Plasma Albumin, Bilirubin, and Uric Acid and the Subsequent Risk of Cancer: A Case-Cohort Study in the Japan Public Health Center-based Prospective Study.

Several epidemiological studies have investigated the circulating levels of albumin, bilirubin, and uric acid (UA) in relation to cancer risk; however, they have provided equivocal evidence. In this prospective case-cohort study, we aimed to explore the association of plasma albumin, bilirubin, and UA levels with cancer incidence. We measured the plasma levels of albumin, bilirubin, and UA and investigated their association with cancer incidence in 3,584 cases and 4,270 randomly selected participants with a median follow-up of 15.8 years. The adjusted hazard ratios (HR) and 95% confidence intervals (CI) of total cancer for the highest (Q4) versus lowest quartile (Q1) was 0.77 (95% CI: 0.67-0.90, P for trend: <0.001) for albumin. This association was attenuated after excluding liver cancer cases with lower plasma albumin levels. Plasma bilirubin levels were positively related to liver cancer but inversely to total cancer after excluding liver cancer with adjusted HR Q4 vs. Q1 of 0.86 (95% CI: 0.74-0.99, P for trend = 0.015). Plasma UA levels were not dose-responsively associated with total cancer risk. Higher plasma bilirubin levels were associated with a decreased risk of total cancer after excluding liver cancer, which is likely attributed to the antioxidant properties of bilirubin.

GWAS meta-analysis of kidney function traits in Japanese populations.

BACKGROUND: Genetic epidemiological evidence for the kidney function traits in East Asian population including Japanese remain still relatively unclarified. Especially, the number of GWASs for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. METHODS: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). RESULTS: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; p < 5×10-8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; p < 5×10-8), of which one locus (more than 1Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. CONCLUSIONS: The present GWAS meta-analysis of largest genome cohort studies in Japanese provided some original genomic loci associated with kidney function in Japanese, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people.

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

Three-dimensional morphological analysis of the human spleen and its surrounding organs during the early fetal period.

The spleen has variations in its morphology and is considered to acquire a defined shape in the third month of gestation. However, few studies have investigated spleen development during the first 3 months of fetal life. This study aimed to determine the three-dimensional (3D) morphogenesis of the spleen during the third month of gestation. In this study, 30 fetal specimens (crown-rump length [CRL]: 22-103 mm) were subjected to magnetic resonance imaging analysis. We manually segmented the spleen, stomach, and adrenal gland, reconstructed 3D models, and analyzed the volume and shape of these organs. The results showed that the variation in spleen size was large compared to that in other organs. Spleen morphology was classified into six types based on the number of splenic surfaces as follows: two-faced, three-faced, four-faced, five-faced, ovoid, and irregular. Two-faced spleens were only observed in small specimens, whereas three- and four-faced spleens were observed in larger specimens. We also revealed that the number of fetal splenic surfaces increased as CRL enlarged. Additionally, 3D models indicated that some specimens formed their splenic surfaces without contact with the adjacent organs. This suggested that the splenic surface may be caused not only by pressure from the faced organs but also by an intrinsic program. This study may provide a better understanding of the normal development of the spleen during the early fetal period, and may potentially assist future studies in investigating congenital morphological anomalies of the spleen.

Smoking and risk of colorectal cancer according to KRAS and BRAF mutation status in a Japanese prospective Study.

