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.

Evaluation of the usefulness of plasma 4ß-hydroxycholesterol concentration normalized by 4α-hydroxycholesterol for accurate CYP3A phenotyping.

Plasma 4ß-hydroxycholesterol (OHC) has drawn attention as an endogenous substrate indicating CYP3A activity. Plasma 4ß-OHC is produced by hydroxylation by CYP3A4 and CYP3A5 and by cholesterol autoxidation. Plasma 4α-OHC is produced by cholesterol autoxidation and not affected by CYP3A activity. This study aimed to evaluate the usefulness of plasma 4ß-OHC concentration minus plasma 4α-OHC concentration (4ß-OHC-4α-OHC) compared with plasma 4ß-OHC concentration and 4ß-OHC/total cholesterol (TC) ratio in cross-sectional evaluation of CYP3A activity. Four hundred sixteen general adults were divided into 191 CYP3A5*1 carriers and 225 non-carriers. Twenty-six patients with chronic kidney disease (CKD) with CYP3A5*1 allele were divided into 14 with CKD stage 3 and 12 with stage 4-5D. Area under the receiver operating characteristic curve (AUC) for the three indices were evaluated for predicting presence or absence of CYP3A5*1 allele in general adults, and for predicting CKD stage 3 or stage 4-5D in patients with CKD. There was no significant difference between AUC of 4ß-OHC-4α-OHC and AUC of plasma 4ß-OHC concentration in general adults and in patients with CKD. AUC of 4ß-OHC-4α-OHC was significantly smaller than that of 4ß-OHC/TC ratio in general adults (p = 0.025), but the two indices did not differ in patients with CKD. In conclusion, in the present cross-sectional evaluation of CYP3A activity in general adults and in patients with CKD with CYP3A5*1 allele, the usefulness of 4ß-OHC-4α-OHC was not different from plasma 4ß-OHC concentration or 4ß-OHC/TC ratio. However, because of the limitations in study design and subject selection of this research, these findings require verification in further studies.

One Cup of Coffee a Day Modulates the Relationship between Metabolic Syndrome and Eating Fast: A Cross-Sectional Study.

BACKGROUND: Eating speed has been implicated as a leading cause of metabolic syndrome (MetS). However, it is difficult to break the habit of eating fast. Since coffee consumption is associated with a lower risk of MetS, we investigated the association between eating speed and the amount of coffee consumed with MetS. METHODS: This study included data from 3881 participants (2498 females and 1383 males). We used a self-administered questionnaire to collect information on participants' coffee consumption (<1 cup/day and ≥1 cup/day) and eating speed (slow, normal, or fast). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression analyses to investigate the relationship between the prevalence of MetS due to eating speed and the amount of coffee consumed. RESULTS: The group that consumed ≥1 cup/day of coffee (filtered or instant) had a lower OR for MetS compared to the group that consumed <1 cup/day (OR: 0.695; 95% Cl: 0.570-0.847). The eating fast group, compared to the eating slow group, had a higher OR for MetS (OR: 1.689; 95% Cl: 1.227-2.324). When the data were stratified by coffee consumption and eating speed groups, the slow-eating group among those who consumed <1 cup/day of coffee (filtered or instant) had a lower OR for MetS (OR: 0.502; 95% CI: 0.296-0.851) compared to the fast-eating group. In contrast, the groups who consumed ≥1 cup/day of coffee were associated with lower OR for MetS, regardless of their eating speed. CONCLUSIONS: This suggests that drinking ≥1 cup/day of coffee may help prevent MetS induced by eating fast.

Association between bone health and dynapenic obesity in postmenopausal women.

AIM: The combination of dynapenia (age-related muscle weakness) and obesity is referred to as dynapenic obesity. We examined the associations between dynapenic obesity and cortical bone thickness and trabecular bone density. METHODS: The participants were 797 community-dwelling postmenopausal women (with an average age of 62.5 years) who were stratified into normopenia without obesity, dynapenia without obesity (dynapenia), normopenia with obesity (obesity) and dynapenia with obesity (dynapenia obesity) groups based on their grip strength and body fat percentage. Cortical bone thickness and trabecular bone density were measured using ultrasonic bone densitometry. The participants were further divided into those with low cortical bone thickness and low trabecular bone density. Logistic regression analysis was used to identify associated factors. RESULTS: Individuals with dynapenia (odds ratio [OR] 1.77, 95% confidence interval [CI] 1.16-2.68), obesity (OR 2.46, 95% CI 1.62-3.75) and dynapenic obesity (OR 4.07, 95% CI 2.44-6.79) all significantly increased the odds of low cortical bone thickness. Conversely, the odds of low trabecular bone density were significantly lower in the obesity group (OR 0.65, 95% CI 0.43-0.99) and dynapenic obesity group (OR 0.60, 95% CI 0.37-0.97). CONCLUSIONS: Dynapenic obesity was found to be associated with cortical bone thinning that might compromise bone health. Postmenopausal women with dynapenic obesity might need to be closely monitored for preserving bone health. Geriatr Gerontol Int 2024; 24: 378-384.

