Genetic evidence for involvement of ß2-adrenergic receptor in brown adipose tissue thermogenesis in humans.

BACKGROUND: Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the ß-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding ß-ARs and BAT activity in human adults. METHODS: Single nucleotide polymorphisms (SNPs) in ß1-, ß2-, and ß3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIRTRS) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber. RESULTS: We found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIRTRS or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits. CONCLUSIONS: The present study supports the importance of ß2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor's BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.

The factors affecting implementing shared decision-making in clinical trials: a cross-sectional survey of clinical research coordinators' perceptions in Japan.

BACKGROUND: The shared decision-making model has been proposed as the ideal treatment decision-making process in medical encounters. However, the decision to participate in clinical trials rarely involves shared decision-making. In this study, we investigated the perceptions of Japanese clinical research coordinators who routinely support the informed consent process. METHODS: This study aimed to (1) identify clinical research coordinators' perceptions of the current status of shared decision-making implementation and its influencing factors, and (2) obtain suggestions to enhance the shared decision-making process in clinical trials. A cross-sectional survey was conducted using a web questionnaire based on the Theory of Planned behaviour. Invitations were sent to 1087 Japanese medical institutions, and responses from the participants were captured via the web. The shared decision-making process in clinical trials was defined according to the Shared Decision-Making Questionnaire for Doctors. The effect of the attitudes toward shared decision-making, clinical research coordinators' subjective norms towards its implementation, perceived barriers to autonomous decision-making, and the number of difficult steps in the shared decision-making process on the shared decision-making current status as the shared decision-making intention was assessed by multiple regression analysis. RESULTS: In total, 373 clinical research coordinators responded to the questionnaire. Many believed that they were already implementing shared decision-making. Attitudes toward shared decision-making (t = 3.400, p < .001), clinical research coordinators' subjective norms towards its implementation (t = 2.239, p = .026), perceived barriers to autonomous decision-making (t = 3.957, p < .001), and the number of difficult steps in the shared decision-making process (t = 3.317, p = .001) were found to significantly influence current status (Adjusted R2 = .123). However, results on perceived barriers to autonomous decision-making and the number of difficult steps in the shared decision-making process indicate a lack of knowledge of shared decision-making and decision-support skills among clinical research coordinators. CONCLUSIONS: Clinical research coordinators might positively perceive shared decision-making based on normative beliefs without sufficient knowledge of it. Therefore, providing appropriate training on shared decision-making to clinical research coordinators and increasing awareness among stakeholders could enable its improvement. TRIAL REGISTRATION: Not applicable.

Identifying correlates of salt reduction practices among rural, middle-aged Muslim Indonesians with hypertension through structural equation modeling.

Background: In 2016, the World Health Organization recommended salt reduction strategies. In most low- and middle-income countries, little is known about what causes people to reduce their salt intake. Aim: In rural West Java, Indonesia, we conducted a cross-sectional survey to describe self-reported salt reduction practices among middle-aged Muslims with hypertension (n = 447) and to identify correlates of salt reduction. Methods: We developed a questionnaire with Likert scales to measure self-reported frequency of efforts to reduce salt intake, and degree of agreement/disagreement with 51 statements about variables hypothesized to influence salt reduction practices. We compared groups using t-tests and one-way ANOVAs. Through one-factor confirmatory factor analysis and structural equation modeling, we identified correlates of salt reduction practices. Results: About 45% of participants reported regularly reducing their salt intake; only 12.8% reported never attempting. Men reported higher social barriers, while women reported higher family support and spiritual support. Overall, we found that participants' frequency of effort to reduce their salt intake was associated with a constellation of six correlates. Salt reduction practices were directly positively associated with prior health/illness experiences (ß = 0.25), and by seeking health information (ß = 0.24). Seeking health information was in turn positively associated with prior health/illness experiences (ß = 0.34), receiving support from health professionals (ß = 0.23) and Islamic spiritual practice (ß = 0.24). Salt reduction practices were negatively associated with environmental barriers to healthful eating practices (ß = -0.14). Conclusion: In this population, reinforcing positive correlates identified in this study and mitigating against negative correlates may foster salt reduction practices.

Development and field testing of a decision aid to facilitate shared decision making for adults newly diagnosed with attention-deficit hyperactivity disorder.

