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.

Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study used an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability, functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease.

Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer (GU)) or duodenum (duodenal ulcer (DU)). In the present study, we conducted a large-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344 controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU genetic architecture demonstrated that GUs shared the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs, indicating higher heterogeneity of GUs. Helicobacter pylori (HP)-stratified analysis found an HP-related host genetic locus. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD being enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.

Integrated analysis of human DNA methylation, gene expression, and genomic variation in iMETHYL database using kernel tensor decomposition-based unsupervised feature extraction.

Integrating gene expression, DNA methylation, and genomic variants simultaneously without location coincidence (i.e., irrespective of distance from each other) or pairwise coincidence (i.e., direct identification of triplets of gene expression, DNA methylation, and genomic variants, and not integration of pairwise coincidences) is difficult. In this study, we integrated gene expression, DNA methylation, and genome variants from the iMETHYL database using the recently proposed kernel tensor decomposition-based unsupervised feature extraction method with limited computational resources (i.e., short CPU time and small memory requirements). Our methods do not require prior knowledge of the subjects because they are fully unsupervised in that unsupervised tensor decomposition is used. The selected genes and genomic variants were significantly targeted by transcription factors that were biologically enriched in KEGG pathway terms as well as in the intra-related regulatory network. The proposed method is promising for integrated analyses of gene expression, methylation, and genomic variants with limited computational resources.

Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population.

Aims: Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population. Methods: We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate. Results: Genetic variants associated with HbA1c levels were identified in KCNQ1 and TMC6. None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in KCNQ1 with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m2 and BMI < 25 kg/m2. Conclusions: The variant rs2299620 in KCNQ1 might affect HbA1c levels differentially based on BMI grouping in the Japanese population. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00618-0.

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.

Anti-Helicobacter pylori antibody status is associated with cancer mortality: A longitudinal analysis from the Japanese DAIKO prospective cohort study.

Paradoxically, patients with advanced stomach cancer who are Helicobacter pylori-positive (HP+) have a higher survival rate than those who are HP-. This finding suggests that HP infection has beneficial effects for cancer treatment. The present study examines whether HP+ individuals have a lower likelihood of death from cancer than those who are HP-. Prospective cohort data (n = 4,982 subjects enrolled in the DAIKO study between 2008-2010) were used to assess whether anti-HP antibody status was associated with cancer incidence. The median age in the primary registry was 53 years-old (range 35-69 years-old). Over the 8-year observation period there were 234 (4.7%) cancer cases in the cohort and 88 (1.8%) all-cause deaths. Urine anti-HP antibody data was available for all but one participant (n = 4,981; 99.98%). The number of HP+ and HP- individuals was 1,825 (37%) and 3,156 (63%), respectively. Anti-HP antibody distribution per birth year revealed that earlier birth year was associated with higher HP+ rates. With a birth year-matched cohort (n = 3,376), all-cancer incidence was significantly higher in HP+ individuals than those who were HP- (p = 0.00328), whereas there was no significant difference in the cancer death rate between HP+ and HP- individuals (p = 0.888). Cox regression analysis for prognostic factors revealed that the hazards ratio of HP+ was 1.59-fold (95%CI 1.17-2.26) higher than HP- in all-cancer incidence. Potential systemic effects of HP+ status may contribute to reduced likelihood of death for patients after an initial diagnosis of cancer.

Epigenetic profile of Japanese supercentenarians: a cross-sectional study.

