Scoring system to predict positive peritoneal cytology in patients with resectable and borderline resectable pancreatic cancer.

BACKGROUND: The aim of this study was to evaluate factors to predict positive peritoneal cytology, whcih would determine the indication for staging laparoscopy in pancreatic cancer. METHODS: A total of 430 patients that underwent pancreatectomy for resectable and borderline resectable pancreatic cancer were retrospectively reviewed. RESULTS: Among 430 patients, 36 had positive cytology (8.4%). Median survival time in negative cytology was 24.7 months, compared with 15.1 months in positive cytology (p = .004). Factors to predict positive cytology in pancreatic cancer according to multivariate analysis were tumor location (body, tail; OR 2.66; 95% CI: 1.21-5.85; p = .015), tumor size ≥30 mm (OR 2.95; 95% CI: 1.35-6.47; p = .007) and radiographic other-organ invasion (HR 2.79; 95% CI: 1.01-7.67; p = .047). Patients were scored 0 to 3 corresponding with these factors. Rates of positive cytology increases in each score were: score 0: 2.9%, score 1: 6.7%, score 2: 18.3%, score 3: 36.8%. CONCLUSIONS: Tumor location (body or tail), tumor size ≥30 mm, and radiographic other-organ invasions were risk factors for positive cytology in pancreatic cancer. This scoring system might be a useful indicator to perform staging laparoscopy to diagnose positive cytology.

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.

The Health History of First-Degree Relatives' Dyslipidemia Can Affect Preferences and Intentions following the Return of Genomic Results for Monogenic Familial Hypercholesterolemia.

Genetic testing is key in modern healthcare, particularly for monogenic disorders such as familial hypercholesterolemia. This Tohoku Medical Megabank Project study explored the impact of first-degree relatives' dyslipidemia history on individual responses to familial hypercholesterolemia genomic results. Involving 214 participants and using Japan's 3.5KJPN genome reference panel, the study assessed preferences and intentions regarding familial hypercholesterolemia genetic testing results. The data revealed a significant inclination among participants with a family history of dyslipidemia to share their genetic test results, with more than 80% of participants intending to share positive results with their partners and children and 98.1% acknowledging the usefulness of positive results for personal health management. The study underscores the importance of family health history in genetic-testing perceptions, highlighting the need for family-centered approaches in genetic counseling and healthcare. Notable study limitations include the regional scope and reliance on questionnaire data. The study results emphasize the association between family health history and genetic-testing attitudes and decisions.

Relationship between traditional risk factors for hypertension and systolic blood pressure in the Tohoku Medical Megabank Community-based Cohort Study.

Risk factors for hypertension have been emphasized in the Japanese Society of Hypertension Guidelines for the Management of Hypertension. However, large-scale studies on the association of smoking, potassium excretion, and gamma-glutamyl transferase level with BP in the Japanese population are limited. We conducted a cross-sectional study to examine the association between hypertension risk factors and systolic blood pressure in the Tohoku Medical Megabank Community-based Cohort Study (23,446 men and 38,921 women aged ≥20 years). A model adjusted for age, body mass index, smoking status, drinking status, estimated daily salt intake, potassium excretion, (or urinary sodium-to-potassium ratio), gamma-glutamyl transferase, physical activity, education level, status of damage to homes during the Great East Japan Earthquake, and residential areas was used. The average age and systolic blood pressure were 62.5 (10.3) years for men and 59.6 (11.3) years for women, 128.9 (16.7) mmHg for men and 124.7 (17.5) mmHg for women, respectively. Body mass index estimated daily salt intake, urinary sodium-to-potassium ratio and gamma-glutamyl transferase levels were positively associated with systolic blood pressure. Compared with never-drinkers, current drinkers who consumed 23-45 g/day and ≥46.0 g/day had significantly increased systolic blood pressure. Conversely, current smokers (1-10 cigarettes/day and 11-20 cigarettes/day) were inversely associated with systolic blood pressure compared to never-smokers. Overall, systolic blood pressure was associated with gamma-glutamyl transferase and hypertension risk factors, including body mass index, alcohol consumption, estimated daily salt intake, urinary sodium-to-potassium ratio, and potassium excretion. Our findings support the notion that lifestyle modifications should be attempted to prevent hypertension.

Correlation between breast cancer and background parenchymal uptake on 18F-fluorodeoxyglucose positron emission tomography.

