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The PNPLA3 and TM6SF2 gene variants have been found to cause NAFLD with a favourable cardiovascular risk profile.To investigate the effects of the NAFLD risk alleles on the all-cause and cause-specific mortality in 5581 Chinese adults.The genome-wide genotypes were detected using a genotyping array and serum lipoprotein profiles were examined using 1H NMR platform. Liver fat content (LFC) was measured using a quantitative ultrasound method. The vital status was determined using official registration data.Genome-wide association analysis showed that a series of variants in PNPLA3 were associated with LFC, including rs738409 CG variant (P = 8.6 × 10The PNPLA3 rs738409 CG variant and its combination with TM6SF2 rs58542926 CT and MBOAT7 rs641738 CT variants increase liver-specific mortality but reduce cardiovascular mortality in overweight/obese Chinese.

Context Previous genome-wide association studies (GWASs) of bone mineral density (BMD) were mainly conducted in Europeans. Objective To explore genetic variants that affect BMD and sex differences in a Chinese population. Methods A total of 5428 middle-aged and elderly Chinese were included. Dual-energy X-ray absorptiometry was used to measure BMD at the lumbar spine, and total and specific sites of the hip. A mixed linear model was used to analyze the associations between BMD and autosomal genetic variants, adjusting for age, age squared, sex, and menopausal women (model 1); model 2 was further adjusted for height and weight. A GWAS of osteoporosis in the Biobank Japan (BBJ) project was used for replication. GWAMA software was used to detect the statistical significance of sex differences of estimated effects. Gene annotation and pathway enrichment analysis were performed. Results Women lost BMD at earlier ages and faster than men. The 2 models identified a total of 12 loci that were associated with BMD at any site. Single nucleotide polymorphisms rs72354346, rs2024219, rs1463093, rs10037512, and rs5880932 were successfully replicated in the BBJ. Variations of rs79262027 G>A (VKORC1L1) and rs4795209 A>G (DDX52) were associated with BMD only in men, and rs1239055408 G>GA (KCNJ2) was associated with BMD only in women. Gene enrichment analysis showed that BMD in a Chinese elderly population was mainly related to ossification, bone resorption, sex hormones, and kidney physiology. Conclusion The present GWAS identified 12 loci that were significantly associated with BMD at any site in a Chinese population, and 3 of them showed sex differences in their effects.

Recent advances indicate that bone and energy metabolism are closely related. However, little direct evidence on causality has been provided in humans. We aimed to assess the association of three bone-related biomarkers-25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and osteocalcin (OCN)-with several metabolic phenotypes and investigate any causal relevance to the associations using a Mendelian randomization (MR) study. Serum 25OHD, PTH, and total OCN were measured at baseline in 5169 eligible Chinese participants in Changfeng study. Partial correlation and bivariate GREML analysis were used to estimate phenotypic and genetic correlations, respectively. Multiple linear regression and logistic regression were used to assess linear associations. Genomewide association analysis (GWAS) was performed. Bidirectional two-sample MR analyses were conducted to examine causal relationships between OCN and body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), glycated hemoglobin A1c (HbA1c), and type 2 diabetes (T2DM), using our GWAS result of OCN and GWAS statistics from Biobank Japan project (BBJ) and the largest meta-analysis of T2DM GWAS in East Asian population. Circulating OCN was significantly associated with higher DBP and HDL-C and decreased TG, blood glucose level, insulin resistance, liver fat content, bone mineral density, BMI, and a favorable body fat distribution pattern. GWAS identified one novel serum PTH locus and two novel serum OCN loci, explaining 0.81% and 1.98% of variances of PTH and OCN levels, respectively. MR analysis suggested a causal effect of T2DM on lower circulating OCN concentration (causal effect: -0.03; -0.05 to -0.01; p = 0.006 for T2DM_BBJ and -0.03; -0.05 to -0.01; p = 0.001 for T2DM_EAS). These findings indicate that T2DM might impact bone remodeling and provide a resource for understanding complex relationships between osteocalcin and metabolic (and related) traits in humans. © 2021 American Society for Bone and Mineral Research (ASBMR).

Osteocalcin regulates energy metabolism in an active undercarboxylated/uncarboxylated form. However, its role on the development of non-alcoholic fatty liver disease (NAFLD) is still controversial. In the current study, we investigated the causal relationship of circulating osteocalcin with NAFLD in two human cohorts and studied the effect of uncarboxylated osteocalcin on liver lipid metabolism through animal models. We analyzed the correlations of serum total/uncarboxylated osteocalcin with liver steatosis/fibrosis in a liver biopsy cohort of 196 participants, and the causal relationship between serum osteocalcin and the incidence/remission of NAFLD in a prospective community cohort of 2055 subjects from Shanghai Changfeng Study. Serum total osteocalcin was positively correlated with uncarboxylated osteocalcin (r = 0.528, p < .001). Total and uncarboxylated osteocalcin quartiles were inversely associated with liver steatosis, inflammation, ballooning, and fibrosis grades in both male and female participants (all p for trend