BACKGROUND: The number of individuals who are diagnosed with attention-deficit hyperactivity disorder (ADHD) during adulthood has increased in recent years. However, there is still no decision aid (DA) to help adults newly diagnosed with ADHD make decisions regarding further treatments. OBJECTIVE: This study aimed to describe the development process of a DA for adults newly diagnosed with ADHD and its field testing during the shared decision-making (SDM) process in a clinical setting. METHODS: The development process involved the creation of a DA prototype using the International Patient Decision Aid Standards criteria and revision of the prototype through the stakeholders' reviews. The field testing of the DA compared scores before and after the SDM process on the service users' knowledge scale, decisional conflict scale and the Conners Adult ADHD Rating Scales. RESULTS: The developed DA contained options of watchful waiting with own coping skills and pharmacological treatment, which consisted of several kinds of drug options. Fifteen adults newly diagnosed with ADHD participated in the field testing. The participant decision-making quality outcomes such as their knowledge and decisional conflict improved after the SDM process. ADHD severity did not change. CONCLUSION: A DA for adults with ADHD was systematically developed following the international criteria. Field testing indicated that the DA could serve as a tool to facilitate the SDM process. Further research on this DA is necessary before its routine implementation. PATIENT OR PUBLIC CONTRIBUTION: During the development process of the DA, the service users who had already been diagnosed with ADHD reviewed the DA prototype and provided feedback, which improved the final version of the DA.

Associations between health literacy and information-evaluation and decision-making skills in Japanese adults.

BACKGROUND: Health literacy among Japanese is often low, making it difficult for them to evaluate health information and make informed decisions. However, the health literacy scales applied measure the perceived difficulty of health-related tasks; they do not directly assess the specific skills needed to perform the tasks: the skills to judge the reliability of diverse information using evaluation criteria and implement rational decision-making. Therefore, the study objectives were to investigate the following issues using a nationwide survey in Japan. (1) When obtaining information, to what extent do people apply criteria for evaluating information to confirm its reliability; when making decisions, to what extent do they seek out available options and compare pros and cons based on their own values? (2) How strongly are such skills associated with health literacy and demographic characteristics? (3) What opportunities are available to learn these skills? METHODS: We conducted an online questionnaire survey using a Japanese Internet research company; 3,914 valid responses were received. The measures comprised health literacy (European Health Literacy Survey Questionnaire), five items on information evaluation, four items on decision-making, and items on the availability and location of learning opportunities. We calculated Pearson correlations to explore the association of health literacy with information-evaluation and decision-making skills. Multivariate analyses were also conducted using these factors as dependent variables. RESULTS: Fewer than half (30%-50%) of respondents reported always or often evaluating information and engaging in decision-making. Health literacy was significantly and positively correlated with the specific skills of information evaluation and decision-making (r = .26 and .30, respectively) as were multivariate analyses (beta = .15 and .22, respectively). Over 40% of respondents had never learned those skills. The most common resources for learning the skills were the Internet and television; less-used resources were schools and workplaces. CONCLUSIONS: Both information-evaluation and decision-making skills were associated with health literacy. However, these skills are not sufficiently widespread in Japan because there are few opportunities to acquire them. More research is needed to raise awareness of the importance of such skills for improving health literacy and providing learning opportunities.

Healthcare providers' perception of advance care planning for patients with critical illnesses in acute-care hospitals: a cross-sectional study.

BACKGROUND: In acute-care hospitals, patients treated in an ICU for surgical reasons or sudden deterioration are treated in an outpatient ward, ICU, and other multiple departments. It is unclear how healthcare providers are initiating advance care planning (ACP) for such patients and assisting them with it. The purpose of this study is to clarify healthcare providers' perceptions of the ACP support provided to patients receiving critical care in acute-care hospitals. METHODS: A cross-sectional study was conducted using questionnaires. In this study, 400 acute-care hospitals with ICUs in Japan were randomly selected, and 1490 subjects, including intensivists, surgeons, ICU nurses, surgical floor nurses, and surgical outpatient nurses, participated. Survey items examined whether ICU patients received ACP support, the participants' degree of confidence in providing ACP support, the patients' treatment preferences, and the decision-making process, and whether any discussion was conducted on change of values. RESULTS: Responses were obtained from 598 participants from 157 hospitals, 41.4% of which reportedly supported ACP provision to ICU patients. The subjects with the highest level of ACP understanding were surgeons (45.8%), and differences in understanding were observed across specialties (P < 0.001). Among the respondents, physicians and nurses expressed high levels of confidence in providing ACP support to patients requiring critical care. However, 15.2% of all the subjects mentioned that they would not attempt to resuscitate the patients. In addition, 25.7% of the participants handed over patients' values to other departments or hospitals, whereas 25.3% handed over the decision-making process. CONCLUSIONS: Among the participating hospitals, 40% provided ACP support to patients receiving critical care. The low number is possibly because support providers lack understanding of the content of patients' ACP or about how to support and use ACP. Second, it is sometimes too late to start providing ACP support after ICU admission. Third, healthcare providers differ in their perception of ACP, widely considered an ambiguous concept. Finally, in acute-care hospitals with different healthcare settings, it is necessary to confirm and integrate the changes in feelings and thoughts of patients.