BACKGROUND: Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline. METHODS: In this cross-sectional study, we enrolled Japanese non-centenarians (eligible participants aged 20-80 years) from the Tohoku Medical Megabank Community-Based Cohort Study and centenarians and supercentenarians (aged 101-115 years) from the Tokyo Centenarian Study and the Japanese Semi-supercentenarian Study. We assessed participants' whole-blood DNA methylation profiles and then developed sex-specific and non-specific first-generation epigenetic clocks by elastic net regression, calculated individuals' epigenetic ages, and assessed their age acceleration. We also screened for age-related CpG sites in non-centenarians by epigenome-wide linear regression analyses and ANOVA. We subsequently investigated which CpG sites in centenarians and supercentenarians had DNA methylation patterns following the age-related findings obtained from non-centenarians and which did not. We further characterised CpG sites with hypermethylation or hypomethylation in the centenarians and supercentenarians using enrichment and protein-protein interaction network analyses. FINDINGS: We enrolled 421 non-centenarians (231 [55%] women and 190 [45%] men; age range 20-78 years), recruited between May 20, 2013, and March 31, 2016, and 94 centenarians and supercentenarians (66 women [70%] and 28 [30%] men; age range 101-115 years), recruited between Jan 20, 2001, and April 17, 2018. Non-sex-specific epigenetic clock showed the highest accuracy (r=0·96) based on which centenarians and supercentenarians had negative epigenetic age acceleration. Epigenome-wide association analyses further showed that centenarians and supercentenarians had younger-than-expected epigenetic states (DNA methylation profiles similar to those of non-centenarians) for 557 CpG sites enriched in cancer-related and neuropsychiatric-related genes, whereas these individuals had advanced (or older) epigenetic states for 163 CpG sites represented by genes related to TGF-ß signalling, which is involved in anti-inflammatory responses and known to contribute to healthy ageing. INTERPRETATION: These results indicate that exceptionally healthy longevity depends not only on maintaining young epigenetic states but also on advanced states of specific epigenetic regions. FUNDING: The Japan Agency for Medical Research and Development, KDDI Research, and Keio University. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

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.

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.

Evaluation of short-term epigenetic age fluctuation.

Considerable effort has been spent on lowering and maintaining the epigenetic age. However, the extent to which epigenetic age fluctuates under normal conditions is poorly understood. Therefore, we analyzed methylation data from monocytes and peripheral blood mononuclear cells collected from two Japanese men. The ranges of the Pan-tissue, Skin and blood, and DNAm PhenoAge epigenetic age during 3 months were ≥ 5.62, ≥ 3.04, and ≥ 8.23 years, and the maximum daily changes were 5.21, 3.20, and 6.53 years, respectively. These fluctuations were not suppressed by correcting for cell-type composition. Although the underlying biological mechanism remains unclear, there was a nonnegligible degree of age fluctuation which should inform personalized clinical applications.

Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats.

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

A genome-wide association study on adherence to low-carbohydrate diets in Japanese.

BACKGROUND/OBJECTIVES: Low-carbohydrate diets (LCD) are useful for weight reduction, and 50-55% carbohydrate consumption is associated with minimal risk. Genetic differences were related to nutritional consumption, food preferences, and dietary patterns, but whether particular genetic differences in individuals influence LCD adherence is unknown. SUBJECTS/METHODS: We conducted a GWAS on adherence to LCD utilizing 14,076 participants from the Japan Multi-Institutional Collaborative Cohort study. We used a previously validated semiquantitative food frequency questionnaire to estimate food consumption. Association of the imputed variants with the LCD score by Halton et al. we used linear regression analysis adjusting for sex, age, total dietary energy consumption, and components 1 to 10 by principal component analysis. We repeated the analysis with adjustment for alcohol consumption (g/day) in addition to the above-described variables. RESULTS: Men and women combined analysis without adjustment for alcohol consumption; we found 395 variants on chromosome 12 associated with the LCD score having P values <5 × 10-8. A conditional analysis with the addition of the dosage data of rs671 on chromosome 12 as a covariate, P values for all 395 SNPs on chromosome 12 turned out to be insignificant. In the analysis with additional adjustment for alcohol consumption, we did not identify any SNPs associated with the LCD score. CONCLUSION: We found rs671 was inversely associated with adherence to LCD, but that was strongly confounded by alcohol consumption.

DNA Methylation Abnormalities and Altered Whole Transcriptome Profiles after Switching from Combustible Tobacco Smoking to Heated Tobacco Products.

