BMI and Cardiometabolic Traits in Japanese: A Mendelian Randomization Study.

BACKGROUND: Although many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated. METHODS: We conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index (BMI)-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses using the two-stage least squares estimator method. The ß-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses. RESULTS: In individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with increased risks of higher blood pressure, triglycerides, and uric acid, as well as lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent using different methods, including the directions. CONCLUSION: The results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.

GWAS of folate metabolism with gene-environment interaction analysis revealed the possible role of lifestyles in the control of blood folate metabolites in Japanese - the J-MICC Study.

BACKGROUND: The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites as well as to detect related gene-environment interactions in Japanese. METHODS: We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene-environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. RESULTS: For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5×10-8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity > 33% on Hcy (ß = 0.039, 0.038 and -0.054, P = 0.018, 0.021 and < 0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (ß = 0.033, P = 0.048). CONCLUSIONS: The present GWAS revealed the folate metabolism-associated genetic loci and gene-environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized CVD prevention.

Association between awareness of limiting food intake and all-cause mortality: A cohort study in Japan.

BACKGROUND: Improving diets requires an awareness of the need to limit foods for which excessive consumption is a health problem. Since there are limited reports on the link between this awareness and mortality risk, we examined the association between awareness of limiting food intake (energy, fat, and sweets) and all-cause mortality in a Japanese cohort study. METHODS: Participants comprised 58,772 residents (27,294 men; 31,478 women) aged 35-69 years who completed baseline surveys of the Japan Multi-Institutional Collaborative Cohort Study from 2004 to 2014. Hazard ratios (HRs) for all-cause mortality and 95% confidence intervals (CIs) were estimated by sex using a Cox proportional hazard model, with adjustment for related factors. Mediation analysis with fat intake as a mediator was also conducted. RESULTS: The mean follow-up period was 11 years and 2,516 people died. Estimated energy and fat intakes according to the Food Frequency Questionnaire were lower in those with awareness of limiting food intake than in those without this awareness. Women with awareness of limiting fat intake showed a significant decrease in mortality risk (HR=0.73; 95% CI, 0.55 to 0.94). Mediation analysis revealed that this association was due to the direct effect of the awareness of limiting fat intake and that the total effect was not mediated by actual fat intake. Awareness of limiting energy or sweets intake was not related to mortality risk reduction. CONCLUSION: Awareness of limiting food intake had a limited effect on reducing all-cause mortality risk.

Sex-specific Relationship Between Stress Coping Strategies and All-cause Mortality: Japan Multi-Institutional Collaborative Cohort Study.

BACKGROUND: Stress coping strategies are related to health outcomes. However, there is no clear evidence for sex differences between stress-coping strategies and mortality. We investigated the relationship between all-cause mortality and stress-coping strategies, focusing on sex differences among Japanese adults. METHODS: A total of 79,580 individuals aged 35-69 years participated in the Japan Multi-Institutional Collaborative Cohort Study between 2004 and 2014 and were followed up for mortality. The frequency of use of the five coping strategies was assessed using a questionnaire. Sex-specific, multivariable-adjusted hazard ratios (HRs) for using each coping strategy ("sometimes," and "often/very often" use versus "very few" use) were computed for all-cause mortality. Furthermore, relationships were analyzed in specific follow-up periods when the proportion assumption was violated. RESULTS: During the follow-up (median: 8.5 years), 1,861 mortalities were recorded. In women, three coping strategies were related to lower total mortality. The HRs for "sometimes" were 0.81 (95% confidence interval [CI], 0.67-0.97) for emotional expression, 0.79 (95% CI, 0.66-0.95) for emotional support-seeking, and 0.80 (95% CI, 0.66-0.98) for disengagement. Men who "sometimes" used emotional expression and sometimes or often used problem-solving and positive reappraisal had a 15-41% lower HRs for all-cause mortality. However, those relationships were dependent on the follow-up period. There was evidence that sex modified the relationships between emotional support-seeking and all-cause mortality (P for interaction = 0.03). CONCLUSION: In a large Japanese sample, selected coping strategies were associated with all-cause mortality. The relationship of emotional support-seeking was different between men and women.