Implementation of advance care planning decision aids for patients undergoing high-risk surgery: a field-testing study.

BACKGROUND: Patients undergoing high-risk surgery are at a risk of sudden deterioration of their health. This study aimed to examine the feasibility of the development of two patient decision aids (PtDAs) to assist patients undergoing high-risk surgeries in informed decision-making about their medical care in a crisis. METHODS: This field testing implemented two PtDAs that met the international criteria developed by the researchers for patients before surgery. Study participants were patients scheduled to be admitted to the intensive care unit after surgery at one acute care hospital in Japan and their families. The study used a mixed-methods approach. The primary outcome was patients' decision satisfaction evaluated by the SURE test. Secondary outcomes were the perception of the need to discuss advance care planning (ACP) before surgery and mental health status. The families were also surveyed on their confidence in proxy decision-making (NRS: 0-10, quantitative data). In addition, interviews were conducted after discharge to assess the acceptability of PtDAs. Data were collected before (preoperative outpatients, baseline: T0) and after providing PtDAs (in the hospital: T1) and following discharge (T2, T3). RESULTS: Nine patients were enrolled, of whom seven agreed to participate (including their families). The SURE test scores (mean ± SD) were 2.1 ± 1.2 (T0), 3.4 ± 0.8 (T2), and 3.9 ± 0.4 (T3). The need to discuss ACP before surgery was 8.7 ± 1.3 (T1) and 9.1 ± 0.9 (T2). The degree of confidence in family surrogate decision-making was 6.1 ± 2.5 (T0), 7.7 ± 1.4 (T1), and 8.1 ± 1.5 (T2). The patients reported that using PtDAs provided an opportunity to share their thoughts with their families and inspired them to start mapping their life plans. Additionally, patients wanted to share and discuss their decision-making process with medical professionals after the surgery. CONCLUSIONS: PtDAs supporting ACP in patients undergoing high-risk surgery were developed, evaluated, and accepted. However, they did not involve any discussion of patients' ACP treatment wishes with their families. Medical providers should be coached to provide adequate support to patients. In the future, larger studies evaluating the effectiveness of PtDAs are necessary.

Shared decision making, physicians' explanations, and treatment satisfaction: a cross-sectional survey of prostate cancer patients.

BACKGROUND: Hormone therapy is one option for some types of prostate cancer. Shared decision making (SDM) is important in the decision making process, but SDM between prostate cancer patients receiving hormone therapy and physicians is not fully understood. This study tested hypotheses: "Patients' perception of SDM is associated with treatment satisfaction, mediated by satisfaction with physicians' explanations and perceived effective decision making" and "The amount of information provided to patients by physicians on diseases and treatment is associated with treatment satisfaction mediated by patients' perceived SDM and satisfaction with physicians' explanations." METHODS: This cross-sectional study was conducted using an online panel via a private research company in Japan. The participants in this study were patients registered with the panel who had received or were currently receiving hormone therapy for prostate cancer and physicians registered with the panel who were treating patients with prostate cancer. Measures used in this study included a nine-item Shared Decision Making Questionnaire, levels of satisfaction with physicians' explanations and treatment satisfaction, and effective decision making for patients (feeling the choice is informed, value-based, likely to be implemented and expressing satisfaction with the choice), and a Shared Decision Making Questionnaire for Doctors. The hypotheses were examined using path analysis. RESULTS: In total, 124 patients and 150 physicians were included in the analyses. In keeping with our hypotheses, perceived SDM significantly correlated with the physicians' explanations and perceived effective decision making for patients, and satisfaction with physicians' explanations and perceived effective decision making for patients were both related to treatment satisfaction. Although the amount of information provided to patients was correlated with the perceived SDM, it was indirectly related to their satisfaction with physicians' explanations. CONCLUSIONS: When physicians encourage patients to be actively involved in making decisions about treatment through the SDM process while presenting a wide range of information at the start of hormone therapy, patients' effective decision making and physicians' explanations may be improved; consequently, the patients' overall treatment satisfaction may be improved. Physicians who treat patients with prostate cancer may have underestimated the importance of SDM before starting hormone therapy, even greater extent than patients.