PURPOSE: This study aimed to investigate differences in background parenchymal uptake (BPU) between patients with and without breast cancer using 18F-fluorodeoxyglucose positron emission tomography. METHODS: Female patients (n = 130, 62.9 ± 12.7 years) with newly diagnosed breast cancer and 50 healthy participants (59.6 ± 13.3 years) without breast cancer were retrospectively included. BPU was evaluated using the maximum standardized uptake value. Data on participant age, body mass index, blood glucose level, and menopausal status were collected from medical records. Breast density was evaluated using mammography. Logistic regression analysis and receiver operating characteristic curves were used to examine the correlation between breast cancer and various characteristic factors, including BPU. RESULTS: The BPU of patients with breast cancer was significantly higher than that of controls (P < 0.001). The results of logistic regression analysis regarding the presence of breast cancer demonstrated that BPU and menopausal status showed higher odds ratios of 13.6 and 4.25, respectively. The area under the receiver operating characteristic curve for BPU was 0.751. CONCLUSIONS: Patients with breast cancer showed higher 18F-fluorodeoxyglucose-BPU. Glucose metabolism of mammary glands may correlate with the development of breast cancer.

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.

Short-term serial circulating tumor DNA assessment predicts therapeutic efficacy for patients with advanced pancreatic cancer.

PURPOSE: We investigated the potential clinical utility of short-term serial KRAS-mutated circulating cell-free tumor DNA (ctDNA) assessment for predicting therapeutic response in patients undergoing first-line chemotherapy for advanced pancreatic cancer. METHODS: We collected 144 blood samples from 18 patients with locally advanced or metastatic cancer that were undergoing initial first-line chemotherapy of gemcitabine plus nab-paclitaxel (GEM plus nab-PTX). Analysis of KRAS-mutated ctDNA was quantified by digital droplet polymerase chain reaction (ddPCR) as mutant allele frequency (MAF). This study investigated pretreatment KRAS-mutated ctDNA status and ctDNA kinetics every few days (days 1, 3, 5 and 7) after initiation of chemotherapy and their potential as predictive indicators. RESULTS: Of the 18 enrolled patients, an increase in KRAS-mutated ctDNA MAF values from day 0-7 after initiation of chemotherapy was significantly associated with disease progression (P < 0.001). Meanwhile, positive pretreatment ctDNA status (MAF ≥ 0.02%) (P = 0.585) and carbohydrate antigen 19-9 (CA19-9) values above the median (P = 0.266) were not associated with disease progression. In univariate analysis, this short-term increase in ctDNA MAF values (day 0-7) was found to be associated with significantly shorter progression free survival (PFS) (hazard ration [HR], 24.234; range, (2.761-212.686); P = 0.0002). CONCLUSION: This short-term ctDNA kinetics assessment may provide predictive information to reflect real-time therapeutic response and lead to effective refinement of regimen in patients with advanced pancreatic cancer undergoing systemic chemotherapy.

jMorp: Japanese Multi-Omics Reference Panel update report 2023.

Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.

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.

Metabolomics profiles alterations in cigarette smokers and heated tobacco product users.

BACKGROUND: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment. METHODS: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey. RESULTS: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels. CONCLUSIONS: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

Association between vascular endothelial dysfunction and stroke incidence in the general Japanese population: Results from the tohoku medical megabank community-based cohort study.

Background: Flow-mediated dilation (FMD) measures vascular endothelial function by evaluating the vasodilatory response of blood vessels to increased blood flow. Nevertheless, the association between FMD and stroke incidence in a general population remains unclear. This study investigated the association between vascular endothelial function and stroke incidence in the general Japanese population. Methods: Based on cohort data from the Tohoku Medical Megabank Community-based Cohort Study, participants aged ≥18 years were recruited from Iwate Prefecture, with the final sample comprising 2952 subjects. Results: The FMD level was 0.5%-27.1%, with a median of 5.0% (interquartile, 4.2%-11.3%). The mean follow-up period was 5.5 ± 1.8 years (range, 0.6-6.9 years). After dividing the participants into two subgroups according to the median FMD value, a multivariate Cox regression analysis adjusting for gender, age, smoking, alcohol consumption, systolic blood pressure, low-density lipoprotein cholesterol, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin T and hemoglobin A1c revealed that a lower FMD value was strongly associated with incidences of total stroke (hazard ratio[HR] = 2.13, 95% confidence interval[CI] = 1.48-3.07, p < 0.001), ischemic stroke (HR = 3.33, 95%CI = 2.00-5.52, p < 0.001), nonlacunar stroke (HR = 2.77, 95%CI = 1.49-5.16, p = 0.001), and lacunar stroke (HR = 5.12, 95%CI = 1.74-16.05, p = 0.003). Conclusions: This study showed that a low FMD value might reflect vascular endothelial dysfunction and then was associated with ischemic stroke incidence in the general Japanese population, suggesting that FMD can be used as a tool to identify future stroke risk.