A nationwide survey of Schaaf-Yang syndrome in Japan.

Schaaf-Yang syndrome (SYS) is a congenital disorder characterized by developmental delay, autism spectrum disorder and congenital joint contractures. In this study, a nationwide epidemiological questionnaire-based survey of SYS in the Japanese population was conducted to establish patient numbers, clinical features and genetic information. In the primary survey, we investigated the number of SYS patients. In the secondary survey, we obtained and analyzed detailed clinical and genetic information of SYS patients. This survey collected information on 25 genetically-confirmed patients. The major clinical symptoms included neonatal hypotonia (96% of the patients), poor suck in infancy (82%), developmental delay (100%) and joint contractures (83%). Other main symptoms and findings included characteristic facial features (100%), small hands (92%), eye abnormalities (92%) and short stature (79%). Based on the information collected on activities of daily living, 71% of patients were unable to walk, while 67%, 71%, and 81% of patients required full assistance with eating, toileting and bathing, respectively. Regarding inheritability, the genetic analysis of 21 patients revealed that 14 (67%) carried de novo truncating variants in the melanoma antigen L2 (MAGEL2) gene and seven (33%) had inherited truncating variants from their fathers who were carriers. This survey revealed the clinical and genetic features in Japanese SYS patients. The majority of SYS patients required assistance in many aspects of daily living, and there were a certain number of carriers of the imprinting disorder.

The Impact of Marital Transitions on Vegetable Intake in Middle-aged and Older Japanese Adults: A 5-year Longitudinal Study.

BACKGROUND: Marital transitions are associated with adverse health events, such as mortality and cardiovascular disease. Since marital transitions (eg, becoming widowed) are unavoidable life events, it is necessary to identify modifiable intermediate outcomes. Thus, we examined the association between marital transitions and vegetable intake among middle-aged and older Japanese adults. METHODS: This longitudinal study included Japanese adults aged 40-79 years who received an annual health checkup between 2007 and 2011 (baseline) and 5 years later (follow-up). Marital transitions were classified as whether and what type of transition occurred during the 5-year period and comprised five groups: consistently married, married to widowed, married to divorced, not married to married, and remained not married. Changes in total vegetable, green and yellow vegetable, and light-colored vegetable intake from baseline to follow-up were calculated using the Food Frequency Questionnaire. RESULTS: Data from 4,813 participants were analyzed (mean age, 59.4 years; 44.1% women). Regarding marital transitions, 3,960 participants were classified as "consistently married," 135 as "married to widowed," 40 as "married to divorced," 60 as "not married to married," and 529 as "remained not married." Multivariable linear regression analysis revealed that compared to consistently married, married to widowed was inversely associated with the change in total vegetable intake (ß = -16.64, SE = 7.68, P = 0.030) and light-colored vegetable intake (ß = -11.46, SE = 4.33, P = 0.008). CONCLUSION: Our findings suggest that being widowed could result in a reduced intake of vegetables. Hence, dietary counseling according to marital situation is necessary.

Assessing the Relationship Between High-sensitivity C-reactive Protein and Kidney Function Employing Mendelian Randomization in the Japanese Community-based J-MICC Study.

BACKGROUND: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches. METHODS: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. RESULTS: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], -0.019 to 0.020 and -0.003; 95% CI, -0.019 to 0.014, respectively). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, -0.020 to 0.010 and -0.004; 95% CI, -0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: -0.008; 95% CI, -0.058 to 0.042; IVAsian: 0.001; 95% CI, -0.036 to 0.036). CONCLUSION: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.

Application of the RNA interference technique to Xenopus embryos: Specific reduction of the ß-catenin gene products by short double-stranded RNA produced by recombinant human Dicer.