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.

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.

Association between poor sleep quality and locomotive syndrome in middle-aged and older women: A community-based, cross-sectional study.

OBJECTIVE: Poor sleep quality, such as nocturnal arousal and sleep inefficiency, is associated with frailty and sarcopenia. Herein, we evaluated the relationship between poor sleep quality and locomotive syndrome (LS), a motor organ dysfunction common among community-dwelling middle-aged and older women. METHODS: Participants comprised 2246 Japanese middle-aged and older women. LS was classified into stages LS-1, LS-2, and LS-3 (from least to most severe) according to the results of the stand-up test, two-step test, and 25-question Geriatric Locomotive Function Scale. Sleep quality was assessed using the Pittsburgh Sleep Quality Index. RESULTS: The Pittsburgh Sleep Quality Index scores were significantly higher in the LS group than that in the non-LS group (P < .001). Multivariate logistic regression analyses adjusted for potential confounders identified poor sleep quality as an independent factor of LS (odds ratio 1.59 [95% confidence interval 1.30-1.93], P < .001). Similar results were observed in the sensitivity analysis in postmenopausal women. LS and trouble sleeping because of pain showed stepwise association in all LS stages. CONCLUSIONS: Poor sleep quality was independently associated with LS among community-dwelling middle-aged and older women. As the stage of LS progressed, the proportion of women with poor sleep quality increased significantly.

Seven-plus hours of daily sedentary time and the subsequent risk of breast cancer: Japan Multi-Institutional Collaborative Cohort Study.

This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35-69 years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07-1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure-time METs, ≥3 days/week of leisure-time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11-2.25), 1.77 (95% CI, 1.20-2.61), and 1.42 (95% CI, 1.10-1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with ≥7 h/d of sedentary time.

The combination of locomotive syndrome and poor sleep quality is a risk factor of falls among community-dwelling middle-aged and older women: A cross-sectional study.

AIM: The combination of locomotive syndrome (LS) and poor sleep quality (PQ) has not yet been shown to result in falls or to affect bone conditions in old age and middle age. [Correction added on 1 December 2023, after first online publication: The preceding sentence has been updated for clarity.] METHODS: This cross-sectional study enrolled 2233 community-dwelling middle-aged to older Japanese women. LS and PSQ were assessed by the stand-up test, two-step test, the 25-question Geriatric Locomotive Function Scale, and the Pittsburgh Sleep Quality Index (PSQI). Participants with both LS 1-3 (any) and a PSQI score ≥6 were classified as belonging to the LS(+)/PSQ(+) group. The incidence of falls in the previous month was collected using a self-administered questionnaire. Bone conditions were evaluated using an ultrasonic bone densitometer. RESULTS: The LS(+)/PSQ(+) group independently had a higher risk of falls after adjusting for confounding factors than the LS(-)/PSQ(-) group using multiple logistic regression analysis (odds ratio 1.92, 95% confidence interval 1.01-3.65, P < 0.05). No relationships between LS(-)/PSQ(+) and LS(+)/PSQ(-) groups and the incidences of fall were observed (P > 0.05). [Correction added on 1 December 2023, after first online publication: The two preceding sentences have been corrected to provide greater clarity.] The LS(+)/PSQ(+) group had lower trabecular bone density and cortical bone thickness than the LS(-)/PSQ(-) group (P < 0.05). CONCLUSION: The combination of LS and PSQ is an independent risk factor of falls, indicating that assessing both LS and PSQ could be useful in detecting middle-aged and older women with low bone density and thickness who fall easily at an early stage. Geriatr Gerontol Int 2023; 23: 912-918.

Locomotive syndrome and depressive symptoms: A cross-sectional study in middle-aged women.