Remnant liver function is associated with long-term survival in patients with hepatocellular carcinoma undergoing hepatectomy.

It is important to assess the prognosis and intervene before and after surgery in patients with hepatocellular carcinoma. This study aims to elucidate the association of outcomes and residual liver function after hepatectomy. A total of 176 patients who underwent the initial resection for hepatocellular carcinoma between January 2011 and March 2021 at Jichi Medical University were included. Hepatic clearance of the remnant liver was measured using 99mTc-galactosyl serum albumin scintigraphy. The log-rank test was used to analyze survival using the Kaplan-Meier method. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival were calculated using Cox's proportional hazard model. In multivariate analysis, microvascular invasion, intraoperative blood loss, and hepatic clearance of the remnant liver were independently associated with overall survival. Hepatic clearance of the remnant liver was independently associated with recurrence free survival. This is the first report to show that lower residual liver function is associated with shorter survival in patients with hepatocellular carcinoma undergoing hepatectomy. Preoperative determination of remnant liver function may allow assessment of prognosis in patients planned to undergo resection of hepatocellular carcinoma. Preservation of liver functional reserve may be crucial for improved long-term outcomes after hepatectomy.

Impact of patient characteristic factors on the dynamics of liver glucose metabolism: Evaluation of multiparametric imaging with dynamic whole-body 18 F-fluorodeoxyglucose-positron emission tomography.

AIMS: To assess the impact of various patient characteristics on the dynamics of liver glucose metabolism using automated multiparametric imaging with whole-body dynamic 18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). MATERIALS AND METHODS: We retrospectively enrolled 540 patients who underwent whole-body dynamic FDG-PET. Three quantitative indices representing hepatic glucose metabolism [mean standardized uptake value normalized by lean body mass (SULmean), metabolic glucose rate (kinetic index) and distribution volume (DV)] were measured from multiparametric PET images produced automatically based on the Patlak plot model. Patient characteristics including age, sex, body mass index, fasting time, blood glucose level, and the presence of diabetes mellitus (DM) or hepatic steatosis (HS) were collected. We examined the correlations between the characteristic factors and three quantitative indices using multiple regression analysis. RESULTS: The success rate of kinetic analysis using multiparametric PET imaging was 93.3% (504/540). Hepatic SULmean was significantly correlated with age (p < .001), sex (p < .001) and blood glucose level (p = .002). DV was significantly correlated with age (p = .033), sex (p < .001), body mass index (p = .002), fasting time (p = .043) and the presence of HS (p = .002). The kinetic index was significantly correlated with age (p < .001) and sex (p = .004). In the comparison of the healthy, DM and HS groups, patients with DM had a significantly increased SULmean, whereas patients with HS had a significantly decreased DV. CONCLUSIONS: Our results showed that liver glucose metabolism was influenced by various patient characteristic factors. Multiparametric FDG-PET imaging can be used to analyse the kinetics of liver glucose metabolism in routine clinical practice.

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.

Radiographic duodenal invasion is associated with poor prognosis and early recurrence in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The prognostic impact of radiographic duodenal invasion (rDI) of pancreatic ductal adenocarcinoma (PDAC) has yet to be fully elucidated. This retrospective study aimed to investigate the prognostic and clinicopathological significance of rDI in patients with PDAC after pancreatoduodenectomy (PD). MATERIALS AND METHODS: We retrospectively analyzed 223 consecutive patients with resectable (R) and borderline resectable (BR)-PDAC that underwent up-front PD between 2002 and 2018. rDI was assessed by preoperative multi-detector row computed tomography. RESULTS: Ninety-three (42%) patients with PDAC had rDI, and all of them had pathological DI (pDI). The rDI(+) group had larger tumor size, BR-PDAC was more common, there was higher serum CA19-9 level, and microscopic lymphovascular invasion was more common than in the rDI(-) group. rDI was associated with significant reduction in overall survival (OS) (P < 0.001) and recurrence-free survival (RFS) (P < 0.001). In multivariate analysis, rDI was an independent prognostic factor in OS [hazard ratio (HR) = 0.52; 95% confidence interval (CI) 0.38-0.73, P < 0.001] and RFS [HR = 0.56; 95% CI 0.40-0.78, P = 0.001]. rDI was also an independent risk factor for early recurrence within 12 months [odds ratio (OR) = 0.36; 95% CI 0.18-0.73, P = 0.005]. rDI had positive correlation with liver recurrence (P = 0.024). CONCLUSION: Biological aggressiveness of PDAC with rDI implies short OS and early recurrence with frequent liver metastasis. Aggressive perioperative chemotherapy is recommended to improve prognosis, especially for R-PDAC patients with rDI.