Although smoking is a major modifiable risk factor for many types of cancer, evidence for colorectal cancer is equivocal in Asian populations. Recent Western studies have proposed that the association between smoking and colorectal cancer is restricted to specific tumor molecular subtypes. However, no studies have evaluated the association according to tumor molecular subtypes in Asian populations. In a Japanese prospective population-based cohort study of 18 773 participants, we collected tumor tissues from incident colorectal cancer cases and evaluated KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B) mutation status using target sequencing. Multivariable-adjusted Cox proportional hazard model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of smoking with the risk of overall colorectal cancer and its subtypes defined by KRAS and BRAF mutation status. Among 339 cases, KRAS and BRAF mutations were identified in 164 (48.4%) and 16 (4.7%) cases, respectively. The multivariable-adjusted HR for ever smoking compared with never smoking was 1.24 [95% CI: 0.93-1.66], 1.75 [1.14-2.68], 0.87 [0.59-1.29], 1.24 [0.93-1.67] and 1.22 [0.38-3.93] for overall, KRAS wild-type, KRAS-mutated, BRAF wild-type and BRAF-mutated colorectal cancer, respectively. The statistically significant heterogeneity was indicated between KRAS mutation status (Pheterogeneity = 0.01) but not between BRAF mutation status. This study is the first to demonstrate that smokers have an approximately 2-fold higher risk of KRAS wild-type colorectal cancer than never smokers in an Asian population. Our findings support that smoking is a risk factor for colorectal cancer, especially for its subtype without KRAS mutations, in Asian populations.

Investigating the association between glycaemic traits and colorectal cancer in the Japanese population using Mendelian randomisation.

Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer; however, the causal association remains unknown, particularly in Asian populations. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. The odds ratios of colorectal cancer were 1.01 (95% confidence interval [CI], 0.99-1.04, P = 0.34) for fasting glucose (per 1 mg/dL increment), 1.02 (95% CI, 0.60-1.73, P = 0.95) for HbA1c (per 1% increment), and 1.47 (95% CI, 0.97-2.24, P = 0.06) for fasting C-peptide (per 1 log increment). Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer (P > 0.20). In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. The potential association between insulin resistance and colorectal cancer should be validated in further studies.

Association of 25-hydroxyvitamin D with risk of overall and colorectal cancer among Japanese using a Mendelian randomization approach.

The association between vitamin D and total and colorectal cancer risk was inconsistent in observational studies. We conducted Mendelian randomization approach in which the effect of confounding might be reduced. 110 single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D concentrations were systematically selected according to the "GWAS Catalog" from all ethnic populations. For the SNP-vitamin D concentration association, 3978 individuals from two Japanese cohorts were included. Regarding SNP-total and colorectal cancer association, 4543 cancer cases and 14,224 controls and 7936 colorectal cancer cases and 38,042 controls, respectively were included from the Japanese Consortium of Genetic Epidemiology and other studies in Japan. There was no significant association between the genetically predicted plasma 25-hydroxyvitamin D concentration and total or colorectal cancer in any of the MR analyses. Odds ratios per doubling in vitamin D concentration were 0.83 (95% confidence interval [CI] 0.63-1.09) for total cancer and 1.00 (95% CI 0.80-1.24) for colorectal cancer in inverse variance weighted method, 0.83 (95% CI 0.57-1.19) for total cancer and 1.01 (95% CI 0.75-1.37) for colorectal cancer in MR-Egger method. Consistent with previous MR analyses among European ancestries, there was no significant association identified between 25-hydroxyvitamin D levels and total or colorectal cancer among Asians.

Development and validation of genome-wide polygenic risk scores for predicting breast cancer incidence in Japanese females: a population-based case-cohort study.

PURPOSE: This study aimed to develop an ancestry-specific polygenic risk scores (PRSs) for the prediction of breast cancer events in Japanese females and validate it in a longitudinal cohort study. METHODS: Using publicly available summary statistics of female breast cancer genome-wide association study (GWAS) of Japanese and European ancestries, we, respectively, developed 31 candidate genome-wide PRSs using pruning and thresholding (P + T) and LDpred methods with varying parameters. Among the candidate PRS models, the best model was selected using a case-cohort dataset (63 breast cancer cases and 2213 sub-cohorts of Japanese females during a median follow-up of 11.9 years) according to the maximal predictive ability by Harrell's C-statistics. The best-performing PRS for each derivation GWAS was evaluated in another independent case-cohort dataset (260 breast cancer cases and 7845 sub-cohorts of Japanese females during a median follow-up of 16.9 years). RESULTS: For the best PRS model involving 46,861 single nucleotide polymorphisms (SNPs; P + T method with PT = 0.05 and R2 = 0.2) derived from Japanese-ancestry GWAS, the Harrell's C-statistic was 0.598 ± 0.018 in the evaluation dataset. The age-adjusted hazard ratio for breast cancer in females with the highest PRS quintile compared with those in the lowest PRS quintile was 2.47 (95% confidence intervals, 1.64-3.70). The PRS constructed using Japanese-ancestry GWAS demonstrated better predictive performance for breast cancer in Japanese females than that using European-ancestry GWAS (Harrell's C-statistics 0.598 versus 0.586). CONCLUSION: This study developed a breast cancer PRS for Japanese females and demonstrated the usefulness of the PRS for breast cancer risk stratification.

