Search

Purpose: The association between metabolic syndrome (MetS) and the risk of death from cancer is still a controversial issue. The purpose of this study was to examine the associations of MetS and metabolically unhealthy obesity (MUHO) with cancer mortality in a Japanese population., Methods: We used data from the Japan Multi-Institutional Collaborative Cohort Study. The study population consisted of 28,554 eligible subjects (14,103 men and 14,451 women) aged 35-69 years. MetS was diagnosed based on the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the Japan Society for the Study of Obesity (JASSO), using the body mass index instead of waist circumference. The Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for total cancer mortality in relation to MetS and its components. Additionally, the associations of obesity and the metabolic health status with cancer mortality were examined., Results: During an average 6.9-year follow-up, there were 192 deaths from cancer. The presence of MetS was significantly correlated with increased total cancer mortality when the JASSO criteria were used (HR = 1.51, 95% CI 1.04-2.21), but not when the NCEP-ATP III criteria were used (HR = 1.09, 95% CI 0.78-1.53). Metabolic risk factors, elevated fasting blood glucose, and MUHO were positively associated with cancer mortality (P <0.05)., Conclusion: MetS diagnosed using the JASSO criteria and MUHO were associated with an increased risk of total cancer mortality in the Japanese population., Competing Interests: The authors have declared that no competing interests existed.

Previous studies have reported that the number of pregnancies and childbirths affected the risk of cardiovascular diseases (CVDs). However, the influence of reproductive history on hypertension and obesity, which are important risk factors for CVDs, is still unclear. Moreover, this association may vary depending on menopausal status. We evaluated the association of reproductive history with hypertension and obesity using a large cross-sectional dataset from the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). At the baseline survey, physical data, blood samples, and self-reported health questionnaires were collected. Participants with insufficient data were excluded, and 24,558 women from eight study regions were included in this study. Logistic regression analysis was conducted to evaluate the association of reproductive history with hypertension and obesity using multivariable-adjusted odds ratios. In premenopausal women, childbirth showed a generally protective effect on hypertension but not on obesity. In postmenopausal women, childbirth was positively associated with obesity and hypertension but not with hypertension after adjusting for BMI. In conclusion, reproductive history was associated with hypertension and obesity in a large Japanese population, and this association differed between premenopausal and postmenopausal women., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Selenoprotein P (SELENOP) is a major selenium (Se)-containing protein (selenoprotein) in human plasma that is mainly synthesized in the liver. SELENOP transports Se to the cells, while SELENOP synthesized in peripheral tissues is incorporated in a paracrine/autocrine manner to maintain the levels of cellular selenoproteins, called the SELENOP cycle. Pancreatic β cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP. Here, using MIN6 cells as a mouse model for pancreatic β cells and Selenop small interfering (si)RNA, we found that Selenop gene knockdown (KD) resulted in decreased cell viability, cellular pro/insulin levels, insulin secretion, and levels of several cellular selenoproteins, including glutathione peroxidase 4 (Gpx4) and selenoprotein K (Selenok). These dysfunctions induced by Selenop siRNA were recovered by the addition of Se. Ferroptosis-like cell death, regulated by Gpx4, was involved in the decrease of cell viability by Selenop KD, while stress-induced nascent granule degradation (SINGD), regulated by Selenok, was responsible for the decrease in proinsulin. SINGD was also observed in the pancreatic β cells of Selenop knockout mice. These findings indicate a significant role of SELENOP expression for the function of pancreatic β cells by maintaining the levels of cellular selenoproteins such as GPX4 and SELENOK., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The aim of the present study was to investigate the associations between breastfeeding and the prevalence of metabolic syndrome in community-dwelling parous women and to clarify whether the associations depend on age., Methods: The present cross-sectional study included 11,118 women, aged 35-69 years. Participants' longest breastfeeding duration for one child and their number of breastfed children were assessed using a self-administered questionnaire, and their total breastfeeding duration was approximated as a product of the number of breastfed children and the longest breastfeeding duration. The longest and the total breastfeeding durations were categorized into none and tertiles above 0 months. Metabolic syndrome and cardiovascular risk factors (obesity, hypertension, dyslipidemia, and hyperglycemia) were defined as primary and secondary outcomes, respectively. Associations between breastfeeding history and metabolic syndrome or each cardiovascular risk factor were assessed using multivariable unconditional logistic regression analysis., Results: Among a total of 11,118 women, 10,432 (93.8%) had ever breastfed, and 1,236 (11.1%) had metabolic syndrome. In participants aged <55 years, an inverse dose-response relationship was found between the number of breastfed children and the prevalence of metabolic syndrome; multivariable-adjusted odds ratios for 1, 2, 3, and ≥4 breastfed children were 0.60 (95% confidence interval [CI]: 0.31 to 1.17), 0.50 (95% CI: 0.29 to 0.87), 0.44 (95% CI: 0.24 to 0.84), and 0.35 (95% CI: 0.14 to 0.89), respectively. The longest and total breastfeeding durations of longer than 0 months were also associated with lower odds of metabolic syndrome relative to no breastfeeding history in participants aged <55 years. In contrast, all measures of breastfeeding history were not significantly associated with metabolic syndrome and cardiovascular risk factors in participants aged ≥55 years old., Conclusions: Breastfeeding history may be related to lower prevalence of metabolic syndrome in middle-aged parous women., Competing Interests: The authors have declared no conflict of interest in the present study.

Elucidating the risk factors for chronic kidney disease is important for preventing end-stage renal disease and reducing mortality. However, little is known about the roles of psychosocial stress and stress coping behaviors in deterioration of the renal function, as measured by the estimated glomerular filtration rate (eGFR). This cross-sectional study of middle-aged and older Japanese men (n = 31,703) and women (n = 38,939) investigated whether perceived stress and coping strategies (emotional expression, emotional support seeking, positive reappraisal, problem solving, and disengagement) were related to the eGFR, with mutual interactions. In multiple linear regression analyses adjusted for age, area, lifestyle factors, and psychosocial variables, we found a significant inverse association between perceived stress and the eGFR in men (P trend  = 0.02), but not women. This male-specific inverse association was slightly attenuated after adjustment for the history of hypertension and diabetes and was more evident in lower levels of emotional expression (P interaction  = 0.003). Unexpectedly, problem solving in men (P trend  < 0.001) and positive reappraisal in women (P trend  = 0.002) also showed an inverse association with the eGFR. Perceived stress may affect the eGFR, partly through the development of hypertension and diabetes. The unexpected findings regarding coping strategies require the clarification of the underlying mechanisms, including the hormonal and immunological aspects., (© 2022. The Author(s).)

