate gene for schizophrenia. The DYM gene encodes dymeclin that has been identified to be associated with the Golgi apparatus and with transitional vesicles of the reticulum-Golgi interface. A three-step case-control study of total of 2105 Japanese cases of schizophrenia and 2087 Japanese control subjects was carried out for tag single-nucleotide polymorphisms (SNPs) in the DYM gene and an association between an SNP, rs833497, and schizophrenia was identified (allelic P=2 × 10(-5), in the total sample). DYM is the causal gene for Dyggve-Melchior-Clausen syndrome and this study shows the second neuropsychiatric disorder in which the DYM gene is involved. The present data support the involvement of Golgi function and vesicular transport in the presynapse in schizophrenia. Show less

Mice lacking apolipoprotein A-V (apoA-V) displayed an increase in serum triglyceride (TG) levels; however, the correlation of apoA-V levels with TG levels in humans is controversial, and the exact mechanism by which apoA-V affects TG levels is unclear. The aim of the present study was to clarify the impact of apoA-V on the lipoprotein subclass profile in preadolescent children, which has not been studied. The study subjects were 178 (89 male, 89 female) 4th grade elementary school children (mean+/-SD: 9.5+/-0.5 years old). ApoA-V levels were determined by an enzyme-linked immunosorbent assay, and the lipid component of each lipoprotein fraction and their particle sizes were measured by HPLC. Levels of apoA-V showed no gender difference in preadolescent children, and were not affected by anthropometric variables. ApoA-V had a negative association with serum TG levels and TG levels in each lipoprotein fraction, and a positive association with HDL-C. In particular, apoA-V appears to contribute to the increase in cholesterol levels in the larger HDL fraction. It was suggested that apoA-V is a potent modulator of HDL and VLDL components in preadolescent children. Show less