NOTCH2NLC GGC repeat expansion causes retinal pathology with intranuclear inclusions throughout the retina and causes visual impairment.

The retinal pathology of genetically confirmed neuronal intranuclear inclusion disease (NIID) is yet unknown. We report the ocular findings in four NIID patients with NOTCH2NLC GGC repeat expansion to investigate the pathology of retinopathy. All four NIID patients were diagnosed by skin biopsy and NOTCH2NLC GGC repeat analysis. Ocular findings in patients with NIID were studied using fundus photographs, optical coherence tomographic images (OCT), and full-field electroretinograms (ERGs). The histopathology of the retina was studied on autopsy samples from two cases with immunohistochemistry. All patients had an expansion of the GGC repeat (87-134 repeats) in the NOTCH2NLC. Two patients were legally blind and had been diagnosed with retinitis pigmentosa prior to the diagnosis of NIID and assessed with whole exome sequencing to rule out comorbidity with other retinal diseases. Fundus photographs around the posterior pole showed chorioretinal atrophy in the peripapillary regions. OCT showed thinning of the retina. ERGs showed various abnormalities in cases. The histopathology of autopsy samples showed diffusely scattered intranuclear inclusions throughout the retina from the retinal pigment epithelium to the ganglion cell layer, and optic nerve glial cells. And severe gliosis was observed in retina and optic nerve. The NOTCH2NLC GGC repeat expansion causes numerous intranuclear inclusions in the retina and optic nerve cells and gliosis. Visual dysfunction could be the first sign of NIID. We should consider NIID as one of the causes of retinal dystrophy and investigate the GGC repeat expansion in NOTCH2NLC.

Low birth weight is associated with decline in renal function in Japanese male and female adolescents.

BACKGROUND: Low birth weight (LBW) is a risk factor for chronic kidney disease (CKD) in later life and is becoming increasingly common in developed countries, including Japan. Furthermore, a serial decrease in birth weight has been associated with an increasing prevalence of CKD stage 2 in male Japanese adolescents. Sex-specific differences affect CKD susceptibility, and the association between birth weight and CKD in women, has not been elucidated. In this study, we investigated the sex-specific effect of LBW on renal function. METHODS: Annual cross-sectional data of 2417 Japanese adolescents (males 1736; females 681), aged 15-16 years, were evaluated over 8 years (2007-2014). RESULTS: Over the study period, mean birth weights decreased significantly in males (p < 0.01) and females (p < 0.05). Furthermore, both sexes showed significant decrease in estimated glomerular filtration rates corresponding to the birth weight reduction. The prevalence of CKD stage 2 also increased in males (from 26.0 to 32.4%, p < 0.01) and females (from 6.3 to 18.5%, p < 0.05). The incidence of CKD stage 2 was significantly related to history of LBW (males: odds ratio 1.73; 95% confidence interval 1.06-2.80; p < 0.05; females: odds ratio 3.29; 95% confidence interval 1.25-8.02; p < 0.05). CONCLUSIONS: Our data revealed that renal function and birth weight have decreased over time, in healthy Japanese adolescents. In view of the recent declining trend demonstrated by birth weight in Japan, we speculate that the prevalence of CKD might increase in the future.

Features of and preventive measures against hypertension in the young.

The Japanese hypertension guidelines report that essential hypertension is detected in 1-3% of upper elementary and high school students during blood pressure (BP) screenings. Hypertension in these age groups is an emerging public health concern mainly attributed to the rising rate of pediatric obesity. Considering the existence of BP tracking phenomenon, early preventive education and instruction are necessary, especially for male students with moderately elevated BP showing a tendency toward obesity, despite the low prevalence of hypertension in high school students. Students with a positive family history of hypertension and those born with low birth weight need the same measures. Lifestyle habits, such as increased alcohol intake, dramatically change once students begin university; thus, early education and instruction regarding the factors influencing BP are necessary. In particular, for male students with higher BP during high school, caution regarding increased body weight is required irrespective of their level of obesity. Young adults aged <40 years should be educated about the association between body weight and hypertension. Particular caution surrounding lifestyle habits, including drinking and smoking, is warranted in male hypertensive subjects because hypertension at a young age is strongly associated with obesity. BP monitoring and the management of obesity should be considered efficient approaches to the detection and treatment of hypertension. For the lifetime prevention of hypertension, it is essential to be aware of one's health status and learn about healthy lifestyles beginning in childhood. BP measurement may be an appropriate means to achieve this goal.

Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21.