Complex biomedical data generated during clinical, omics and mechanism-based experiments have increasingly been exploited through cloud- and visualization-based data mining techniques. However, the scientific community still lacks an easy-to-use web service for the comprehensive visualization of biomedical data, particularly high-quality and publication-ready graphics that allow easy scaling and updatability according to user demands. Therefore, we propose a community-driven modern web service, Hiplot (https://hiplot.org), with concise and top-quality data visualization applications for the life sciences and biomedical fields. This web service permits users to conveniently and interactively complete a few specialized visualization tasks that previously could only be conducted by senior bioinformatics or biostatistics researchers. It covers most of the daily demands of biomedical researchers with its equipped 240+ biomedical data visualization functions, involving basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modelling, etc. Moreover, to improve the efficiency in use and development of plugins, we introduced some core advantages on the client-/server-side of the website, such as spreadsheet-based data importing, cross-platform command-line controller (Hctl), multi-user plumber workers, JavaScript Object Notation-based plugin system, easy data/parameters, results and errors reproduction and real-time updates mode. Meanwhile, using demo/real data sets and benchmark tests, we explored statistical parameters, cancer genomic landscapes, disease risk factors and the performance of website based on selected native plugins. The statistics of visits and user numbers could further reflect the potential impact of this web service on relevant fields. Thus, researchers devoted to life and data sciences would benefit from this emerging and free web service.

Bariatric surgery has emerged as the most effective therapy for morbid obesity. There is increasing evidence that bariatric surgery could alleviate systemic inflammation and influence thyroid function. The current study aimed to investigate the associations of preoperative thyroid autoimmune status with the changes in body weight and thyroid function after bariatric surgery. We recruited 101 patients with morbid obesity (44 men and 57 women) who received bariatric surgery at Zhongshan Hospital, Fudan University. Those who had used thyroid hormone replacement or antithyroid drugs were excluded. General linear models were used to compare the changes in body weight and thyroid function in participants with different thyroid autoimmune statuses. After bariatric surgery, serum-free triiodothyronine (FT3) (4.94 ± 0.73 vs 4.33 ± 0.59 pmol/L, P

A metabolically healthy status, whether obese or not, is a transient stage with the potential to develop into metabolic disorders during the course of life. We investigated the incidence of metabolic disorders in 1078 metabolically healthy Chinese adults from the Shanghai Changfeng Study and looked for metabolites that discriminated the participants who would develop metabolic disorders in the future. Participants were divided into metabolically healthy overweight/obesity (MHO) and metabolically healthy normal weight (MHNW) groups according to their body mass index (BMI) and metabolic status. Their serum metabolomic profile was measured using a (1)H nuclear magnetic resonance spectrometer ((1)H-NMR). The prevalence of diabetes, hypertriglyceridemia, hypercholesterolemia and metabolic syndrome was similar between the MHNW and MHO participants at baseline. After a median of 4.2 years of follow-up, more MHO participants became metabolically unhealthy than MHNW participants. However, a subgroup of MHO participants who remained metabolically healthy (MHO → MHO) had a similar prevalence of metabolic disorders as the MHNW participants at the follow-up examination, despite a significant reduction in their serum concentrations of high-density lipoprotein (HDL) and an elevation in valine, leucine, alanine and tyrosine. Further correlation analysis indicated that serum intermediate-density lipoprotein (IDL) and very low-density lipoprotein cholesterol (VLDL-CH) might be involved in the transition from metabolically healthy to unhealthy status and could be valuable to identify the MHNW and MHO with increased metabolic risks.

Fat mass and fat-free mass are found to be associated with different health outcomes in observational studies, but the underlying causality remains unclear. We aimed to investigate the causal relationships between body composition and cardiometabolic traits using a two-sample Mendelian randomization (MR) approach. Independent genetic variants associated with body fat mass, fat-free mass, and fat percentage in UK Biobank population were used as genetic instrumental variables, and their causal effects on circulatory diseases, type 2 diabetes, glycemic traits, and lipid fractions were estimated from large-scale genome-wide association studies (GWAS) in European populations. Univariable, multivariable, and bidirectional MR analyses were performed. Genetically predicted high fat mass and fat percentage significantly increased risks of most cardiometabolic diseases, and high fat-free mass had protective effects on most cardiometabolic diseases after accounting for fat mass. Fat mass, fat-free mass, and fat percentage were all positively associated with higher risks of atrial fibrillation and flutter, varicose veins, and deep vein thrombosis and pulmonary embolism. High fat mass increased fasting glucose, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, decreased high-density lipoprotein cholesterol, and high fat-free mass reduced HOMA-IR, triglycerides, and low-density lipoprotein cholesterol. Genetically predicted fat-free mass was bidirectionally negatively associated with 2-h glucose and total cholesterol. The findings may be helpful in risk stratification and tailoring management of body composition in patients with different cardiometabolic statuses.