Discrepancy between invasive and echocardiographic transvalvular gradient after TAVI: Insights from the LAPLACE-TAVI registry.

BACKGROUND: Echocardiography-based transvalvular mean pressure gradient (ECHO-mPG) used to assess the forward valve function and structural valve deterioration could overestimate the true pressure gradient. This study evaluated the discrepancy between invasive and ECHO-mPG after transcatheter aortic valve implantation (TAVI) with respective valve type and size, its impact on a device success criterion, and predictors of a pressure discrepancy. METHODS: We analyzed 645 patients registered in a multicenter TAVI registry (balloon-expandable valve [BEV]: 500; self-expandable valve [SEV]: 145). The invasive transvalvular mPG was measured after valve implantation using two Pigtail catheters (CATH-mPG), while the ECHO-mPG was measured within 48 h after TAVI. Pressure recovery (PR) was calculated using the following formula: ECHO-mPG × effective orifice area (EOA)/ascending aortic area (AoA) × (1 - EOA/AoA). RESULTS: ECHO-mPG was weakly correlated with (r = 0.29, p < 0.0001), and consistently overestimated CATH-mPG in both BEV and SEV, and respective valve sizes. The magnitude of the discrepancy was larger for BEV than SEV (p < 0.001) and smaller valves (p < 0.001). After the correction of PR using the above formula, the pressure discrepancy remained for BEV (p < 0.001) but not SEV (p = 0.10). The proportion of patients with an ECHO-mPG > 20 mmHg decreased from 7.0% to 1.6% after correction (p < 0.0001). Among the baseline and procedural variables, post-procedural ejection fraction, BEV versus SEV, and smaller valves were associated with a larger discrepancy in mPG. CONCLUSIONS: ECHO-mPG could be overestimated after TAVI, especially in patients with a smaller BEV. A higher ejection fraction, BEV, and smaller valves were predictors of a pressure discrepancy between CATH- and ECHO-mPG.

Impact of periprocedural bleeding on mid-term outcome in nonagenarians who underwent transcatheter aortic valve implantation: insights from LAPLACE registry.

Data from several recent studies have demonstrated the safety and efficacy of transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) even in nonagenarians. However, the impact of periprocedural bleeding following TAVI on their outcome remains unclear. In the aLliAnce for exPloring cLinical prospects of AortiC valvE disease (LAPLACE) registry, we compared outcomes between the bleeding and no-bleeding groups among 1953 patients < 90 years old (mean age, 83.0 ± 4.6 years old) and 316 nonagenarians (mean age, 91.7 ± 1.9 years old) who underwent TAVI with a median follow-up period of 628 days. The group with any periprocedural bleeding showed a higher 30-day mortality than the no-bleeding group in patients < 90 years old (3.3% vs. 0.5%, p = 0.001) and nonagenarians (7.9% vs. 0.7%, p = 0.001). In patients < 90 years old, severe periprocedural bleeding (n = 85) was associated with a higher mid-term all-cause mortality rate than no severe bleeding (n = 1,868), even after adjusting for covariates (hazard ratio [HR], 1.994; 95% confidence interval [CI] 1.287-2.937; p = 0.002). On the other hand, in nonagenarians, any periprocedural bleeding (n = 38) was associated with a higher mid-term cardiovascular (CV) mortality rate (21.1% vs. 4.3%, log-rank p = 0.014) than no bleeding (n = 278), even after adjusting for covariates (HR, 3.104; 95% CI 1.140-8.449; p = 0.027). In conclusion, any periprocedural bleeding after TAVI was associated with mid-term CV mortality in nonagenarians, whereas severe bleeding was associated with mid-term all-cause mortality in patients < 90 years old.

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.