BACKGROUND: The use of heated tobacco products (HTP) has increased exponentially in Japan since 2016; however, their effects on health remain a major concern. METHODS: Tsuruoka Metabolome Cohort Study participants (n = 11,002) were grouped on the basis of their smoking habits as never smokers (NS), past smokers (PS), combustible tobacco smokers (CS), and HTP users for <2 years. Peripheral blood mononuclear cells were collected from 52 participants per group matched to HTP users using propensity scores, and DNA and RNA were purified from the samples. DNA methylation (DNAm) analysis of the 17 smoking-associated DNAm biomarker genes (such as AHRR, F2RL3, LRRN3, and GPR15), as well as whole transcriptome analysis, was performed. RESULTS: Ten of the 17 genes were significantly hypomethylated in CS and HTP users compared with NS, among which AHRR, F2RL3, and RARA showed intermediate characteristics between CS and NS; nonetheless, AHRR expression was significantly higher in CS than in the other three groups. Conversely, LRRN3 and GPR15 were more hypomethylated in HTP users than in NS, and GPR15 expression was markedly upregulated in all the groups when compared with that in NS. CONCLUSIONS: HTP users (switched from CS <2 years) display abnormal DNAm and transcriptome profiles, albeit to a lesser extent than the CS. However, because the molecular genetic effects of long-term HTP use are still unknown, long-term molecular epidemiologic studies are needed. IMPACT: This study provides new insights into the molecular genetic effects on DNAm and transcriptome profiles in HTP users who switched from CS.

Low MICA Gene Expression Confers an Increased Risk of Graves' Disease: A Mendelian Randomization Study.

Background: Expression of natural killer group 2 member D (NKG2D) ligand (NKG2DL) plays a major role as a "danger signal" on stressed cells to promote removal of the latter by NKG2D-expressing cytotoxic lymphocytes. NKG2DL expression has been found in peripheral immune cells as well, such as in macrophages; however, the effect of this expression is yet to be determined. Methods: We determined instrumental variables (IVs; R2 <0.01 in linkage disequilibrium), explaining the major variance in major histocompatibility complex class I chain-related protein A (MICA) and B (MICB) gene expression levels from the expression-quantitative trait locus (eQTL) of NKG2DLs based on the RNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from 381 Japanese. Simultaneously, the target outcomes were filtered by PheWAS from 58 health risks, using a community-based cohort study composed of 44,739 Japanese residents. Finally, we estimated the causal effect of gene expression levels on the outcomes using the Mendelian randomization approach. Results: We determined nine and four IVs, explaining 87.6% and 33.0% of MICA and MICB gene expression levels, respectively. In the association test, we identified 10 or 13 significant outcomes associated with the MICA or MICB eQTLs, respectively, as well as the causal effect of MICA expression on Graves' disease (GD) (p = 4.2 × 10-3; odds ratio per 1 S.D. difference in the expression: 0.983 [confidence interval: 0.971-0.995]), using the weighted median estimator, without significant pleiotropy (p > 0.05), and the results were consistent across the sensitivity analyses. Conclusions: Our study provide novel evidence associating NKG2DL expression with GD, an autoimmune thyroiditis; direction of the effect indicated the immunoregulatory role of MICA expression in PBMCs, suggesting the importance of further functional assays in inflammatory diseases.

Longitudinal DNA methylation dynamics as a practical indicator in clinical epigenetics.

BACKGROUND: One of the fundamental assumptions of DNA methylation in clinical epigenetics is that DNA methylation status can change over time with or without interplay with environmental and clinical conditions. However, little is known about how DNA methylation status changes over time under ordinary environmental and clinical conditions. In this study, we revisited the high frequency longitudinal DNA methylation data of two Japanese males (24 time-points within three months) and characterized the longitudinal dynamics. RESULTS: The results showed that the majority of CpGs on Illumina HumanMethylation450 BeadChip probe set were longitudinally stable over the time period of three months. Focusing on dynamic and stable CpGs extracted from datasets, dynamic CpGs were more likely to be reported as epigenome-wide association study (EWAS) markers of various traits, especially those of immune- and inflammatory-related traits; meanwhile, the stable CpGs were enriched in metabolism-related genes and were less likely to be EWAS markers, indicating that the stable CpGs are stable both in the short-term within individuals and under various environmental and clinical conditions. CONCLUSIONS: This study indicates that CpGs with different stabilities are involved in different functions and traits, and thus, they are potential indicators that can be applied for clinical epigenetic studies to outline underlying mechanisms.

A genome-wide association study on meat consumption in a Japanese population: the Japan Multi-Institutional Collaborative Cohort study.

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

Body mass index and colorectal cancer risk: A Mendelian randomization study.

Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.