Introduction: Healthy diet and physical activity (PA) are essential for preventing type 2 diabetes, particularly, a combination of diet and PA. However, reports on interaction between PA and diet, especially from large epidemiological studies, are limited. We investigated the effect of interaction between PA and macronutrient intake on hemoglobin A1c (HbA1c) levels in the general population., Research Design and Methods: We conducted a cross-sectional study of 55 469 men and women without diabetes who participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. A self-administered questionnaire ascertained PA and macronutrient intake (carbohydrate, fat, and protein). Multiple linear regression analyses were performed to adjust for confounding variables and examine the interactions. In addition, we conducted a longitudinal study during a 5-year period within a subcohort (n=6881) with accelerometer-assessed PA data., Results: Overall, PA had a weak inverse association (β=-0.00033, p=0.049) and carbohydrate intake had a strong positive association (β=0.00393, p<0.001) with HbA1c. We observed a tendency of interactions between PA and carbohydrate or fat intake, but not protein intake, on HbA1c levels after adjusting for age, sex, study area, total energy intake, alcohol consumption, smoking, and medication for hypertension or hypercholesterolemia (P interaction =0.054, 0.006, and 0.156, respectively). The inverse associations between PA and HbA1c level were more evident in participants with high-carbohydrate (or low-fat) intake than in participants with low-carbohydrate (or high-fat) intake. Although further adjustment for body mass index slightly attenuated the above interactions (P interaction =0.098 for carbohydrate and 0.068 for fat), the associations between PA and HbA1c level in stratified analyses remained unchanged. Similar associations and interactions were reproduced in the longitudinal study., Conclusions: The present results suggest that the effect of PA on HbA1c levels is modified by intake of macronutrient composition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Differences in individual eating habits may be influenced by genetic factors, in addition to cultural, social or environmental factors. Previous studies suggested that genetic variants within sweet taste receptor genes family were associated with sweet taste perception and the intake of sweet foods. The aim of this study was to conduct a genome-wide association study (GWAS) to find genetic variations that affect confection consumption in a Japanese population. We analysed GWAS data on confection consumption using 14 073 participants from the Japan Multi-Institutional Collaborative Cohort study. We used a semi-quantitative FFQ to estimate food intake that was validated previously. Association of the imputed variants with confection consumption was performed by linear regression analysis with adjustments for age, sex, total energy intake and principal component analysis components 1-3. Furthermore, the analysis was repeated adjusting for alcohol intake (g/d) in addition to the above-described variables. We found 418 SNP located in 12q24 that were associated with confection consumption. SNP with the ten lowest P-values were located on nine genes including at the BRAP, ACAD10 and aldehyde dehydrogenase 2 regions on 12q24.12-13. After adjustment for alcohol intake, no variant was associated with confections intake with genome-wide significance. In conclusion, we found a significant number of SNP located on 12q24 genes that were associated with confections intake before adjustment for alcohol intake. However, all of them lost statistical significance after adjustment for alcohol intake.

Background: The Japan Multi-institutional Collaborative Cohort (J-MICC) study was launched in 2005 to examine gene-environment interactions in lifestyle-related diseases, including cancers, among the Japanese. This report describes the study design and baseline profile of the study participants., Methods: The participants of the J-MICC Study were individuals aged 35 to 69 years enrolled from respondents to study announcements in specified regions, inhabitants attending health checkup examinations provided by local governments, visitors at health checkup centers, and first-visit patients at a cancer hospital in Japan. At the time of the baseline survey, from 2005 to 2014, we obtained comprehensive information regarding demographics, education, alcohol consumption, smoking, sleeping, exercise, food intake frequency, medication and supplement use, personal and family disease history, psychological stress, and female reproductive history and collected peripheral blood samples., Results: The baseline survey included 92,610 adults (mean age: 55.2 [standard deviation, 9.4] years, 44.1% men) from 14 study regions in 12 prefectures. The participation rate was 33.5%, with participation ranging from 19.7% to 69.8% in different study regions. The largest number of participants was in the age groups of 65-69 years for men and 60-64 years for women. There were differences in body mass index, educational attainment, alcohol consumption, smoking, and sleep duration between men and women., Conclusions: The J-MICC Study collected lifestyle and clinical data and biospecimens from over 90,000 participants. This cohort is expected to be a valuable resource for the national and international scientific community in providing evidence to support longer healthy lives.

The purpose of the study was to investigate sex-specific associations of skipping breakfast and short sleep duration with metabolic syndrome (MetS) and their interaction. We analyzed baseline data of 14,907 men and 14,873 women aged 35-69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study from 2005. MetS was diagnosed using a modification of the National Cholesterol Education Program Adult Treatment Panel III revised definition (NCEP-R 2005), using body mass index instead of waist circumference. Breakfast consumption was classified into two categories: ≥6 days/week (consumers) or <6 days/week (skippers). Sleep duration was classified into three categories: <6h, 6 to <8 h, and ≥8 h/day. Multivariate logistic regression analysis was performed to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) and examine the presence of interaction. In men, skipping breakfast and short sleep duration were independently associated with an increased prevalence of MetS (OR 1.26, 95%CI 1.12-1.42 and OR 1.28, 95%CI 1.12-1.45, respectively), obesity, and components of MetS. However, no significant interaction was observed between skipping breakfast and short sleep duration. In women, skipping breakfast and short sleep duration were associated with an increased prevalence of obesity, but not with MetS. These findings indicate that breakfast consumption and moderate sleep duration may be associated with a lower risk of MetS, particularly in men., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1-10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population., (© The Author(s) 2021.)

Background: Renal hypouricemia (RHUC) is characterized by a low serum uric acid (SUA) level and high fractional excretion of uric acid (FE UA ). Further studies on FE UA in hypouricemic individuals are needed for a more accurate diagnosis of RHUC., Methods: In 30,685 Japanese health-examination participants, we genotyped the two most common nonfunctional variants of URAT1 (NFV- URAT1 ), W258X (rs121907892) and R90H (rs121907896), in 1040 hypouricemic individuals (SUA ≤ 3.0 mg/dL) and 2240 individuals with FE UA data. The effects of NFV- URAT1 on FE UA and SUA were also investigated using linear and multiple regression analyses., Results: Frequency of hypouricemic individuals (SUA ≤ 3.0 mg/dL) was 0.97% (male) and 6.94% (female) among 30,685 participants. High frequencies of those having at least one allele of NFV- URAT1 were observed in 1040 hypouricemic individuals. Furthermore, NFV- URAT1 significantly increased FE UA and decreased SUA, enabling FE UA and SUA levels to be estimated. Conversely, FE UA and SUA data of hypouricemic individuals are revealed to be useful to predict the number of NFV- URAT1 ., Conclusions: Our findings reveal that specific patterns of FE UA and SUA data assist with predicting the number of nonfunctional variants of causative genes for RHUC, and can also be useful for practical diagnosis of RHUC even before genetic tests.

Background This study aimed to determine the association between sedentary time and mortality with regard to leisure-time physical activity with or without cardiometabolic diseases such as hypertension, dyslipidemia, and diabetes mellitus. Methods and Results Using data from the J-MICC (Japan Multi-Institutional Collaborative Cohort) Study, 64 456 participants (29 022 men, 35 434 women) were analyzed. Hazard ratios (HRs) and 95% CIs were used to characterize the relative risk of all-cause mortality to evaluate its association with sedentary time (categorical variables: <5, 5 to <7, 7 to <9, ≥9 h/d and 2-hour increments in exposure) according to the self-reported hypertension, dyslipidemia, and diabetes mellitus using a Cox proportional hazards model. A total of 2257 participants died during 7.7 years of follow-up. The corresponding HRs for each 2-hour increment in sedentary time among participants with all factors, no factors, hypertension, dyslipidemia, and diabetes mellitus were 1.153 (95% CI, 1.114-1.194), 1.125 (95% CI, 1.074-1.179), 1.202 (95% CI, 1.129-1.279), 1.176 (95% CI, 1.087-1.273), and 1.272 (95% CI, 1.159-1.396), respectively. Furthermore, when analyzed according to the combined different factors (hypertension, dyslipidemia, and diabetes mellitus), HRs increased with each additional factor, and participants reporting all 3 conditions had the highest HR of 1.417 (95% CI, 1.162-1.728) independently of leisure-time metabolic equivalents. Conclusions The association between sedentary time and increased mortality is stronger among patients with hypertension, dyslipidemia, and diabetes mellitus regardless of leisure-time physical activity in a large Japanese population.