RNA interference (RNAi) is a technique for suppressing the function of specific genes and is widely used in many organisms, including yeast, nematodes, flies, plants, mice, and cultured mammalian cells. As of date, this technique has not been successfully applied to Xenopus laevis embryos. In this study, we applied RNAi to Xenopus embryos using ß-catenin as a model gene. Injection of long double-stranded RNA (dsRNA) corresponding to the 3'-untranslated region of ß-catenin mRNA into embryos induced embryonic lethality without any specific phenotype. However, injection of short dsRNA, generated from long dsRNA by treatment with recombinant human Dicer, into embryos resulted in decreased expression of endogenous ß-catenin mRNA and protein, as well as decreased Wnt signaling activity in the embryos. The decrease in ß-catenin mRNA and protein levels was observed only after mid-blastula transition. Embryos injected with short dsRNA showed a characteristic phenotype of enlarged anterior structures and loss of posterior structures. These phenotypes, as well as the increased expression of the anterior gene and decreased expression of the posterior gene, suggest that RNAi against the ß-catenin gene suppresses the "late Wnt signaling" involved in proper anterior-posterior patterning of Xenopus embryos. The effect of RNAi on Xenopus embryos was also found to be sensitive to temperature. These results strongly suggest that the RNAi technique can be applied to Xenopus embryos using short dsRNAs, appropriate temperature control, and proper selection of target genes.

Study Profile of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study.

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.

High phospho-histone H3 expression uniquely predicts favorable survival among four markers of cellular proliferation in colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal cancers worldwide, with high morbidity and mortality rates. Despite numerous attempts to identify prognostic markers for the CRC patients, the significance of the association of cellular proliferation markers with survival is controversial. Here we used immunohistochemistry to detect four markers of cellular proliferation expressed in primary CRC tissue specimens (n = 269) to assess their potential to serve as prognostic factors. CRC cells variably expressed phospho-histone H3 (PHH3) (range, 0-76 per high-powered field (HPF); median, 7 per HPF), cyclin A (CCNA) (range, 11.3-73.7%; median, 32%), geminin (GMNN) (range, 7.8-82.0%; median, 37.1%), and marker of proliferation Ki-67 (MKI67) (range, 4.9-96.6%; median, 49.6%). Among them, patients with PHH3-high (≥7 per HPF) tumors uniquely experienced significantly longer 5-year survival than those with PHH3-low (≤6 per HPF) (81.8% vs. 65.5%; P = 0.0047). Multivariable Cox hazards regression analysis identified PHH3-high (hazard ratio, 0.54; 95% confidence interval, 0.31-0.92; P = 0.025) as potential favorable factors. PHH3 levels inversely associated with pT stage (P < 0.0001) and were significantly and inversely associated with tumor diameter (ρ = -0.314, P < 0.0001). These findings support the use of PHH3 immunohistochemistry for predicting the prognoses of patients with CRC.

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients.

OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

Association Between Second-hand Smoke Exposure and Depressive Symptoms Among Japanese Adults: A Cross-sectional Study.

BACKGROUND: Second-hand smoke exposure has been associated with poor mental health. However, among Japanese adults, little is known about the association between second-hand smoking and depressive symptoms. We examined this association in a cross-sectional study among a Japanese general adult population sample. METHODS: Japanese adults were recruited from the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area between 2012 and 2017. Second-hand smoke exposure and smoking status were assessed using a self-administered questionnaire. Based on their frequency of exposure to second-hand smoke, non-smokers and smokers were categorized as "almost never," "sometimes," and "almost every day". Depressive symptoms were defined by a Kessler 6 score ≥5 points. We performed a multivariable Poisson regression analysis to obtain adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for depressive symptoms. RESULTS: Overall, 5,121 participants (4,547 non-smokers and 574 smokers) were included whose mean age was 63.6 (standard deviation [SD], 10.3) years for non-smokers and 59.33 (SD, 10.2) years for smokers. The association between second-hand smoking and depressive symptoms was significant among non-smokers, but not among smokers. Among non-smokers, PRs compared with "almost never" were 1.25 (95% CI, 1.09-1.42) for "sometimes" and 1.41 (95% CI, 1.09-1.84) for "almost every day" (P for trend <0.001); among smokers, PRs compared with "almost never" were 1.30 (95% CI, 0.82-2.06) for "sometimes" and 1.44 (95% CI, 0.90-2.33) for "almost every day" (P for trend = 0.144). CONCLUSIONS: Second-hand smoking and depressive symptoms were associated among non-smokers. Our findings indicate the importance of tobacco smoke control for mental health.

The Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) for DSM-5: A validation for neurodevelopmental disorders in Japanese outpatients.

OBJECTIVE: The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL) is a widely used semi-structured diagnostic interview in child and adolescent psychiatry. However, given the extensive use of the K-SADS-PL in clinical practice and research and its adaptation for use in many languages and cultures, validation studies of the instrument are scarce. This study was designed to examine the inter-rater reliability, criterion validity and construct validity of the updated instrument, the K-SADS-PL for DSM-5, in Japanese outpatients totaling 95 children and adolescents. METHOD: We translated and adapted the updated instrument into Japanese using a standard forward-backward translation procedure. Two of nine experienced clinicians independently made diagnoses using the interview for each patient in a conjoint session. Discrepancies in diagnosis between two clinicians were resolved by consensus, and the consensus diagnosis was compared with a "best-estimate" diagnosis made by five experienced clinicians using all available data sources for patients who were blinded to the diagnosis using the K-SADS-PL for DSM-5. The "best-estimate" diagnosis of ASD was also based on the Diagnostic Interview for Social and Communication Disorders. RESULTS: The inter-rater reliability was very good, as shown by κ ≥ 0.8 for all disorders examined: autism spectrum disorder (ASD), attention-deficit hyperactivity disorder, tic disorders, selective mutism, enuresis and encopresis. The criterion validity was good, as shown by κ ≥ 0.6 for all disorders examined, except for ASD (κ = 0.59). This study also revealed good construct validity of the instrument by confirming the expected associations with each scale from the Social Responsiveness Scale-2nd edition and the Strengths and Difficulties Questionnaire. CONCLUSION: These results suggest that the K-SADS-PL for DSM-5 generates valid diagnoses in child and adolescent psychiatry.

GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy.

Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10-7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10-8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10-27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.

Comparison of the detection of Helicobacter pylori infection by commercially available serological testing kits and the 13C-urea breath test.

BACKGROUND: Serum Helicobacter pylori (H. pylori) antibody kits (LZ and LIA) using the latex agglutination immunoassay method are commercially available, but few studies have been performed to determine their diagnostic accuracy or to compare their results with those of enzyme-linked immunosorbent assay (ELISA) kits (EP and EIA). METHODS: Sera were obtained from 213 hospital outpatients with dyspeptic symptoms. The serological results were compared with the result of the 13C-urea breath test (UBT) which seems to be reliable. RESULTS: Of the 213 subjects, 154 were diagnosed as positive for H. pylori infection according to the UBT. The sensitivities and specificities of these tests were 97.4% and 76.3%, 98.1% and 78.0%, 99.4% and 74.6%, and 98.1% and 71.2% for the EP, LZ, EIA and LIA tests, respectively. When the 13 subjects whose seropositive results of the four kits were completely opposite to the negative results of the UBT were excluded, the specificities of evaluated kits were all higher than 90%. The concordance rate between the EP and EIA tests was 98.1% (Spearman's rank correlation coefficient = 0.83) and that between the LZ and LIA tests was 97.1% (correlation coefficient = 0.91). The LZ gave higher antibody titer value than EP (p < 0.0001, Z = 9.82; Wilcoxon signed-rank test), and EIA gave higher value than LIA (p < 0.0001, Z = 6.43; Wilcoxon signed-rank test). CONCLUSIONS: The latex immunoassay method provided the same reliability to ELISA in terms of the diagnostic accuracy for current H. pylori infection, although we should take into account the titer value differences by each test method in practical use.

Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. RESULTS: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. CONCLUSION: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

Association of genetic variants of PD1 with recurrent pregnancy loss.