OBJECTIVE: Evidence for an association between locomotive syndrome (LS) and depression is lacking in middle-aged women. This study aimed to investigate the relationship between LS severity and depressive symptoms in community-dwelling middle-aged women. METHODS: This cross-sectional study included 1,520 middle-aged women (mean age 52 ± 6 years). LS severity was evaluated using the 25-question Geriatric Locomotive Function Scale (GLFS-25) questionnaire and motor function test. Depressive symptoms were assessed using the Zung self-rating depression scale (SDS). Multiple logistic regression analyses were performed to determine the association between depressive symptoms and LS severity, adjusting for potential confounding factors. RESULTS: LS severity, as evaluated through both questionnaires and motor function tests, was significantly associated with depressive symptoms (SDS ≥ 40 points) in middle-aged women. The relationship between LS and depressive symptoms was only significant when assessed through the GLFS-25 questionnaire rather than the motor function tests. Additionally, a stepwise association was observed between pain severity, as assessed by the GLFS-25, and the prevalence of depressive symptoms. CONCLUSIONS: LS severity is significantly associated with depressive symptoms in community-dwelling middle-aged women, suggesting the need for additional mental status assessment in participants with LS and concurrent pain.

Copeptin is associated with microalbuminuria and renal function in the general Japanese population.

An association between copeptin (precursor molecule of arginine vasopressin) and markers for renal function has been reported, but data on the Japanese population has been limited. In this study, we investigated whether elevated copeptin levels are associated with microalbuminuria and renal dysfunction in the general Japanese population. A total of 1,262 participants (842 female and 420 male) were enrolled. Multiple regression analysis was performed to assess the association of copeptin levels (logarithm) with estimated glomerular filtration rate (eGFR) and the urine albumin-to-creatinine ratio (UACR) after adjusting for age, BMI, and lifestyle variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression methods in which chronic kidney disease (CKD) was the dependent variable. The copeptin levels differed significantly with sex, but were not found to be related to age or the span of time from preceding meal to blood sampling. In female participants, copeptin level was negatively correlated with eGFR (beta = -0.100, p-value = 0.006) and positively correlated with UACR (beta = 0.099, p-value = 0.003). In male participants, a negative correlation (beta = -0.140, p-value = 0.008) was observed for eGFR. In both females and males, those with high copeptin levels had more than double the ORs of CKD (OR = 2.1-2.9) adjusted for CKD-related factors. The present study found elevated copeptin levels to be associated with renal function loss in the Japanese population and microalbuminuria in female. Moreover, it was evident that high copeptin levels are associated with CKD. These results suggest that copeptin could be considered a marker of renal function.

Association of kidney function with cancer incidence and its influence on cancer risk of smoking: The Japan Multi-Institutional Collaborative Cohort Study.

The association between kidney function and cancer incidence is inconsistent among previous reports, and data on the Japanese population are lacking. It is unknown whether kidney function modifies the cancer risk of other factors. We aimed to evaluate the association of estimated glomerular filtration rate (eGFR) with cancer incidence and mortality in 55 242 participants (median age, 57 years; 55% women) from the Japan Multi-Institutional Collaborative Cohort Study. We also investigated differences in cancer risk factors between individuals with and without kidney dysfunction. During a median 9.3-year follow-up period, 4278 (7.7%) subjects developed cancer. Moderately low and high eGFRs were associated with higher cancer incidence; compared with eGFR of 60-74 ml/min/1.73 m2 , the adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) for eGFRs of ≥90, 75-89, 45-59, 30-44 and 10-29 ml/min/1.73 m2 were 1.18 (1.07-1.29), 1.09 (1.01-1.17), 0.93 (0.83-1.04), 1.36 (1.00-1.84) and 1.12 (0.55-2.26), respectively. High eGFR was associated with higher cancer mortality, while low eGFR was not; the adjusted subdistribution HRs (95% CIs) for eGFRs of ≥90 and 75-89 ml/min/1.73 m2 were 1.58 (1.29-1.94) and 1.27 (1.08-1.50), respectively. Subgroup analyses of participants with eGFRs ≥60 and <60 ml/min/1.73 m2 revealed elevated cancer risks of smoking and family history of cancer in those with eGFR <60 ml/min/1.73 m2 , with significant interactions. Our findings suggest that the relationship between eGFR and cancer incidence was U-shaped. Only high eGFR was associated with cancer mortality. Kidney dysfunction enhanced cancer risk from smoking.

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.

Diagnostic utility of trefoil factor families for the early detection of lung cancer and their correlation with tissue expression.