Background/objectives: Individual eating habits may be influenced by genetic factors, in addition to environmental factors. Previous studies suggested that adherence to Japanese food patterns was associated with a decreased risk of all-cause and cardiovascular disease mortality. We conducted a genome-wide association study (GWAS) in a Japanese population to find genetic variations that affect adherence to a Japanese food pattern., Subjects/methods: We analyzed GWAS data using 14,079 participants from the Japan Multi-Institutional Collaborative Cohort study. We made a Japanese food score based on six food groups. Association of the imputed variants with the Japanese food score was performed by linear regression analysis with adjustments for age, sex, total energy intake, alcohol intake (g/day), and principal components 1-10 omitting variants in the major histocompatibility region., Results: We found one SNP in the 14q11.2 locus that was significantly associated with the Japanese food score with P values <5 × 10 -8 . Functional annotation revealed that the expression levels of two genes (BCL2L2, SLC22A17) were significantly inversely associated with this SNP. These genes are known to be related to olfaction and obesity., Conclusion: We found a new SNP that was associated with the Japanese food score in a Japanese population. This SNP is inversely associated with genes link to olfaction and obesity.

Endothelial fenestrae are the transcellular pores existing on the capillary walls which are organized in clusters referred to as sieve plates. They are also divided by a diaphragm consisting of plasmalemma vesicle-associated protein (PLVAP). In this study, we examined the involvement of fibronectin signaling in the formation of fenestra and diaphragm in endothelial cells. Results showed that Itga5 and Itgb1 were expressed in PECAM1-positive endothelial cells isolated from the anterior lobe (AL) of the rat pituitary, and integrin α5 was localized at the fenestrated capillaries of the rat pituitary and cultured PECAM1-positive endothelial cells isolated from AL (CECAL). Inhibition of both integrin α5β1 and FAK, a key molecule for integrin-microtubule signaling, respectively, by ATN-161 and FAK inhibitor 14, caused the delocalization of PLVAP at the sieve plates and depolymerization of microtubules in CECAL. Paclitaxel prevented the delocalization of PLVAP by the inhibition of integrin α5β1. Microtubule depolymerization induced by colcemid also caused the delocalization of PLVAP. Treatment of CECAL with ATN-161 and colcemid caused PLVAP localization at the Golgi apparatus. The localization of PLVAP at the sieve plates was inhibited by BFA treatment in a time-dependent manner and spread diffusely to the cytoplasm. These results indicate that a constant supply of PLVAP proteins by the endomembrane system via the Golgi apparatus is essential for the localization of PLVAP at sieve plates. In conclusion, the endomembrane transport pathway from the Golgi apparatus to sieve plates requires microtubule cytoskeletons, which are regulated by fibronectin-integrin α5β1 signaling.

Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m 2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Reducing the number of pitches thrown is regarded as the most effective way to prevent throwing injuries in youth baseball pitchers. However, few studies have compared the effectiveness of limiting the pitch count versus the limiting the number of innings pitched in terms of elbow injuries., Hypothesis: We hypothesized that, compared with inning limits, pitch count limits would lead to greater decreases in elbow pain, range of motion deficits, positive moving valgus stress test results, and the risk of capitellar osteochondritis dissecans (OCD)., Study Design: Cohort study; Level of evidence, 3., Methods: This study retrospectively reviewed baseball pitchers aged 8 to 12 years in 2017 and 2018. Inning and pitch count limits in games were set to a daily maximum of 7 innings in 2017 and 70 pitches in 2018. Elbow pain, range of motion, and moving valgus stress test results were evaluated. The presence of capitellar OCD was assessed on ultrasonographic and radiographic images., Results: A total of 352 pitchers in 2017 and 367 pitchers in 2018 participated. The mean pitch count per game was lower in the pitch count limit (CL) group (52.5 ± 16.0) than in the inning limit (IL) group (98.2 ± 19.5) ( P < .001). Compared with the IL group, the CL group had significantly lower rates of elbow pain (40.9% vs 31.9%, respectively; P = .01) and reduced flexion (19.0% vs 10.6%, respectively; P = .001). Multivariate analysis revealed a significant association between elbow pain and age in both the IL and the CL groups ( P < .0001 and P = .02, respectively) and between OCD and elbow pain in the CL group ( P = .04)., Conclusion: A pitch count limit of ≤70 pitches per day for baseball pitchers ≤12 years could be more protective against elbow pain and reduced flexion than a limit of ≤7 innings per day, but it may not be effective for reducing the risk of capitellar OCD., Competing Interests: The authors declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Background/objective: Although benefits of fish consumption for health are well known, a significant percentage of individuals dislike eating fish. Fish consumption may be influenced by genetic factors in addition to environmental factors. We conducted a genome-wide association study (GWAS) to find genetic variations that affect fish consumption in a Japanese population., Methods: We performed a two-stage GWAS on fish consumption using 13,739 discovery samples from the Japan Multi-Institutional Collaborative Cohort study, and 2845 replication samples from the other population. We used a semi-quantitative food frequency questionnaire to estimate food intake. Association of the imputed variants with fish consumption was analyzed by separate linear regression models per variant, with adjustments for age, sex, energy intake, principal component analysis components 1-10, and alcohol intake (g/day). We also performed conditional analysis., Results: We found 27 single nucleotide polymorphisms (SNPs) located in 12q24 and 14q32.12 that were associated with fish consumption. The 19 SNPs were located at 11 genes including six lead SNPs at the BRAP, ACAD10, ALDH2, NAA25, and HECTD4 regions on 12q24.12-13, and CCDC197 region on 14q32.12. In replication samples, all five SNPs located on chromosome 12 were replicated successfully, but the one on chromosome 14 was not. Conditional analyses revealed that the five lead variants in chromosome 12 were in fact the same signal., Conclusion: We found that new SNPs in the 12q24 locus were related to fish intake in two Japanese populations. The associations between SNPs on chromosome 12 and fish intake were strongly confounded by drinking status.

Prostate cancer is emerging as a significant global public health burden. The incidence and prevalence of prostate cancer has increased in Japan, as westernized lifestyles become more popular. Recent advances in genetic epidemiology, including genome-wide association studies (GWASs), have identified considerable numbers of human genetic factors associated with diseases. Several GWASs have reported significant loci associated with serum prostate-specific antigen (PSA) levels. One GWAS, which was based on classic GWAS microarray measurements, has been reported for Japanese so far. In the present study, we conducted a GWAS of serum PSA using 1000Genomes imputed GWAS data (n =1,216) from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study, to detect candidate novel genetic loci that influence serum PSA levels in Japanese. The association of SNPs/genetic variants with serum PSA as a continuous variable was tested using the linear Wald test. SNP rs10000006 in SGMS2 (sphingomyelin synthase 2) on chromosome 4 had genome-wide significance ( P <5×10 -8 ), and eight variants on three chromosomes (chromosomes 12, 14, 15) had genome-wide suggestive levels of significance ( P <1×10 -6 ). With an independent data set from the J-MICC Shizuoka Study (n = 2,447), the association of the SGMS2 SNP with blood PSA levels was not replicated. Although our GWAS failed to detect novel loci associated with serum PSA levels in the Japanese cohort, it confirmed the significant effects of previously reported genetic loci on PSA levels in Japanese. Importantly, our results confirmed the significance of KLK3 SNPs also in Japanese, implying that consideration of individual genetic information in prostate cancer diagnosis may be possible in the future., Competing Interests: We have no financial relationship to disclose.