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10-8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10-10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10-13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10-11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.

Temporal trends in renal function and birthweight in Japanese adolescent males (1998-2015).

Background: Low birthweight (LBW) is a worldwide public health problem, demonstrating an increasing incidence in developed countries, including Japan. LBW is also a risk factor for later development of chronic kidney disease (CKD). To date, studies have not evaluated the population impacts of increasing LBW rates on renal function. Methods: Estimated glomerular filtration rate (eGFR) was evaluated in 3737 Japanese adolescent males (15-16 years old) using annual cross-sectional data over an 18-year period (1998-2015). Results: Between the initial (1998-2003) and final (2010-15) periods of the study, the mean birthweight decreased from 3213.4 ± 383.8 to 3116.2 ± 382.3 g and the LBW rate increased from 2.5 to 5.5% (both P ≤ 0.01). Additionally, the mean eGFR decreased from 105.1 ± 15.9 to 97.4 ± 13.8 mL/min/1.73 m2 and the prevalence of mildly reduced renal function (eGFR ≤ 60- <90 mL/min/1.73 m2) increased from 16.4 to 30.0% (both P ≤ 0.01), most evident in the LBW group (from 10.3 to 41.7%, P ≤0.01). The prevalence of proteinuria also increased significantly. Mildly reduced renal function was significantly associated with LBW [odds ratio (LBW 3000-3999 g) 1.51; 95% confidence interval 1.00-2.55; P = 0.047]. Conclusions: In this population of Japanese adolescents, the frequency of mildly reduced renal function increased as the LBW frequency increased. Our findings may have implications for the broader Japanese population as well as for other populations in which the prevalence of LBW is increasing.

Relationships between Composition of Major Fatty Acids and Fat Distribution and Insulin Resistance in Japanese.

Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r = -0.411, p < 0.0001), fasting glucose (r = -0.330, p < 0.0001), HbA1c (r = -0.231, p = 0.0146), and systolic blood pressure (r = -0.224, p = 0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r = -0.416, p < 0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.

Investigation of Metabolic Factors Associated with eGFR Decline Over 1 Year in a Japanese Population without CKD.

AIM: Early intervention before the progression of chronic kidney disease (CKD) is essential to prevent end-stage renal disease (ESRD) and cardiovascular complications. This study evaluated the correlation between metabolic and lifestyle-related factors and the decline of estimated glomerular filtration rate (eGFR) over 1 year in a Japanese population without CKD. METHODS: Subjects who received two consecutive annual health checkups from 2013 to 2015 were involved. Factors associated with eGFR decline were identified using multiple regression models. RESULTS: A total of 2531 subjects aged 58.9±11.7 years old were included in this study. Baseline levels of HDL-C and ApoA1 correlated with the eGFR decline over 1 year defined as eGFR reduction rate of 15% or more and/or eGFR at the next year ＜60 ml/min/m2 (odds ratio (OR) 0.87 (per 10 mg/dl); 95% CI, 0.80-0.94; p=0.0012, 0.90 (per 10 mg/dl); 0.86-0.96; p=0.0004, respectively). A U-shaped relationship between the eGFR decline and HDL-C or ApoA1 levels was not observed in non-CKD population of this study. Metabolic syndrome was significantly associated with eGFR decline (OR 1.32; 1.04-1.67; p=0.0205), although obesity-related factors did not show a significant correlation with eGFR decline over 1 year. CONCLUSION: Low HDL-C and ApoA1 levels significantly correlated with eGFR decline in a short period of 1 year. Metabolic syndrome also showed a significant association with eGFR decline. This study suggests the importance of hypertension and low HDL-C in the metabolic syndrome effect on eGFR decline rather than obesity in non-CKD population.

Intravitreal tPA Injection and Pneumatic Displacement for Submacular Hemorrhage in a 10-Year-Old Child.

Background. Submacular hemorrhage can occur after blunt trauma to the eye. Intravitreal tissue plasminogen activator (tPA) and gas injection are often used for treatment and are effective for submacular hemorrhage caused by age-related macular degeneration. This report describes the clinical outcome in a child with submacular hemorrhage caused by traumatic choroidal rupture who underwent successful intravitreal tPA injection and pneumatic displacement. Case Presentation. A 10-year-old boy developed sudden decrease of vision and a central scotoma in his right eye after trauma. Submacular hemorrhage was found in the eye. Visual acuity was 20/70 OD. Tissue plasminogen activator (12.5 µg in 0.05 mL) and 0.3 mL of pure sulfur hexafluoride were injected into the vitreous cavity under general anesthesia. After surgery, the patient was instructed to maintain a prone position. Displacement of the submacular hemorrhage from the fovea revealed a choroidal rupture, presumed to be the cause of the hemorrhage. After 4 months of follow-up, visual acuity was restored and final visual acuity is 20/16. Conclusion. Intravitreal tPA and gas injection can be an effective treatment for children with submacular hemorrhage.

Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies.

AIM: We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. METHODS: We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. RESULTS: Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019-1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026-1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. CONCLUSIONS: Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population.

Vitamin D Deficiency with High Intact PTH Levels is More Common in Younger than in Older Women: A Study of Women Aged 39-64 Years.

Low serum 25-hydroxyvitamin D (25(OH)D) levels are implicated as a risk factor for hip and spine fractures. Studies of the relation between 25(OH)D levels and fractures have primarily involved elderly osteoporosis patients or patients with fractures; however, the serum 25(OH)D and parathyroid hormone (PTH) status in younger adult populations remains largely unknown. We evaluated serum 25(OH)D and intact PTH levels in 411 women aged 39-64 years who were not receiving medication for osteoporosis or other bone diseases. Serum 25(OH)D levels were positively correlated with age (P = 0.019), whereas intact PTH levels were inversely correlated with 25(OH)D levels (P < 0.001). Thus, low vitamin D levels with high intact PTH levels were more common in younger than in older women. Our data show that serum 25(OH)D insufficiency could be a more serious concern in the younger population than had been previously anticipated. Because serum 25(OH)D insufficiency is reportedly a risk factor for hip and spine fracture, the number of fracture patients could increase in the future, suggesting that we may need to correct the serum vitamin D/intact PTH status to prevent future osteoporosis.

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes.

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10(-8)), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.

Palmitic acid-rich diet suppresses glucose-stimulated insulin secretion (GSIS) and induces endoplasmic reticulum (ER) stress in pancreatic islets in mice.

The objective was to clarify whether dietary palmitic acid supplementation affects glucose-stimulated insulin secretion (GSIS) and the endoplasmic reticulum (ER) stress pathway in pancreatic islets in mice. Eight-week-old male C57BL/6J mice were randomly divided into three treatment diet groups: control diet, palmitic acid-supplemented diet (PAL) and oleic acid-supplemented diet (OLE). After 2 weeks of treatment, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were performed. GSIS was assessed by pancreatic perfusion in situ with basal (100 mg/dL) glucose followed by a high (300 mg/dL) glucose concentration. We measured mRNA levels of ER stress markers such as C/EBP homologous protein (CHOP), immunoglobulin heavy-chain binding protein (BIP) and X-box binding protein (XBP)-1 using real-time polymerase chain reaction (PCR) analyses in isolated islets. Immunohistochemical staining was also performed. Mice fed PAL showed significantly decreased glucose tolerance (p < 0.05). In the perfusion study, GSIS was significantly suppressed in the PAL group (p < 0.05). Semi-quantitative RT-PCR revealed that islet CHOP, BIP, and XBP-1 mRNA expression were significantly increased in the PAL group (p < 0.05). TUNEL-positive ß-cells were not detected in all groups. Dietary palmitic acid-supplementation for 2 weeks might suppress GSIS and induce ER stress in pancreatic islets in mice, in the early stage of lipotoxicity.

Effects of Aging on Visceral and Subcutaneous Fat Areas and on Homeostasis Model Assessment of Insulin Resistance and Insulin Secretion Capacity in a Comprehensive Health Checkup.

AIM: The association between aging and insulin resistance has been unclear. We evaluated the effects of aging on visceral fat area (VFA) and subcutaneous fat area (SFA) measured by computed tomography, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of ß-cell function (HOMA-ß) among participants in a comprehensive health checkup. METHODS: This study included 1,050 male and 700 female Japanese participants aged 35-84 years in our comprehensive health checkup program during a 2-year period. Participants who were on medication for diabetes mellitus or those who met the pre-determined exclusion criteria were excluded. The participants were divided into five groups according to age. RESULTS: As age increased from Group 1 to Group 5, both VFA and VFA/SFA ratio significantly increased in both male and female participants, whereas log[HOMA-IR] linearly and significantly decreased (p＜0.0001 for each). Body mass index (BMI), waist circumference (WC), and SFA increased with age in female participants but decreased in male participants. Although age was not or only weakly correlated with log[glucose] and log[HbA1c] in both male and female participants, age showed significant negative correlations with log[insulin], log[HOMA-IR], and log[HOMA-ß] even after adjusting for BMI and WC (p＜0.0001 for each). Serum high-molecular-weight adiponectin (HMW-ADPN) levels were measured in 114 male and 87 female participants, and log[HMW-ADPN] was negatively correlated with log[HOMA-IR] and positively correlated with age in both male and female participants. CONCLUSIONS: In the present study, both male and female participants showed increases in VFA and VFA/SFA ratio and decreases in insulin, HOMA-IR, and HOMA-ß with age.

Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes.

AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.

Effects of oral propranolol on a juxtapapillary capillary hemangioma: a single-subject pilot study.

Oral propranolol hydrochloride has been proven effective in treating infantile hemangiomas, and its potential efficacy in choroidal hemangiomas has been suggested. A 57-year-old woman with a juxtapapillary capillary hemangioma was treated with oral propranolol at Nagoya Medical Center in Japan in 2012. Although the condition of this patient partially improved, oral propranolol did not appear to have a critical therapeutic effect. To the authors' knowledge, this is the first pilot study to describe a case in which oral propranolol was used as a therapeutic approach for a retinal hemangioma.

Genome-wide association study identifies three novel loci for type 2 diabetes.

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

Disturbed tumor necrosis factor system is linked with lower eGFR and chronic inflammation in hypertension.

BACKGROUND: The relationship between tumor necrosis factor (TNF)-related parameters and cardiorenal metabolic factors is still controversial in clinical hypertension. METHODS: Normotensive men (NT, n=60) and treated stage 2 and 3 essential hypertensive men (HT, n=89) were enrolled in this study. The relationship between TNF-related parameters and cardiorenal metabolic factors was examined in NT and HT, separately. RESULTS: HT showed higher rates of insulin resistance and enhanced chronic inflammation compared with NT. The levels of soluble TNF receptor 1 and 2 were significantly higher in HT than in NT, although TNF-α levels were unexpectedly lower in HT than in NT. Regression analysis indicated that the TNF-related parameters were closely linked with mild renal dysfunction both in NT and HT, and moderately related to chronic inflammation only in HT. HT taking inhibitors of the renin-angiotensin system showed improved insulin resistance, but no difference in the TNF-related parameters. CONCLUSION: These results suggest that the disturbed TNF system is closely linked with chronic inflammation rather than with insulin resistance in HT.

Replication study for the association of 9 East Asian GWAS-derived loci with susceptibility to type 2 diabetes in a Japanese population.

AIMS: East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. METHODS: We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2-R3HDML-HNF4A, rs6467136 near GCCI-PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis. RESULTS: With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10(-4), OR = 1.05, 95% confidence interval: 1.02-1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of ß-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits. CONCLUSIONS: These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.

Effects of oral propranolol on circumscribed choroidal hemangioma: a pilot study.

IMPORTANCE: Oral propranolol hydrochloride treatment has been proven effective for infantile hemangiomas. To our knowledge, this study is the first to report multiple cases in which oral propranolol therapy was used for patients with circumscribed choroidal hemangioma. OBSERVATIONS: Five patients with circumscribed choroidal hemangioma were treated at Nagoya Medical Center, Nagoya, Japan, from 2011 to 2012. Oral propranolol hydrochloride was initiated at 10 mg 3 times a day and was increased monthly by 30 mg/d until the desired effects were observed. The mean (SD) height of the tumor (based on the B-mode at the end of the study) was 84.5% (13.6%) relative to the initial height. Similarly, the mean (SD) tumor area (based on indocyanine green angiography) was 94.2% (6.0%), the mean (SD) visual acuity was 0.04 (0.21) logMAR, and the mean (SD) Humphrey visual field mean deviation was -0.98 (1.1) dB. In 3 patients with macular edema, the mean (SD) foveal thickness (measured with optical coherence tomography) was 114.0% (13.9%). CONCLUSIONS AND RELEVANCE: Although oral propranolol therapy may partially improve the condition of patients with circumscribed choroidal hemangioma, it does not seem to have a critical therapeutic effect, at least at blood concentrations lower than 50 to 100 ng/mL. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000006623.

Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY).

AIM: This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. METHODS: This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 40 mg once a day (n = 12) [DOSAGE ERROR CORRECTED] or losartan at a dose of 50 mg once a day (n = 7) for 12 months. RESULTS: The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 ± 0.26 to 0.59 ± 0.22 mEq/L (mean ± SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group. CONCLUSION: Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.