Association Between Glycemic Traits and Primary Open-Angle Glaucoma: A Mendelian Randomization Study in the Japanese Population.

PURPOSE: A meta-analysis suggests a relationship between abnormal glucose metabolism and primary open-angle glaucoma (POAG); however, the causal association between them remains controversial. We therefore conducted a Mendelian randomization (MR) study to assess the causal association between genetically predicted glycemic traits and the risk of POAG. DESIGN: Two-sample MR design. METHODS: We examined the genetically predicted measures of fasting glucose, hemoglobin A1c (HbA1c), and fasting C-peptide, in relation to POAG. For the single nucleotide polymorphism (SNP)-exposure analyses, we meta-analyzed the study-level genome-wide associations of fasting glucose levels (n = 17,289; n of SNPs = 34), HbA1c (n = 52,802; n of SNPs = 43), and fasting C-peptide levels (n=1666; n of SNPs = 17) from the Japanese Consortium of Genetic Epidemiology studies. We used summary statistics from the BioBank Japan projects (n = 3980 POAG cases and 18,815 controls) for the SNP-outcome association. RESULTS: We observed no association of genetically predicted HbA1c and fasting C-peptide with POAG. The MR inverse-variance-weighted (IVW) odds ratios (ORs) were 1.44 (95% confidence interval [CI], 0.78-2.65; P = .25) for HbA1c (per 1% increment) and 0.92 (95% CI, 0.56-1.53; P = .76) for fasting C-peptide (per 2-fold increment). A significant association between fasting glucose (per 10 mg/dL-increment) and POAG was observed according to the MR IVW analysis (OR = 1.48 [95% CI, 1.10-1.79, P = .009]); however, sensitivity analyses, including MR-Egger and weighted-median methods, did not support this association (P > .10). CONCLUSIONS: We did not observe strong evidence to support the association between genetically predicted glycemic traits and POAG in the Japanese population.

p53 Arg72Pro polymorphism, adiposity status, and cancer risk: Two case-cohorts within a Japanese prospective study.

The tumor suppressor protein, p53, is a critical molecule involved in cancer development. However, the association between p53 Arg72Pro polymorphism and cancer risk remains unclear, possibly due to the pro-tumor potential of p53 under metabolic stress. Here, we hypothesized that the p53 Arg72Pro polymorphism plays different roles during tumorigenesis by adiposity status. We measured baseline body mass index (BMI) and p53 Arg72Pro polymorphism for two case-cohorts, which included 4264 cancers with up to 20 years of follow-up. Multivariable-adjusted hazard ratios (HRs) and confidence intervals (CIs) were estimated using weighted Cox proportional-hazards method. Without consideration of adiposity status, p53 Arg72Pro polymorphism was not associated with cancer risk. However, proline (Pro) homozygous genotype conferred an increased cancer risk for individuals with a BMI <25 kg/m2 (HR [95% CI]: 1.12 [1.00-1.26] for total cancer and 1.19 [1.02-1.38] for obesity-related cancer), but not for those with a BMI ≥ 25 kg/m2 . The heterogeneous effect of p53 Arg72Pro polymorphism on cancer risk according to adiposity status was indicated (pheterogeneity : 0.07 for total cancer and 0.03 for obesity-related cancer). Furthermore, the association between overweight and cancer risk was only observed in arginine (Arg) carriers, but not in Pro homozygous carriers (pheterogeneity : 0.07 for total cancer and 0.02 for obesity-related cancer). Pro homozygous carriers were more likely to be predisposed to cancer than Arg carriers with normal-weight conditions. In addition, overweight was related to a higher cancer risk in Arg carriers than Pro homozygous carriers. Our findings may suggest the adiposity-dependent dual effects of p53 Arg72Pro polymorphism during tumorigenesis.