To determine the association of birth weight (BW) and waist circumference (WC) on cardiovascular disease (CVD). The longitudinal cohort study consisted of 745 participants who were able to provide their birth weight information and were followed from 2002 to 2014. During the follow-up, 83 events of CVD were confirmed. After adjusting for confounding factors, subjects with birth weight

Background MicroRNA-26a (miR-26a) is a key player in tumor suppression and plays important roles in glucose and lipid metabolism. However, its function in adipose tissue is not well defined. Objective The study aimed to examine the effect on fat expansion and function of miR-26a in adipose tissue. Methods Adipose-specific miR-26a transgenic mice (Ap2-miR-26a) were firstly generated by breeding miR-26a floxed (Mir26aloxP/loxP) mice with Ap2-Cre recombinase transgenic mice. The effects of miR-26a adipose-specific overexpression on body weight, body fat composition, fat pad weight, adipocyte size, blood lipid levels, glucose metabolism, and adipogenesis were investigated in mice on a chow diet and a high fat diet. White adipose tissue browning was evaluated by energy expenditure, adipocyte morphology and browning related genes expression levels both at room temperature and after cold exposure. Gene expression was determined by Real-Time quantitative PCR and western blotting. Results MiR-26a was specifically overexpressed in adipose by ~4 folds. Ap2-miR-26a mice had a moderate decrease in body weight, body fat composition, epididymal white adipose (eWAT) weight and blood lipid levels, along with smaller adipocytes in eWAT. The favorable phenotype was not due to white adipose tissue browning (even after cold exposure) or adipogenesis or lipolysis. Ap2-miR-26a mice exhibited no significant metabolic phenotype under high-fat-diet feeding. Conclusion This study suggests that adipose-specific overexpression of miR-26a could moderately reduce visceral fat pad mass and lipid levels independent of white adipose tissue browning, adipogenesis and adipose lipolysis based on the gene expression level.

To investigate the metabolic biomarkers of predicting the transition from pre-diabetes (pre-DM) to normal glucose regulation (NGR) and diabetes (DM) in a longitudinal cohort study. 108 participants with pre-DM were followed up for ten years and divided into 3 groups according to different glycemic outcomes. 20 participants progressed to DM, 20 regressed to NGR, and 68 remained at pre-DM. Alterations in plasma metabolites in these groups were evaluated by untargeted ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Twenty three metabolites related to glycerophospholipid metabolism, oxidation and antioxidation were associated with the process from pre-DM to NGR, while twenty two metabolites related to amino acid metabolism, glycerophospholipid metabolism and mitochondrial β-oxidation played important roles in the progression to DM. Results from stepwise logistic regression analysis showed that five biomarkers (20-Hydroxy-leukotriene E4, Lysopc(20:4), 5-methoxytryptamine, Endomorphin-1, Lysopc(20:3)) were good prediction for the restoration to NGR, and five biomarkers (Iso-valeraldehyde, linoleic acid, Lysopc(18:1), 2-Pyrroloylglycine, Dityrosine) for the development of DM. The findings suggest that the combination of these potential metabolites may be used for the prognosis of pre-DM. Targeting the pathways that involved in these prognostic biomarkers would be beneficial for the regression to NGR and the early prevention of DM among pre-DM.

To investigate the metabolic biomarkers of predicting the transition from pre-diabetes (pre-DM) to normal glucose regulation (NGR) and diabetes (DM) in a longitudinal cohort study. 108 participants with pre-DM were followed up for ten years and divided into 3 groups according to different glycemic outcomes. 20 participants progressed to DM, 20 regressed to NGR, and 68 remained at pre-DM. Alterations in plasma metabolites in these groups were evaluated by untargeted ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Twenty three metabolites related to glycerophospholipid metabolism, oxidation and antioxidation were associated with the process from pre-DM to NGR, while twenty two metabolites related to amino acid metabolism, glycerophospholipid metabolism and mitochondrial β-oxidation played important roles in the progression to DM. Results from stepwise logistic regression analysis showed that five biomarkers (20-Hydroxy-leukotriene E4, Lysopc(20:4), 5-methoxytryptamine, Endomorphin-1, Lysopc(20:3)) were good prediction for the restoration to NGR, and five biomarkers (Iso-valeraldehyde, linoleic acid, Lysopc(18:1), 2-Pyrroloylglycine, Dityrosine) for the development of DM. The findings suggest that the combination of these potential metabolites may be used for the prognosis of pre-DM. Targeting the pathways that involved in these prognostic biomarkers would be beneficial for the regression to NGR and the early prevention of DM among pre-DM.