Genetic variants influencing obesity-related traits in Japanese population.

Context: Adipose tissue is the main organ that stores energy and participates in adaptive thermogenesis of the human body. The adipose tissue content in an individual is determined by a combination of genetic factors and lifestyle related factors. While Japanese people, along with the closely related East Asians, are generally thinner than individuals of European ancestry, they are prone to accumulating visceral adipose tissues. Genome-wide discovery of loci influencing obesity-related traits, and application of the genome sequence data to assess natural selection, provides evidence that the obesity-related traits in East Asians might be shaped by natural selection. Objective: This review aims to summarise health and evolutionary implications of genetic variants influencing obesity-related traits in Japanese. Methods: This study gathered recently published papers of medical, genetic and evolutionary studies regarding obesity-related traits in the Japanese and closely related East Asians. Results and conclusion: A high susceptibility to central obesity of Japanese and closely related East Asians might have been shaped by natural selection favouring thrifty genotypes. Moreover, natural selection favouring higher thermogenic activity of brown adipose tissues would contribute to increased non-thrifty alleles in ancestors of East Asians.

Evidence for Very Recent Positive Selection in Mongolians.

Mongols, the founders of the largest continental empire in history, successfully adapted to the harsh environments of Inner Asia through nomadic pastoralism. Considerable interest exists in ascertaining whether genetic adaptation also contributed to the Mongols' success, and dissecting the genome diversity of present-day populations in Mongolia can help address this question. To this end, we determined the genotypes of nearly 2.4 million single nucleotide polymorphisms (SNPs) of 96 unrelated Mongolian individuals in Ulaanbaatar city, and performed genome-wide scans for population-specific positive selection. We discovered signatures of Mongolian-specific positive selection at the chromosomal region 3p12.1, in which hits in genome-wide association studies were reported for medical and biological traits related to energy metabolism and reproduction. The top SNP, rs117799927, showed a distinctive geographic distribution: the frequency of the derived allele, rs117799927 G, was extremely low among worldwide populations (0.005) but exceptionally high in Mongolians (0.247). Approximate Bayesian computation-based age estimation showed that the rs117799927 G allele emerged or positive selection began to operate 50 generations before the present, near the age of the climate anomaly named Late Antique Little Ice Age. Furthermore, rs117799927 showed significant associations with multiple adiposity-related traits in Mongolians and allelic difference in enhancer activity in cells of adipocyte lineage, suggesting that positive selection at 3p12.1 might be related to adaptation in the energy metabolism system. These findings provide novel evidence for a very recent positive-selection event in Homo sapiens and offer insights into the roles of genes in 3p12.1 in the adaptive evolution of our species.

Influence of AHRR Pro189Ala polymorphism on kidney functions.

The function of aryl hydrocarbon receptor repressor (AHRR) in the kidney is unclear. The present study investigated associations between AHRR Pro189Ala polymorphism and estimated glomerular filtration rates (eGFR), serum creatinine, and hemoglobin levels in 2775 Japanese adults without diabetes. In addition, we examined whether AHRR expression levels in the kidney of control and chronic kidney disease (CKD) rats were changed. Multiple linear regression analyses showed that carriers of the Ala allele had increased eGFR and lower concentrations of serum creatinine and hemoglobin (p < 0.05). Immunohistochemical analysis showed that the expression of AHRR was upregulated in the kidneys of rats with CKD. These findings suggest that AHRR plays distinct roles in kidney functions and hemoglobin values. The effects of the AHRR polymorphism might be intensified in the kidneys of patients with CKD.