Endothelial fenestrae are transcellular pores that pierce the capillary walls in endocrine glands such as the pituitary. The fenestrae are covered with a thin fibrous diaphragm consisting of the plasmalemma vesicle-associated protein (PLVAP) that clusters to form sieve plates. The basal surface of the vascular wall is lined by basement membrane (BM) composed of various extracellular matrices (ECMs). However, the relationship between the ECMs and the endothelial fenestrae is still unknown. In this study, we isolated fenestrated endothelial cells from the anterior lobe of the rat pituitary, using a dynabeads-labeled antibody against platelet endothelial cell adhesion molecule 1 (PECAM1). We then analyzed the gene expression levels of several endothelial marker genes and genes for integrin α subunits, which function as the receptors for ECMs, by real-time polymerase chain reaction (PCR). The results showed that the genes for the integrin α subunit, which binds to collagen IV, fibronectin, laminin-411, or laminin-511, were highly expressed. When the PECAM1-positive cells were cultured for 7 days on collagen IV-, fibronectin-, laminins-411-, or laminins-511-coated coverslips, the sieve plate structures equipped with probably functional fenestrae were maintained only when the cells were cultured on fibronectin. Additionally, real-time PCR analysis showed that the fibronectin coating was effective in maintaining the expression pattern of several endothelial marker genes that were preferentially expressed in the endothelial cells of the fenestrated capillaries. These results indicate that fibronectin functions as the principal factor in the maintenance of the sieve plate structures in the endothelial cells of the fenestrated capillary.

Background: While duodenal ulcer (DU) and gastric cancer (GC) are both H. pylori infection-related diseases, individuals with DU are known to have lower risk for GC. Many epidemiological studies have identified the PSCA rs2294008 T-allele as a risk factor of GC, while others have found an association between the rs2294008 C-allele and risk of DU and gastric ulcer (GU). Following these initial reports, however, few studies have since validated these associations. Here, we aimed to validate the association between variations in PSCA and the risk of DU/GU and evaluate its interaction with environmental factors in a Japanese population., Methods: Six PSCA SNPs were genotyped in 584 DU cases, 925 GU cases, and 8,105 controls from the Japan Multi-Institutional Collaborative Cohort (J-MICC). Unconditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the SNPs and risk of DU/GU., Results: PSCA rs2294008 C-allele was associated with per allele OR of 1.34 (95% CI, 1.18-1.51; P = 2.28 × 10 -6 ) for the risk of DU. This association was independent of age, sex, study site, smoking habit, drinking habit, and H. pylori status. On the other hand, we did not observe an association between the risk of GU and PSCA SNPs., Conclusions: Our study confirms an association between the PSCA rs2294008 C-allele and the risk of DU in a Japanese population.

To investigate the association between alcohol intake pattern in amount and frequency and metabolic syndrome (Mets) components, we simulated the change in the prevalence of Mets components by intake reduction. In order to manage Mets, alcohol intake reduction with moderation of intake pattern is required. However, evidence investigating the comparative impact of alcohol intake reduction in amount and frequency for Mets components is limited. We conducted a large-scale cross-sectional study in the general Japanese population. The study subjects included 37,371 non-drinkers and current drinkers recruited in the Japan Multi-Institutional Collaborative Cohort Study. Odds ratios (ORs) for Mets components according to alcohol intake amount and frequency were estimated using a multiple logistic regression model. The prevalence of Mets components was estimated after assumed alcohol intake reduction of a) none, b) 10 g/day (men) or 5 g/day (women), c) 20 g/day (men) or 10 g/day (women), d) less than 20 g/day (men) or 10 g/day (women) for moderate-to-heavy drinkers, e) 1-2 times/week, and f) 3-4 times/week. The ORs with alcohol intake amount and frequency increased with high blood pressure while decreasing with dyslipidemia. A J-shaped association was observed between intake amount and Mets. The estimated prevalence (%) of high blood pressure and dyslipidemia in men were a) 45.2, b) 43.0, c) 41.4, d) 40.4, e) 42.9, and f) 42.0; and a) 50.3, b) 51.8, c) 52.9, d) 50.2, e) 52.7, and f) 53.4 in women. The estimated prevalence of high blood pressure in women did not evidently decrease. Simulated alcohol intake reduction showed decreased prevalence for high blood pressure and increased prevalence for dyslipidemia in men after reduced intake amount and frequency. The largest decreased prevalence for high blood pressure was observed in men when all moderate-to-heavy drinkers reduced their alcohol intake amount to less than 20 g/day., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

There are few studies examining the association between homocysteine (Hcy) level and the risk of hypertension with consideration for folate and vitamin B 12 as related to Hcy level. We simultaneously examined the associations of plasma levels of Hcy, folate, and vitamin B 12 , and dietary folate intake with the prevalence of hypertension. Participants included 1046 men and 1033 women (mean age ± standard deviation: 56.0 ± 8.9 years) in the Japan Multi-Institutional Collaborative Cohort Study. Dietary folate intake was estimated using a validated food frequency questionnaire. Hypertension was defined based on measured blood pressure and use of antihypertensive medication. A total of 734 participants (35.3%) had hypertension. Multivariate-adjusted odds ratios of hypertension for the highest quartile group of Hcy were 2.36 (95% CI 1.41-3.96) in men and 1.86 (95% CI 1.11-3.11) in women, as compared with the lowest group (P for trend = 0.014 and 0.005, respectively). Dietary folate intake was not correlated with hypertension in both men and women (P for trend = 0.099 and 0.703, respectively). Plasma vitamin B 12 was positively associated with hypertension only in women (P for trend = 0.027). Plasma Hcy level was positively linked with hypertension after controlling for covariates, including folate and vitamin B 12 .

Background: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD., Methods: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans., Results: We identified 3 new loci on chromosome 1q21 ( CTSS ), 10q26 ( WDR11-FGFR2 ), and 11q22 ( RDX - FDX1 ). Quantitative trait locus analyses suggested the association of CTSS and RDX - FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans., Conclusions: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

The association between dietary acid load and metabolic syndrome (MetS) has not been fully investigated. A cross-sectional study was performed on 14,042 men and 14,105 women (aged 35-69 years) who participated in a baseline survey of the Japan Multi-Institutional Collaborative Cohort study. Dietary acid load was assessed using the net-endogenous-acid-production (NEAP) score that is closely correlated with the rate of renal net acid excretion. MetS was diagnosed according to the Joint Interim Statement Criteria of 2009 using body-mass index instead of waist circumference. After adjusting for potential confounders, higher NEAP scores were associated with a significantly increased odds ratio (OR) of MetS, obesity, high blood pressure, and high fasting blood glucose. These associations remained significant after further adjustment for carbohydrate intake or two nutrient-pattern scores significantly associated with MetS. After adjustment for fiber, iron, potassium, and vitamin pattern scores, the OR of MetS for the highest quartile of NEAP scores, relative to the lowest quartile, was 1.25 (95% confidence interval 1.12-1.39). There was no significant interaction between sex, age, or body-mass index and NEAP. Higher dietary acid load was associated with a higher prevalence of MetS and several of its components, independently of carbohydrate intake or nutrient patterns., Competing Interests: The authors declare that there is no conflict of interest.