PURPOSE: Programmed cell death 1 (PD1) and PD ligand 1 (PDL1) are speculated to have an important role in maintaining a normal pregnancy and there are also a few reports of an association between the single-nucleotide polymorphisms (SNPs) of PD1 or PDL1 and diseases in humans. The association was examined between the polymorphisms of PD1,PDL1,CTLA4 and recurrent pregnancy loss (RPL). METHODS: The study group consisted of 243 women with two or more pregnancy losses and 176 parous women. The frequency of three SNPs of PD1, two of PDL1, and four of CTLA4 were compared between the patients and controls. Next, the subsequent live birth rates in the patients with RPL with and without risk alleles were examined. RESULTS: Two SNPs (rs36084323 and rs3481962) of PD1 were found to occur at significantly higher frequencies in the patient group than in the control group. The subsequent live birth rate of the patients with vs. without the risk alleles of rs36084323 and rs3481962 were 83.3% vs. 83.3% and 81.6% vs. 84.0%, respectively. CONCLUSION: Variations of the PD1 gene were identified as risk factors for RPL. However, the presence or absence of the PD1 risk alleles had no predictive effect on the subsequent pregnancy outcome.

Effectiveness of a psycho-oncology training program for oncology nurses: a randomized controlled trial.

OBJECTIVE: Oncology nurses are expected to play an important role in psychosocial care for cancer patients. The aim of this study was to examine whether a novel training program aimed at enhancing oncology nurses' ability to assess and manage common psychological problems in cancer patients would improve participants' self-reported confidence, knowledge, and attitudes regarding care of patients with common psychological problems (trial register: UMIN000008559). METHODS: Oncology nurses were assigned randomly to either the intervention group (N = 50) or the waiting list control group (N = 46). The intervention group received a 16-h program, the content of which focused on four psychological issues: normal reactions, clinically significant distress, suicidal thoughts, and delirium. Each session included a role-play exercise, group work, and didactic lecture regarding assessment and management of each problem. Primary outcomes were changes in self-reported confidence, knowledge, and attitudes toward the common psychological problems between pre-intervention and 3 months post-intervention. Secondary outcomes were job-related stress and burnout. Intervention acceptability to participants was also assessed. RESULTS: In the intervention group, confidence and knowledge but not attitudes were significantly improved relative to the control group. No significant intervention effects were found for job- related stress and burnout. A high percentage (98%) of participants considered the program useful in clinical practice. CONCLUSIONS: This psycho-oncology training program improved oncology nurses' confidence and knowledge regarding care for patients with psychological problems. Copyright © 2015 John Wiley & Sons, Ltd.

Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects.

BACKGROUND: Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. METHODS: Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk. RESULTS: Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk. CONCLUSIONS: Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.

Association between shift work and the risk of death from biliary tract cancer in Japanese men.

BACKGROUND: There is increasing evidence suggesting that shift work involving night work may increase cancer risk. METHODS: We examined the association between working rotating shifts and the risk of death from biliary tract cancer among Japanese men who participated in the Japan Collaborative Cohort Study. Of the 46,395 men recruited, 22,224 men aged 40-65 at baseline (1988-1990) who reported working full-time or were self-employed were included in the present analysis. The study subjects were followed through December 31, 2009. Information regarding occupation and lifestyle factors was collected using a self-administered questionnaire. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for the risk of death from biliary tract cancer in relation to shift work. RESULTS: During a mean 17-year follow-up, we observed 94 biliary tract cancer deaths, including 23 deaths from gallbladder cancer and 71 deaths from extrahepatic bile duct cancer. Overall, shift work was associated with a statistically non-significant increase in the risk of biliary tract cancer, with an HR of 1.50 (95 % CI: 0.81-2.77), among rotating shift workers. When the analysis was limited to extrahepatic bile duct cancer, a significant association appeared, with a multivariable-adjusted HR of 1.93 (95 % CI: 1.00-3.72) for rotating shift workers. CONCLUSION: Our data indicate that shift work may be associated with increased risk of death from extrahepatic bile duct cancer in this cohort of Japanese men. The association with gallbladder cancer remains unclear because of the small number of deaths.