Blood Lipids and the Risk of Colorectal Cancer: Mendelian Randomization Analyses in the Japanese Consortium of Genetic Epidemiology Studies.

The associations between blood lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and low-density lipoprotein cholesterol (LDL-C), and colorectal cancer risk are controversial. We evaluated potential causal relationships between blood lipids and colorectal cancer risk. Using the baseline data from the Japanese Consortium of Genetic Epidemiology studies, we estimated the single-nucleotide polymorphism (SNP)-exposure associations (n = 34,546 for TC, n = 50,290 for HDL-C, n = 51,307 for triglycerides, and n = 30,305 for LDL-C). We also estimated the SNP-outcome associations in another Japanese dataset (n = 7,936 colorectal cancer cases and n = 38,042 controls). We conducted Mendelian randomization (MR) analyses for the association between each blood lipid type and the risk of colorectal cancer using an inverse variance-weighted method. The total variances explained by the selected SNPs in TC (68 SNPs), HDL-C (50 SNPs), log-transformed triglycerides (26 SNPs), and LDL-C (35 SNPs) were 7.0%, 10.0%, 6.2%, and 5.7%, respectively. The odds ratios for colorectal cancer were 1.15 [95% confidence interval (CI), 1.01-1.32] per 1 standard deviation (SD; 33.3 mg/dL) increase in TC, 1.11 (95% CI, 0.98-1.26) per 1 SD (15.4 mg/dL) increase in HDL-C, 1.06 (95% CI, 0.90-1.26) per 1 SD (0.5 log-mg/dL) increase in log-transformed triglycerides, and 1.17 (95% CI, 0.91-1.50) per 1 SD (29.6 mg/dL) increase in LDL-C. Sensitivity analyses consistently suggested the positive association between TC and colorectal cancer, whereas results of each lipid component were inconsistent. In conclusion, this large MR study of a Japanese population showed a potentially causal association between high TC and colorectal cancer risk, although the association between each lipid component and colorectal cancer remained inconclusive. PREVENTION RELEVANCE: In this large MR analysis of a Japanese population, a positive association was found between genetically predicted high total cholesterol (TC) levels and an increased risk of colorectal cancer. Therefore, lowering TC levels by lifestyle modifications or medications may be justified for the purpose of preventing colorectal cancer.

Association of Plasma Iron Status with Subsequent Risk of Total and Site-Specific Cancer: A Large Case-Cohort Study within JPHC Study.

It is unclear whether prediagnostic iron-related biomarkers in circulation are associated with cancer risk. We constructed a case-cohort of participants who had plasma samples available from the Japan Public Health Center-based Prospective Study and determined the incidence of cancer in these participants. We measured plasma concentrations of iron, ferritin, and hepcidin, and assessed the association between each biomarker and cancer incidence using a weighted Cox regression model. There were 4,253 participants in the sub-cohort (the randomly selected participants from an eligible, at-risk population) and 3,596 incident cancer cases (499 cases occurred in the sub-cohort). Median follow-up was for 16.5 years. In the multivariable adjusted analysis, iron deficiency (plasma ferritin <30 ng/mL) was associated with a higher risk of total cancer [adjusted HR, 1.23; 95% confidence interval (CI), 1.07-1.42] and the association was weaker after excluding those followed-up for <3 years. Iron overload was not significantly associated with total cancer (HR, 1.04; 95% CI, 0.82-1.33), but was associated with liver cancer (HR, 4.49; 95% CI, 2.71-7.43). Lower plasma levels of hepcidin and ferritin are associated with an increased gastrointestinal cancer risk. Meanwhile, lower plasma hepcidin and higher plasma ferritin levels were associated with an increased liver cancer risk. In conclusion, there was no association between iron overload and cancer risk, besides liver cancer. PREVENTION RELEVANCE: High ferritin and low hepcidin levels in the plasma were associated with increased liver cancer risk. Evaluating iron metabolism including hepcidin levels may help identify people with high liver cancer risk.