Although complications of silicone implants and development of new materials have led to a decline in the use of silicone implants for orbital wall fractures, their advantages are still reported. The overall incidence, risk factor and treatment of silicone implant complications, especially those caused by cystic lesions, remain unclear. We aimed to report our experiences of patients with orbital wall fractures that were reconstructed with silicone implants and followed up for a long period. We retrospectively analysed 56 patients who underwent surgical repair of the orbital wall fractures with a silicone implant from January 2006 to December 2017 and were followed up for more than 6 months. A chart review and the assessment of demographic and surgical factors, among others, were performed. There were 47 eligible patients in this study, and the mean post-operative follow-up period was 83.1 months. When comparing the results obtained 6 months post-operatively with those obtained at the final follow-up, the overall complication rate increased from 5/47 to 13/47, and the silicone implant removal rate increased from 0/47 to 10/47. The symptoms caused by the cystic lesions were managed through silicone implant removal. The immediate post-operative bleeding was significantly associated with silicone implant survival (p = 0.008). Silicone implants used for orbital wall fractures were never stabilised during the long-term study. Much attention should be paid during the follow-up of high-risk patients. Most late complications were caused by cystic lesions, and only silicone implant removal would be sufficient and considered safe as the initial intervention., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest directly relevant to the content of this article., (Copyright © 2019. Published by Elsevier Ltd.)

The aim of this study is to show the combined effect of weight gain within normal weight range in adulthood and parental HT on the prevalence of HT. The study subjects were 44,998 individuals (19,039 men and 25,959 women) with normal weight (body mass index [BMI] 18.5-24.9) aged 35-69 years who participated in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. They were categorized into six groups by weight gain from age 20 years (<10 kg, and ≥10 kg) and by the number of parents having HT (no parent, one parent, and both parents). Odds ratios for HT were estimated after adjustment for age, sex, current BMI, estimated daily sodium intake, and other confounding factors. The prevalence of HT (31.5% in total subjects) gradually increased with greater weight gain from age 20 years and with greater number of parents with HT. Subjects who gained weight ≥10 kg and having both parents with HT showed the highest risk of having HT compared with those who gained weight <10 kg without parental HT (59.8% vs. 24.9%, odds ratio 4.25, 95% CI 3.53-5.13 after adjustment). This association was similarly observed in any category of age, sex, and BMI. Subjects who gained weight within normal range of BMI and having one or both parent(s) with HT showed the higher risk of having HT independent of their attained BMI in their middle ages. Thus, subjects having parent(s) with HT should avoid gaining their weight during adulthood, even within normal range of BMI, to reduce the risk of having HT.

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10 -25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.

Background: Elbow injuries are common in young baseball players and evaluating the characteristics of young baseball players in a large-scale population is necessary. However, few studies have compared playing position, length of baseball experience, physical findings, and elbow pain in young baseball players. This retrospective multi-regional cohort study sought to document the physical findings at the elbow in Japanese elementary school baseball players and to examine the relationship between playing position, length of baseball experience, physical findings at the elbow, and elbow pain., Methods: In 2014, 720 fifth-grade baseball players from four regions in Japan were invited to participate in a questionnaire survey and undergo physical examination to obtain data on position played, length of baseball experience, presence of elbow pain, and physical findings at the elbow, including range of motion, tenderness, and valgus stress test results. Potential risk factors associated with elbow pain and correlations between physical findings and playing position, length of baseball experience, and elbow pain were investigated., Results: The 720 subjects had a mean age of 10.4 years and 29.4% reported having experienced elbow pain for ≥1 week. Risk factors for elbow pain included playing pitcher and catcher, playing pitcher and fielder, and length of baseball experience. The most frequent finding was limitation of flexion (21.1%) followed by tenderness of the medial epicondyle (18.3%) and a positive valgus stress test (14.3%). These three findings were also significantly associated with elbow pain. Elbow extension was limited in 14.9% of subjects but there was no correlation with length of baseball experience or elbow pain., Conclusions: Our data show that elementary school baseball players who experienced elbow pain are likely to have valgus stress overload. Elbow pain might be prevented by not playing pitcher and catcher., (Copyright © 2019. Published by Elsevier B.V.)

Objective: We report a rare case of symptomatic vertebral and posterior inferior cerebellar arteries (VA-PICA) aneurysm-caused ipsilateral hemifacial spasm (HFS) for which coil embolization of the aneurysm with the assistance of abnormal muscle response (AMR) monitoring was effective., Case Presentation: A 62-year-old woman presented with left HFS. Magnetic resonance imaging showed a saccular aneurysm of the left VA-PICA which compressed the seventh cranial nerve at its root exit zone (REZ). Stent-assisted coil embolization resulted in intraoperative disappearance of AMR in the intraoperative electrophysiological study and HFS was relieved temporally. One month after endovascular surgery, HFS slightly occurred again with the re-appearance of the AMR, although there was no recurrence of aneurysm. Thereafter, the frequency of her HFS markedly decreased to once per several days 1 year after the coiling., Conclusion: Although complete disappearance of symptoms was not obtained, it was suggested that coil embolization is one of the therapeutic options for HFS which is caused by aneurysmal compression of REZ and intraoperative AMR is useful for identification of responsible lesions and determination of therapeutic effects., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (©2020 The Japanese Society for Neuroendovascular Therapy.)

Context: Nowadays, people with paraplegia and quadriplegia have greater opportunities to venture into the general public. However, there is also an increased risk of associated hazards. Findings: This report describes a 42-year-old man with paraplegia, who was insensate below the T7 level and sustained burns from sitting on a gel wheelchair cushion that had been left on the driver-side seat of a hand control car on a sunny day. Physical examination revealed deep partial-thickness burns on both his buttocks. He underwent surgical debridement and received an autologous split-thickness skin graft, and healed well. Conclusion In modern times, the lives of people with paralysis are no longer restricted to the bed and wheelchair. Active people with spinal cord injuries inevitably diversify the use of wheelchair cushions in many ways; therefore, there is a greater possibility for the occurrence of associated hazards. This is a preventable issue, so both the user and manufacturers should recognize this potential hazard of gel wheelchair cushions.