Trefoil factors (TFFs) are upregulated in numerous types of cancer, including those of the breast, the colon, the lung and the pancreas, suggesting their potential utility as biomarkers for screening. In the present study, the clinical relevance of serum or urinary TFFs as biomarkers were comprehensively evaluated and the correlation with TFF expression levels in lung cancer tissue was examined. Serum and urine were collected from 199 patients with lung cancer and 198 healthy individuals. Concentrations of serum and urinary TFF1, TFF2 and TFF3 were measured using ELISA and the potential of TFF levels to discriminate between cancer and non-cancer samples was evaluated. In 100 of the cancer cases, expression of TFF1-3 was analyzed using immunohistochemical staining of paraffin sections. Furthermore, the relationship between TFF levels and clinicopathological factors among these cancer cases was analyzed using immunohistochemistry of tissue specimens, quantified and statistically analyzed. While serum levels of all TFFs measured using ELISA were significantly higher in patients with lung cancer compared with those in healthy individuals, urinary TFFs were lower. Areas under the curve (AUC) of the receiver operating characteristic curves for serum/urinary TFF1, TFF2 and TFF3 were 0.709/0.594, 0.722/0.501 and 0.663/0.665, respectively. Furthermore, the combination of serum TFF1, TFF2, TFF3 and urinary TFF1 and TFF3 demonstrated the highest AUC (0.826). In the clinicopathological analysis, serum TFF1 was higher in the early pathological T-stage (pTis/1/2) compared with the later stage (pT3/4) and TFF2 was higher in the pN0/1 than the pN2 group. With regards to the histological types, urinary TFF1 was higher in squamous cell carcinoma than adenocarcinoma (AC), but TFF2 tended to be higher in AC. Using immunohistochemical analysis, although TFF1 and TFF3 expression showed positive correlation with serum concentrations, TFF2 was inversely correlated. In conclusion, serum and urinary TFF levels are promising predictive biomarkers, and their measurements provide a useful in vivo and non-invasive diagnostic screening tool. In particular, TFF1 and TFF3 could be surrogate markers of clinicopathological profiles of human lung cancer.

Fear of COVID-19 Among Japanese Workers and Exacerbation of Chronic Pain: A Nationwide Cross-Sectional Study.

OBJECTIVE: To evaluate the association between fear of the coronavirus disease 2019 (COVID-19) and exacerbated chronic pain among workers during the pandemic, as well as productivity loss. METHODS: We collected data using Internet-based self-reported questionnaires, on fear of COVID-19, work productivity status, exacerbation of chronic pain during the pandemic, and several confounding factors. RESULTS: The multivariate logistic regression analysis showed that a high level of fear of COVID-19 was associated with an increased exacerbation of chronic pain (adjusted odds ratio, 2.31; 95% confidence interval, 1.21-4.44). Meanwhile, the presence of fear of COVID-19 and exacerbated chronic pain were associated with productivity impairment (adjusted odds ratio, 2.03; 95% confidence interval, 1.44-2.85). CONCLUSIONS: Our study shows that workers' fear of COVID-19 is correlated with exacerbated chronic pain and risk of presenteeism.

Coffee and metabolic phenotypes: A cross-sectional analysis of the Japan multi-institutional collaborative cohort (J-MICC) study.

BACKGROUND AND AIMS: To date, the relationship between coffee consumption and metabolic phenotypes has hardly been investigated and remains controversial. Therefore, the aim of this cross-sectional study is to examine the associations between coffee consumption and metabolic phenotypes in a Japanese population. METHODS AND RESULTS: We analyzed the data of 26,363 subjects (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Coffee consumption was assessed using a questionnaire. Metabolic Syndrome (MetS) was defined according to the Joint Interim Statement Criteria of 2009, using body mass index (BMI) instead of waist circumference. Subjects stratified by the presence or absence of obesity (normal weight: BMI <25 kg/m2; obesity: BMI ≥25 kg/m2) were classified by the number of MetS components (metabolically healthy: no components; metabolically unhealthy: one or more components) other than BMI. In multiple logistic regression analyses adjusted for sex, age, and other potential confounders, high coffee consumption (≥3 cups/day) was associated with a lower prevalence of MetS and metabolically unhealthy phenotypes both in normal weight (OR 0.83, 95% CI 0.76-0.90) and obese subjects (OR 0.83, 95% CI 0.69-0.99). Filtered/instant coffee consumption was inversely associated with the prevalence of MetS and metabolically unhealthy phenotypes, whereas canned/bottled/packed coffee consumption was not. CONCLUSION: The present results suggest that high coffee consumption, particularly filtered/instant coffee, is inversely associated with the prevalence of metabolically unhealthy phenotypes in both normal weight and obese Japanese adults.

Plasma mid-regional pro-adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke.

Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n = 119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5 h of onset. MR-proADM levels in HAIS were compared to healthy controls (n = 1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (rs  = 0.09, p = 0.348), they were higher in HAIS with CDM (n = 34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n = 26; 0.83 vs. 0.62 nmol/L, p = 0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4.65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.

Population-Based Impact of Smoking, Drinking, and Genetic Factors on HDL-cholesterol Levels in J-MICC Study Participants.

BACKGROUND: Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. METHODS: Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10-8) were selected from the GWAS catalog, of which seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). RESULTS: We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex, and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. CONCLUSION: The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.