Identification of deleterious rare variants in MTTP, PNPLA3, and TM6SF2 in Japanese males and association studies with NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive fat deposits in hepatocytes without excessive alcohol intake. NAFLD is influenced by genetic factors, and the heritability has been estimated at 0.35 to 0.6 by twin studies. We explored rare variants in known NAFLD-associated genes to investigate whether these rare variants are involved in the susceptibility to NAFLD. METHODS: The target genes for re-sequencing were PNPLA3, TM6SF2, and MTTP. All exons of these three genes were amplified from a discovery panel of 950 Japanese males, and the identified rare variants were further tested for genetic association in 3014 individuals from the Japanese general population and for in vitro functional evaluation. RESULTS: Target re-sequencing analysis using next-generation sequencing identified 29 rare variants in 65 Japanese males (6.84%), 12 of which were newly identified base substitutions. A splicing mutation in TM6SF2 that resulted in deletion of 31 amino acids was identified in an NAFLD case. Among eight genotyped rare single-nucleotide polymorphisms (SNPs; minor allele frequency < 0.02), rs143392071 (Tyr220Cys, PNPLA3) significantly increased (odds ratio = 3.52, P = 0.008) and rs756998920 (Val42Ile, MTTP) significantly decreased (odds ratio = 0.03, P = 0.019) the NAFLD risk. Functional assays showed that these two SNPs disrupted protein functions and supported the genetic association. CONCLUSION: Collectively, 1.79% of individuals in our studied population were estimated carriers of rare variants that are potentially associated with NAFLD.

Factors influencing decision regret regarding placement of a PEG among substitute decision-makers of older persons in Japan: a prospective study.

BACKGROUND: A tube feeding decision aid designed at the Ottawa Health Research Institute was specifically created for substitute decision-makers who must decide whether to allow placement of a percutaneous endoscopic gastrostomy (PEG) tube in a cognitively impaired older person. We developed a Japanese version and found that the decision aid promoted the decision-making process of substitute decision-makers to decrease decisional conflict and increase knowledge. However, the factors that influence decision regret among substitute decision-makers were not measured after the decision was made. The objective of this study was to explore the factors that influence decision regret among substitute decision-makers 6 months after using a decision aid for PEG placement. METHODS: In this prospective study, participants comprised substitute decision-makers for 45 inpatients aged 65 years and older who were being considered for placement of a PEG tube in hospitals, nursing homes and patients' homes in Japan. The Decisional Conflict Scale (DCS) was used to evaluate decisional conflict among substitute decision-makers immediately after deciding whether to introduce tube feeding and the Decision Regret Scale (DRS) was used to evaluate decisional regret among substitute decision-makers 6 months after they made their decision. Normalized scores were evaluated and analysis of variance was used to compare groups. RESULTS: The results of the multiple regression analysis suggest that PEG placement (P < .01) and decision conflict (P < .001) are explanatory factors of decision regret regarding placement of a PEG among substitute decision-makers. CONCLUSIONS: PEG placement and decision conflict immediately after deciding whether to allow PEG placement have an influence on decision regret among substitute decision-makers after 6 months.

Development of the health literacy on social determinants of health questionnaire in Japanese adults.

BACKGROUND: Health inequities are increasing worldwide, with mounting evidence showing that the greatest cause of which are social determinants of health. To reduce inequities, a lot of citizens need to be able to access, understand, appraise, and apply information on the social determinants; that is, they need to improve health literacy on social determinants of health. However, only a limited number of scales focus on these considerations; hence, we developed the Health Literacy on Social Determinants of Health Questionnaire (HL-SDHQ) and examined its psychometric properties. METHODS: We extracted domains of the social determinants of health from "the solid facts" and related articles, operationalizing the following ten domains: "the social gradient," "early life," "social exclusion," "work," "unemployment," "social support," "social capital," "addiction," "food," and "transport," Next, we developed the scale items in the ten extracted domains based on the literature and included four aspects of health literacy (ability to access, understand, appraise, and apply social determinants of health-related information) in the items. We also evaluated the ease of response and content validity. The self-administered questionnaire consisted of 33 items. The reliability and construct validity were verified among 831 Japanese adults in an internet survey. RESULTS: The scale items had high reliability with a Cronbach's alpha of 0.92, and also adequate results were obtained for the internal consistency of the information-processing dimensions (Cronbach's alpha values were 0.82, 0.91, 0.84, and 0.92 for accessing, understanding, appraising, and applying, respectively). The goodness of fit by confirmatory factor analysis based on the four dimensions was an acceptable value (comparative fit index = 0.901; root mean square error of approximation = 0.058). Furthermore, the bivariate relationship between HL-SDHQ and the frequency of participation in citizen's activities was similar to the theoretical results. CONCLUSIONS: HL-SDHQ clarifies the relationship between the ten domains of the social determinants of health and health in each domain and is able to measure whether it is possible to access, understand, appraise, and apply related information. The reliability and validity of the scale were adequate.