Objective: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout., Methods: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia)., Results: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F ) and one suggestive locus (rs12980365 of ZNF724 ) at the genome-wide significance level (p<5.0×10 - 8 ). The present study also identified the loci of ABCG2 , ALDH2 and SLC2A9 . One of them, rs671 of ALDH2 , was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci ( CNTN5 , MIR302F and ZNF724 ) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level., Conclusions: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Allergen-specific immunoglobulin isotype formation associated with immunoglobulin class-switching during the lactation period is the immunological background for food allergy in infants. We analyzed the serial changes in the production of feeding type-related egg- and milk-specific immunoglobulin isotypes from birth to 6 months of age with or without eczema in 84 infants., Methods: Allergen-specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, IgA, and IgE levels of hen's egg and bovine milk were measured in cord blood and blood samples from infants at 2, 4, and 6 months of age by the densely carboxylated protein microarray., Results: Formula and mixed feeding were associated with a rapid increase in cow's milk allergen-specific immunoglobulins and feeding type-related significant differences in casein-specific immunoglobulin levels were detected. Breast and mixed feeding were associated with slow but significant increase in ovalbumin-specific IgG1 and IgE levels, but not other immunoglobulins. We found two different immunoglobulin isotype formation at 6 months of age with low- or high-affinity IgE against ovalbumin. One isotype formation pattern had relatively high ovalbumin-specific IgG1 levels, detectable IgG2, and low-affinity IgE, while the other had low ovalbumin-specific IgG1 levels, undetectable IgG2, and high levels of high-affinity IgE. The incidence of eczema was significantly higher in the latter pattern (84.6%), compared with the remaining infants (42.2%)., Conclusions: Feeding practice-related allergen sensitization and immunoglobulin isotype formation were identified during the lactation period. The development of eczema during the lactation period could potentially modify the immunoglobulin isotype formation with high levels of high-affinity IgE., (© 2019 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Chronic kidney disease (CKD) is a public health problem worldwide including Japan. Recent genome-wide association studies have discovered CKD susceptibility variants. We developed a genetic risk score (GRS) based on CKD-associated variants and assessed a possibility that the GRS can improve the discrimination capability for the prevalence of CKD in a Japanese population. The present study consists of 11 283 participants randomly selected from 12 Japan Multi-Institutional Collaborative Cohort Study sites. Individual GRS was constructed combining 18 single-nucleotide polymorphisms identified in a Japanese population. Participants with eGFR <60 mL/min per 1.73 m 2 was defined as case (stage 3 CKD or higher) in this study. Logistic regression analysis was used to examine the association between the GRS and CKD risk with adjustment for sex, age, hypertension and type 2 diabetes mellitus. The frequency of individuals with CKD was 8.3%, which was relatively low compared with those previously reported in a Japanese population. The odds ratio of having CKD was 1.120 (95% confidence interval: 1.042-1.203) per 10 GRS increment in the fully adjusted model (P = 0.002). The C-statistic was significantly increased in the model with the GRS, comparing with the model without the GRS (0.720 vs 0.719, P difference  = 0.008). Increment of the GRS was associated with increased risk of CKD. Additionally, the GRS significantly improved the discriminatory ability of CKD prevalence in a Japanese population; however, the improvement of discriminatory ability brought about by the GRS seemed to be small compared with that of non-genetic CKD risk factors., (© 2018 Asian Pacific Society of Nephrology.)

Purpose: This study aimed to investigate independent relationships of daily non-exercise life activity and leisure-time exercise volume and intensity with the prevalence of metabolic syndrome and its traits in Japanese adults., Methods: Data of 24,625 eligible subjects (12,709 men, 11,916 women) who participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were analyzed. Information about lifestyle characteristics was obtained from a questionnaire. Logistic regression analyses were performed to evaluate the independent associations of daily life activity as well as leisure-time exercise volume and intensity with the prevalence of metabolic syndrome and its traits by sex., Results: Male subjects with higher daily life activity as well as with higher leisure-time exercise volume had a lower prevalence of metabolic syndrome, independently with each other. Female subjects with higher daily life activity also had a lower prevalence of metabolic syndrome. Particularly, male and female subjects with the highest daily life activity quartile showed considerably low odds ratios of 0.66 (95% CI, 0.53-0.81) and 0.64 (0.52-0.79), respectively, for low HDL-cholesterol even after the adjustment for BMI compared with the first quartile. Meanwhile, male subjects with the higher leisure-time exercise showed a quite lower prevalence of elevated triglycerides. Higher moderate-intensity exercise was more intensely associated with a lower prevalence of metabolic syndrome and some of its traits in both sexes., Conclusions: Our results suggest that higher daily life activity and higher moderate-intensity exercise may be independently associated with a lower risk of metabolic syndrome in Japanese adults.

: The association between nutrient patterns and metabolic syndrome (MetS) has not been examined in a Japanese population. A cross-sectional study was performed on 30,108 participants (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Dietary intake was assessed using a 46-item food frequency questionnaire. MetS was diagnosed according to the Joint Interim Statement Criteria of 2009, using body mass index instead of waist circumference. Factor analysis was applied to energy-adjusted intake of 21 nutrients, and three nutrient patterns were extracted: Factor 1 (fiber, potassium and vitamins pattern); Factor 2 (fats and fat-soluble vitamins pattern); and Factor 3 (saturated fatty acids, calcium and vitamin B 2 pattern). In multiple logistic regression analysis adjusted for sex, age, and other potential confounders, Factor 1 scores were associated with a significantly reduced odds ratio (OR) of MetS and all five components. Factor 2 scores were associated with significantly increased prevalence of MetS, obesity, and high blood pressure. Factor 3 scores were significantly associated with lower OR of MetS, high blood pressure, high serum triglycerides and low HDL cholesterol levels. Analysis of nutrient patterns may be useful to assess the overall quality of diet and its association with MetS., Competing Interests: The authors declare no conflict of interest.

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci ( P <5 × 10 -8 ) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci- TMEM18 , TM4SF4 , MXD3-LMAN2 , PSORS1C1-PSORS1C2 , and HNF4A -are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578 , is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout., Competing Interests: The authors declare no competing interests.

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health-related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome-wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi-Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant-level association evidence into gene-level evidence using a gene-based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability-scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10 -6 ) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene-based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10 -6 ). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene-based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression., (© 2018 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Background: Over the past few decades, the Japanese Ministry of the Environment has been biomonitoring dioxins in the general Japanese population and, in response to public concerns, has taken measures to reduce dioxin exposure. The objectives of this study were to assess the current dioxin dietary intake and corresponding body burden in the Japanese and compare Japanese dioxin data from 2011 to 2016 and 2002-2010 surveys. We also examined the relationship between blood dioxins and health parameters/clinical biomarkers., Methods: From 2011 to 2016, cross-sectional dioxin surveys were conducted on 490 Japanese (242 males and 248 females, aged 49.9 ± 7.6 years) from 15 Japanese prefectures. Blood (n = 490) and food samples (n = 90) were measured for 29 dioxin congeners including polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (Co-PCBs) using gas chromatography coupled with high-resolution mass spectrometry. Using the 2006 World Health Organization toxic equivalence factors, the toxic equivalents (TEQs) were calculated. Clinical biomarkers and anthropometric parameters were also measured and information on lifestyle behaviours collected. Data imputations were applied to account for blood dioxins below the detection limit., Results: The median (95% confidence interval or CI) blood levels and dioxin dietary intake was respectively 9.4 (8.8-9.9) pg TEQ/g lipid and 0.3 (0.2-0.4) pg TEQ/kg body weight/day. The median blood dioxin level in the 2011-2016 survey was found to have decreased by 41.3% compared to the 2002-2010 surveys. Participants who were older were found to be more likely to have higher dioxin levels. Blood dioxins were also significantly associated with body mass index, triglycerides, docosahexaenoic acid, eicosapentaenoic acid, and dihomo-gamma-linoleic acid levels in blood. Furthermore, associations between blood dioxin and dietary dioxin intake were evident in the unadjusted models. However, after adjusting for confounders, blood dioxins were not found to be associated with dietary dioxin intake., Conclusions: Blood dioxin levels declined over the past decade. This study showed that the measures and actions undertaken in Japan have possibly contributed to these reductions in the body burden of dioxins in the Japanese population.