A transcription factor PU.1 is critical for Ccl22 gene expression in dendritic cells and macrophages.

The chemokine CCL22 is predominantly produced by dendritic cells (DCs) and macrophages. CCL22 acts on CCR4-expressing cells including Th2 and Treg. Although a correlation between the CCL22-CCR4 axis and allergic diseases has been established, the mechanism of monocyte lineage-specific Ccl22 gene expression is largely unknown. In the current study, we investigated transcriptional regulation of the Ccl22 gene in DCs and macrophages. Using reporter assays, we identified the critical cis-enhancing elements at 21/-18 and -10/-4 in the Ccl22 promoter. Electrophoretic mobility shift assays proved that transcription factor PU.1 directly binds to the cis-elements. Knockdown of PU.1 markedly decreased Ccl22 expression in bone marrow-derived DCs (BMDCs) and BM macrophages (BMDMs). Chromatin immunoprecipitation assays revealed that PU.1 bound to the Ccl22 promoter in not only BMDCs and BMDMs, but also splenic DCs and peritoneal macrophages. LPS stimulation increased the amount of PU.1 recruited to the promoter, accompanied by upregulation of the Ccl22 mRNA level, which was diminished by Spi1 knockdown. We identified similar cis-elements on the human CCL22 promoter, which were bound with PU.1 in human monocytes. Taken together, these findings indicate that PU.1 transactivates the Ccl22 gene in DCs and macrophages by directly binding to the two elements in the promoter.

Novel Imaging Modalities for Human Embryology and Applications in Education.

Advances in imaging technology and development have recently enabled high-resolution three-dimensional (3D) imaging of embryos and fetuses. Embryos and fetuses stored at the Congenital Anomaly Research Center (Kyoto Collection of Human Embryos, Kyoto, Japan) were imaged using multiple modalities including magnetic resonance imaging, episcopic fluorescence image capture, and X-ray computed tomography, both in absorption and phase-contrasted configurations. Using the acquired images, 3D computer graphics were generated and a movie was created to gain further insight into understanding the developmental process. For educational purposes, self-learning materials were also produced. The present review article briefly discusses each project and the results of imaging studies performed using specimens from the Kyoto Collection of Human Embryos. Anat Rec, 301:1004-1011, 2018. © 2018 Wiley Periodicals, Inc.

The Influence of Olfactory Contexts on the Sequential Rating of Odor Pleasantness.

When we sequentially evaluate the characteristics of sensory stimuli, our evaluation of a current stimulus is influenced by those preceding it. One such effect is called hedonic contrast, whereby stimuli are rated more negatively (negative contrast) or positively (positive contrast) if they are preceded by more or less pleasant stimuli. The present study investigated the characteristics of hedonic contrast for olfaction and compared these characteristics with those of a more oft-studied modality, vision. The results from two experiments indicated that both positive and negative contrasts occurred in the sequential rating of picture pleasantness, whereas only negative contrast occurred for olfactory ratings. Notably, overrating of hedonically negative odors following a positive olfactory context was observed even when participants had already rated these same negative odors beforehand; conversely, this did not occur for positive contrast for either sense. These findings indicate that negative odors are more strongly influenced than positive ones, and the rating of positive stimuli may be adjusted to the preceding rating independent of stimulus context. The findings of this study revealed the unique characteristics of hedonic contrast for the olfactory senses.