ZNF70, a novel ILDR2-interacting protein, contributes to the regulation of HES1 gene expression.

A diabetes susceptibility gene, immunoglobulin-like domain containing receptor 2 (Ildr2), encodes a transmembrane protein localized to the endoplasmic reticulum membrane that is closely related to hepatic lipid metabolism. The livers of ob/ob mice in which Ildr2 is transiently overexpressed are relieved of hepatic steatosis. However, the molecular mechanisms through which ILDR2 affects these changes in hepatic lipid metabolism remain unknown. This study aimed to identify ILDR2-interacting proteins to further elucidate the molecular mechanisms underlying the role of ILDR2 in lipid homeostasis. We purified ILDR2-containing protein complexes using tandem affinity purification tagging and identified ZNF70, a member of the Kruppel C2H2-type zinc finger protein family, as a novel ILDR2-interacting protein. We demonstrated that ZNF70 interacts with ZFP64 and activates HES1 transcription by binding to the HES1 promoter. In addition, HES1 gene expression is increased in ILDR2-knockdown HepG2 cells, in which ZNF70 is translocated from the cytoplasm to the nucleus, suggesting that ZNF70 migration to the nucleus after dissociating from the ILDR2-ZNF70 complex activates HES1 transcription. These results support a novel link between ILDR2 and HES1 gene expression and suggest that ILDR2 is involved in a novel pathway in hepatic steatosis.

Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups.

BACKGROUND: The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity. METHODS: Samples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis. RESULTS: rs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (± 3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (± 11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (± 3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289-2.196, p value 0.00013). CONCLUSION: This study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.

Sin3A-associated protein, 18 kDa, a novel binding partner of TRIB1, regulates MTTP expression.

Mammalian tribbles homolog 1 (TRIB1) is a human locus that has been shown to significantly impact plasma lipid levels across several ethnic groups. In addition, the gene has been associated with the occurrence of nonalcoholic fatty liver disease. In the present study, a yeast-two-hybrid system was used to screen for novel molecular targets of TRIB1 binding. Loci corresponding to clones that were positive for TRIB1 binding subsequently were assessed for roles in lipid metabolism in mice using adenoviral constructs to induce knockdown or overexpression. Sin3A-associated protein, 18 kDa (SAP18) was identified as a novel binding partner of TRIB1. Knockdown of the Sap18 in mouse liver decreased plasma lipid levels and increased hepatic lipid levels; SAP18 overexpression showed the opposite effects. Transcriptome analysis of the mouse liver revealed that Sap18 knockdown decreased and SAP18 overexpression increased microsomal TG transfer protein (MTTP) expression levels. Chromatin immunoprecipitation analysis showed that halo-tagged SAP18, halo-tagged TRIB1, and anti-mSin3A antibody enriched precipitates for regulatory sequences of the MTTP gene. Enforced expression of SAP18 enhanced and SAP18 knockdown conversely attenuated the enrichment of MTTP regulatory sequences seen with anti-mSin3A antibody. These studies indicated that SAP18 expression enhanced the recruitment of mSin3A in coordination with TRIB1 to MTTP regulatory elements and increased MTTP expression.

The role of TRIB1 in lipid metabolism; from genetics to pathways.