Purpose: To quantify the 1-year cumulative incidence of capitellar osteochondritis dissecans (OCD) in preadolescent baseball players and identify the risk factors associated with this condition., Methods: In total, 1,275 school-aged baseball players (aged 6-11 years) without an established diagnosis of capitellar OCD were enrolled in this longitudinal, observational study. One year later, all players underwent ultrasonographic examination of the throwing elbow on the playing field. Elbows with abnormal ultrasonographic findings at this time then underwent radiographic examination. Data for the groups with and without capitellar OCD were analyzed using multivariate logistic regression models., Results: The 1-year cumulative incidence of capitellar OCD was 1.8% (95% confidence interval, 1.1%-2.7%). On multivariate analysis, players aged 10 to 11 years were 3.96 times more likely to have capitellar OCD (95% confidence interval, 1.10-18.97) than those aged 6 to 9 years; however, starting baseball at an earlier age, number of years played, training hours per week, player position, and history of elbow pain were not significantly associated with capitellar OCD. Only 34.8% of players with capitellar OCD reported elbow pain., Conclusions: The risk of OCD of the capitellum developing within a 1-year period in preadolescent baseball players was 1.8%. Players aged 10 to 11 years had a significantly greater risk of capitellar OCD development than those aged 6 to 9 years., Level of Evidence: Level III, local nonrandom sample cohort., (Copyright © 2019 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Acetylation of α-tubulin is a well-studied posttranscriptional modification, which is mostly catalyzed by α-tubulin N-acetyltransferase (ATAT1). ATAT1 possibly affects various cellular functions related with microtubules, such as intracellular transport, cell motility, cilia formation, and neuronal signaling. Here, we analyzed the subcellular localization of immunolabeled ATAT1 in human fibroblast KD cells through the cell cycle using confocal laser scanning microscopy. ATAT1 dramatically changed its localization through the cell cycle, depending on the mitotic phase. In interphase, immunolabeled ATAT1 was observed in centrioles, nuclei, and basal bodies if the cells projected primary cilia. ATAT1 was intensely detected as clusters in the nuclei in the G1-G2 phase. In telophase, ATAT1 colocalized with chromatids and spindle poles, and ultimately migrated to the daughter nucleus, newly synthesized centrioles, and midbody. The nucleolus is a core region of ribosomal RNA transcription, and the midbody is associated with severing and depolymerizing of microtubules in the stembody. The specific distributions of ATAT1 through the cell cycle suggest multiple functions of ATAT1, which could include acetylation of microtubules, RNA transcription activity, severing microtubules, and completion of cytokinesis.

Purpose: Although several genetic factors may play a role in leisure-time exercise behavior, there is currently no evidence of a significant genomewide association, and candidate gene replication studies have produced inconsistent results., Methods: We conducted a two-stage genomewide association study and candidate single-nucleotide polymorphisms (SNP) association study on leisure-time exercise behavior using 13,980 discovery samples from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, and 2036 replication samples from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center-2 study. Leisure-time physical activity was measured using a self-administered questionnaire that inquired about the type, frequency and duration of exercise. Participants with ≥4 MET·h·wk of leisure-time physical activity were defined as exhibiting leisure-time exercise behavior. Association testing using mixed linear regression models was performed on the discovery and replication samples, after which the results were combined in a meta-analysis. In addition, we tested six candidate genetic variants derived from previous genomewide association study., Results: We found that one novel SNP (rs10252228) located in the intergenic region between NPSR1 and DPY19L1 was significantly associated with leisure-time exercise behavior in discovery samples. This association was also significant in replication samples (combined P value by meta-analysis = 2.2 × 10). Several SNP linked with rs10252228 were significantly associated with gene expression of DPY19L1 and DP19L2P1 in skeletal muscle, heart, whole blood, and the nervous system. Among the candidate SNP, rs12612420 in DNAPTP6 demonstrated nominal significance in discovery samples but not in replication samples., Conclusions: We identified a novel genetic variant associated with regular leisure-time exercise behavior. Further functional studies are required to validate the role of these variants in exercise behavior.

Brief exposure to passive smoking immediately elevates blood pressure. However, little is known about the association between exposure to passive smoking and chronic hypertension. We aimed to examine this association in a cross-sectional study, after controlling multiple potential confounders.Participants included 32,098 lifetime nonsmokers (7,216 men and 24,882 women) enrolled in the Japan Multi-Institutional Collaborative Cohort Study. Passive smoking was assessed using a self-administered questionnaire. The single question about exposure to passive smoking had five response options: "sometimes or almost never," "almost every day, 2 hours/day or less," "almost every day, 2 to 4 hours/day," "almost every day, 4 to 6 hours/day," and "almost every day, 6 hours/day or longer." Hypertension was defined as any of the following: systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or use of antihypertensive medication. Multivariate-adjusted odds ratio (OR) and 95% confidence interval (CI) for hypertension were estimated by exposure level to passive smoking using unconditional logistic regression models.The multivariate-adjusted OR for hypertension in those exposed almost every day was 1.11 (95% CI: 1.03-1.20) compared with those exposed sometimes or almost never. The OR for a 1-hour per day increase in exposure was 1.03 (95% CI: 1.01-1.06, Pfor trend = .006). This association was stronger in men than in women; the ORs were 1.08 (95% CI: 1.01-1.15, Pfor trend = .036) and 1.03 (95% CI: 1.00-1.05, Pfor trend = .055), respectively.Our findings suggest importance of tobacco smoke control for preventing hypertension.

Introduction: Bone defect reconstruction in orbital wall fractures with absorbable alloplastic such as the unsintered hydroxyapatite and poly L-lactide composite (u-HA/PLLA) system is gaining popularity. The u-HA/PLLA material has osteoconductive and osteosynthetic properties. However, quantitative, long-term outcome data after the use of u-HA/PLLA for orbital wall fractures are lacking., Patients and Methods: We retrospectively analyzed 115 patients who underwent surgical repair of orbital wall fractures with a u-HA/PLLA sheet from 2011 to 2016. A chart review was performed, and the time-dependent changes at fracture sites were assessed by imaging. The immediate postoperative and the latest follow-up bony orbital volumes of the affected side were compared., Results: Seventy patients were eligible for this study (mean age, 44.6 ± 22.1 years; 48 men and 22 women; mean follow-up period, 29.7 ± 12.8 months). Except for one case of hematoma, there were no postoperative wound complications. Of the 70 patients, 10 had postoperative diplopia and 2 had enophthalmos; these conditions were presumably caused by the extension and severity of the fracture. Satisfactory reduction in the entire orbital wall, without pathological changes, was demonstrated. There were no significant differences in the mean bony orbital volumes of the affected side immediately after surgery (24.774 ± 3.092 cm 3 ) and at the latest follow-up (24.749 ± 3.205 cm 3 ) (p = 0.756)., Conclusion: The u-HA/PLLA sheet is useful for orbital wall fracture reconstruction because of its desirable handling characteristics, initial mechanical strength, long-term maintenance of structural stability, radiopacity, and few associated complications. Future randomized controlled trials need to be performed to compare u-HA/PLLA with other conventional materials., (Copyright © 2018. Published by Elsevier Ltd.)

Studies on the associations between soy food consumption and arterial stiffness are rare. The aim of the present study was to evaluate their associations in Japanese men. A total of 652 eligible men, aged 35-69 years, who underwent the measurement of brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness were evaluated in this cross-sectional study. Information on their lifestyle characteristics, including dietary behavior, was obtained from a structured self-administered questionnaire. The frequency of total soy products as well as fermented and non-fermented soy products intakes was calculated, and the amounts of soy protein and soy isoflavone intakes were also estimated; these were then divided into tertiles and their associations with baPWV values were evaluated using general linear models. Higher frequency of fermented soy products intake was associated with decreased baPWV after adjusting for the multivariable covariates (P value for trend was 0.002, in Model 3). This association did not alter after further adjustment with a biomarker of systemic inflammation (serum high-sensitivity C-reactive protein (hs-CRP)) (P value for trend was 0.001, in Model 4). Total soy isoflavone consumption was also inversely associated with baPWV even after adjusting for multivariable covariates including serum hs-CRP (P value for trend was 0.043, in Model 4); however total soy protein consumption was not. These results demonstrated that greater consumption of soy food, especially fermented soy products and soy isoflavone was associated with reduced arterial stiffness, independent of systemic inflammation, in Japanese men.

Background and Purpose: Many epidemiological studies of Guillain-Barré syndrome (GBS) and Fisher syndrome (FS) have been conducted in Europe and America. In contrast, epidemiological studies are rare in Asia where the GBS subtypes differ from those in Western countries. This study was undertaken to clarify the incidence of GBS and FS in a local area in Japan as well as their seasonal trends., Method: Seventy-one GBS and 37 FS patients were recorded from 2006 to 2015 in an area of approximately 1.5 million inhabitants in Japan. The incidence, seasonal trends and clinical features of GBS and FS were examined., Results: The incidence rate of GBS was 0.42 cases per 100 000 person-years and that of FS was 0.22 cases per 100 000 person-years. The incidence of GBS increased with age and FS affected predominantly patients aged from 45 to 64 years old. There was some seasonal clustering of acute motor axonal neuropathy (AMAN) and FS in spring and summer, but it was not significant. AMAN and FS patients had a high frequency of preceding infection (AMAN, 68% gastrointestinal infection; FS, 65% upper respiratory infection). Antecedent respiratory infection was significantly associated with FS as an outcome. Serum antibodies to ganglioside GM1 were detected in 71% of AMAN patients and antibodies to GQ1b were detected in 81% of FS patients., Conclusions: Our study offers evidence of a lower incidence of GBS and a higher incidence of FS in a local area in Japan than in Western countries., (© 2018 EAN.)

Background: Nutrients have been proposed to be related to metabolic syndrome (MetS). The aims of this study were to identify dietary patterns that correlated with several nutrients using reduced rank regression (RRR) and to examine the association between extracted dietary patterns and prevalence of MetS in a Japanese population., Methods: The study population comprised 1,092 Japanese men and women (35-69 years old) who had participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study in Tokushima Prefecture. Dietary patterns were derived with RRR using 46 food items as predictors and six established nutrients (potassium, calcium, vitamin D, vitamin C, insoluble dietary fiber, and carotene) as response variables. Associations between extracted dietary patterns and MetS were then examined with logistic regression models., Results: Among the six dietary patterns, dietary pattern 1 (DP1) explained the largest proportion (60.1%) of variance in the six nutrients. Therefore, only DP1 was selected for further analysis. DP1 was characterized by high intake frequency of vegetables, fruits, fish and small fish, natto (fermented soybeans), and deep-fried tofu. After adjustment for potential confounders, significant inverse associations were found between DP1 score and MetS (odds ratio [OR] for each quartile: 1.00, 0.58, 0.60, 0.52; P trend = 0.02); DP1 and high blood pressure (P trend = 0.0002); and DP1 and high blood glucose (P trend = 0.02)., Conclusion: A dietary pattern characterized by high intake of vegetables, fruits, fish and small fish, natto, and deep-fried tofu was associated with reduced prevalence of MetS in a Japanese population.

Background: Although beneficial associations have been reported between moderate alcohol intake and the serum lipid profile, it is unclear whether polymorphisms in alcohol-metabolizing enzymes can modify these associations. Here, we assessed the effects of ADH1B His48Arg (rs1229984), ALDH2 Glu504Lys (rs671), and their combination on these associations. Furthermore, we examined if the findings for ALDH2 could be replicated., Methods: We categorized 889 male participants in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study into two groups based on presence or absence of minor allele(s) or four groups based on genotype combinations. We performed regression analyses of serum lipid concentrations on alcohol intake, with multivariable adjustment. The replication study was conducted among 2,562 men in the Shizuoka part of the J-MICC Study., Results: The ALDH2 Glu/Lys or Lys/Lys groups showed significant decreases in serum low-density lipoprotein (LDL) cholesterol with increasing alcohol consumption; the coefficient per intake increase of 10 g/day was -2.49 mg/dL (95% confidence interval [CI], -3.85 to -1.13), and a significant interaction with the polymorphism was confirmed (P for interaction = 0.006). This inverse correlation was more evident among the ADH1B His/His + ALDH2 Glu/Lys or Lys/Lys groups (-3.24 mg/dL, 95% CI, -5.03 to -1.45). Serum triglycerides were positively associated with alcohol consumption in the ADH1B His/His group (P for interaction = 0.020). The stronger association between serum LDL cholesterol and alcohol consumption in the ALDH2 Glu/Lys or Lys/Lys groups was replicated., Conclusions: The ALDH2 Glu504Lys polymorphism can modify the association between alcohol intake and serum LDL cholesterol in Japanese men.

Purpose: Our aim was to assess the patterns of practice and treatment outcomes of definitive radiotherapy (RT) for vaginal cancer in Japan., Materials and Methods: RT methods and outcomes of patients with vaginal cancer treated with definitive RT or chemoradiotherapy at 10 institutes of the Japanese Radiation Oncology Study Group between January 2000 and March 2010 were retrospectively evaluated., Results: A total of 90 patients were enrolled in the study. The clinical stages were I, II, III, and IVA in 34, 36, 16, and 4 patients, respectively. Seventy patients were treated with three-dimensional conformal RT (3DCRT) and brachytherapy (BT), 12 with BT alone, and 8 with 3DCRT alone. Chemotherapy was administered to 29 patients. The 5-year overall survival and local control rates were 77 and 83% with a median follow-up period of 94 months for surviving or lost patients. The 5-year overall survival rates according to stage were 94, 71, 56, and 75% for stages I, II, III, and IVA, respectively. The 5-year local control rates according to stage were 94, 77, 74, and 75% for stages I, II, III, and IVA, respectively. Twenty-nine percent (6 of 21 patients) of local recurrences occurred between 5 and 10 years after RT. The 10-year local control rate of all patients was 71%. Significant prognostic factors for overall survival by univariate and multi-variate analyses were performance status, tumor size, and pelvic lymph node metastasis. Grade 3 late radiation morbidity of the rectum, pelvic bone, urinary bladder, and skin developed in 9% (8 of 90 patients)., Conclusions: Good outcomes similar to those of cervical cancer can be achieved with definitive RT delivered by 3DCRT and/or BT for vaginal cancer. Long follow-up is necessary for a continuing risk of local recurrence after 5 years.

The aim of this study was to evaluate the associations between dietary pattern, adiponectin and insulin resistance. The study population consisted of 612 men and women aged 35-69 years old who had participated in the baseline survey of Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima Prefecture. Diets and lifestyle related variables were assessed by questionnaires. Multiple regression analyses were used to analyse the relations between dietary patterns and high molecular weight (HMW) adiponectin. For further analysis, path analysis was used to test the hypothesised model of association between dietary pattern, serum adiponectin and insulin resistance. The result showed that higher score of bread and dairy pattern was directly associated with increased serum level of adiponectin in women, which was inversely related to homeostasis model assessment of insulin resistance (HOMA-IR). In conclusion, higher consumption of bread and dairy products, and low intake of rice may be associated with increased serum adiponectin in women.