The plasma concentration of lipids is a heritable risk factor for the development of atherosclerosis and related coronary artery diseases (CAD). Mammalian tribbles homologue 1 (TRIB1) is a human locus, the downstream linkage disequilibrium (LD) block of which affects plasma low-density lipoprotein (LDL)-associated cholesterol, triglyceride (TG) levels and CAD across multiple ethnic groups. In addition, association of TRIB1 with non-alcoholic fatty liver disease (NAFLD) has also been shown. A regulatory sequence that enhances TRIB1 promoter activity was identified in the LD block and the minor allele of a single nt polymorphism (SNP, rs6982502) in this regulatory sequence reduces the activity of the TRIB1 promoter. The minor allele of rs6982502 is a risk allele for increasing plasma lipid levels and NAFLD. Trib1 deficiency increases plasma cholesterol and TGs in mice and overexpression of TRIB1 in mouse liver reduces these factors. Expression of rate-limiting lipogenic enzymes is increased in Trib1-knockout mouse liver and decreased with overexpression. Recently, carbohydrate-responsive element-binding protein (ChREBP) emerged as a novel binding partner of TRIB1. Furthermore, novel binding partner, Sin3A (Swi-independent 3A)-associated protein, 18 kDa, was identified, which activates microsomal TG transfer protein (MTTP) expression by binding with MTTP regulatory elements in co-ordination with mSin3A and TRIB1. Very recently, a small molecular compound that up-regulates TRIB1 expression in HepG2 cells has been discovered. Further exploration of the binding partners of TRIB1 and their involvement in lipid metabolism may aid discovery of novel pharmacological targets for the management of dyslipidaemia and steatosis.

Comprehensive health literacy in Japan is lower than in Europe: a validated Japanese-language assessment of health literacy.

BACKGROUND: Health literacy, or the ability to access, understand, appraise and apply health information, is central to individuals' health and well-being. A comprehensive, concept-based measure of most dimensions of health literacy has been developed for the general population in Europe, which enables comparisons within and between countries. This study seeks to validate this tool for use in Japan, and to use a Japanese translation to compare health literacy levels in Japan and Europe. METHODS: A total of 1054 Japanese adults recruited through an Internet research service company, completed a Japanese-language version of the 47-item European Health Literacy Survey Questionnaire (HLS-EU-Q47). The survey was administered via an online questionnaire, and participant demographics were closely matched to those of the most recent Japanese national census. Survey results were compared with those previously reported in an eight-country European study of health literacy. RESULTS: Internal consistency for the translated questionnaire was valid across multiple metrics. Construct validity was checked using confirmatory factor analyses. The questionnaire correlated well with existing scales measuring health literacy and mental health status. In general, health literacy in the Japanese population was lower than in Europe, with Japanese respondents rating all test items as more difficult than European respondents. The largest difference (51.5 %) was in the number of respondents finding it difficult to know where to get professional help when they are ill. CONCLUSIONS: This study translated a comprehensive health literacy questionnaire into Japanese and confirmed its reliability and validity. Comparative results suggest that Japanese health literacy is lower than that of Europeans. This discrepancy may be partly caused by inefficiency in the Japanese primary health care system. It is also difficult to access reliable and understandable health information in Japan, as there is no comprehensive national online platform. Japanese respondents found it more difficult to judge and apply health information, which suggests that there are difficulties in health decision-making in Japan. Numerous issues may be linked to lower levels health literacy in Japan, and further studies are needed to improve this by developing individual competencies and building supportive environments.

[Nationally representative score of the Japanese language version of the 13-item 7-point sense of coherence scale].

OBJECTIVES: The amount of research relating to evaluation of intervention programs with regard to sense of coherence, a concept of salutogenic stressor coping capacity, is increasing in Japan. However, a nationally representative score of the Japanese version of the sense of coherence scale has not yet been reported. The aim of this study was to describe the 13-item, 7-point Japanese sense of coherence scale (SOC-13), with scoring by sex and age group, and to examine the relationships between the score and locality and city size. METHODS: Four thousand Japanese men and women were selected by stratified random sampling, and a cross-sectional, self-administered questionnaire survey was conducted using the placement method. Responses were obtained from 2,067 individuals (response rate: 51.7%). This study analyzed 956 men and 1,107 women (mean age [standard deviation]: 50.0 [14.3]). RESULTS: The mean score on the SOC-13 was 59.0 (12.2) in all participants, 59.1 (11.8) in men, and 58.9 (12.5) in women. No significant difference was found between men and women (P=0.784). ANOVA and multiple comparison for age difference showed a clear relationship (P<0.05) between higher age and a higher SOC-13 score. Moreover, the results of main and interaction effects in ANCOVA, with independent variables for locality (11 segments) and city size (four segments), were not significant when controlled for age. CONCLUSION: A nationally representative score for the Japanese SOC-13 was acquired. In future research, application of the SOC-13 in Japan for clinical studies is anticipated based on the nationally representative score.