Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis.

The heterogeneous cellular microenvironment of human airway chronic inflammatory diseases, including chronic rhinosinusitis (CRS) and asthma, is still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on the nasal mucosa of healthy individuals and patients with three subtypes of CRS and identified disease-specific cell subsets and molecules that specifically contribute to the pathogenesis of CRS subtypes. As such, ALOX15+ macrophages contributed to the type 2 immunity-driven pathogenesis of one subtype of CRS, eosinophilic CRS with nasal polyps (eCRSwNP), by secreting chemokines that recruited eosinophils, monocytes and T helper 2 (TH2) cells. An inhibitor of ALOX15 reduced the release of proinflammatory chemokines in human macrophages and inhibited the overactivation of type 2 immunity in a mouse model of eosinophilic rhinosinusitis. Our findings advance the understanding of the heterogeneous immune microenvironment and the pathogenesis of CRS subtypes and identify potential therapeutic approaches for the treatment of CRS and potentially other type 2 immunity-mediated diseases.

A multiomic study uncovers a bZIP23-PER1A-mediated detoxification pathway to enhance seed vigor in rice.

Seed vigor in crops is important in terms of improving grain quality and germplasm conservation; however, little is known about its regulatory mechanisms through the encoded proteome and gene network. Comparative analyses of transcriptome (RNA sequencing [RNA-seq]) and broadly targeted metabolic profiling of two subspecific rice cultivars with distinct seed vigor during accelerated aging revealed various biological pathways and metabolic processes as key influences explaining trait differences. RNA-seq coexpression regulatory network analyses identified several transcription factors, including bZIP23 and bZIP42, that act as nodes in the gene network. Importantly, transgenic seeds of overexpression of bZIP23 enhanced seed vigor, whereas its gene knockout reduced seed vigor, suggesting that the protein it encodes functions as a positive regulator. Similarly, overexpression and knockout of PER1A that encodes a key player in the detoxification pathway enhanced and decreased seed vigor, respectively. We further demonstrated a direct interaction of the PER1A promoter with bZIP23 in seeds, which activates the expression of PER1A, and the genetic evidence suggested that bZIP23 most likely functions in a common pathway with and acts upstream of PER1A to modulate seed vigor. In addition, the control of seed vigor by the bZIP23-PER1A module was connected with that of the abscisic acid signaling pathway. Collectively, we revealed the genetic architecture of variation in seed vigor and uncovered the bZIP23-PER1A-mediated detoxification pathway that enhances the trait in rice.

Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Simultaneous Detection of Aldehyde Metabolites by Light-Assisted Ambient Ionization Mass Spectrometry.

In the clinic, small-molecule metabolites (SMMs) in blood are highly convincing indicators for disease diagnosis, such as cancer. However, challenges still exist for detection of SMMs due to their low concentration and complicated components in blood. In this work, we report the design of a novel "selenium signature" nanoprobe (Se nanoprobe) for efficient identification of multiple aldehyde metabolites in blood. This Se nanoprobe consists of magnetic nanoparticles that can enrich aldehyde metabolites from a complex environment, functionalized with photosensitive "selenium signature" hydrazide molecules that can react with aldehyde metabolites. Upon irradiation with UV, the aldehyde derivatives can be released from the Se nanoprobe and further sprayed by mass spectrometry through ambient ionization (AIMS). By quantifying the selenium isotope distribution (MS/MS) from the derivatization product, accurate detection of several aldehyde metabolites, including valeraldehyde (Val), heptaldehyde (Hep), 2-furaldehyde (2-Fur), 10-undecenal aldehyde (10-Und), and benzaldehyde (Ben), is realized. This strategy reveals a new solution for quick and accurate cancer diagnosis in the clinic.

The ubiquitin-interacting motif-type ubiquitin receptor HDR3 interacts with and stabilizes the histone acetyltransferase GW6a to control the grain size in rice.

For grain crops such as rice (Oryza sativa), grain size substantially affects yield. The histone acetyltransferase GRAIN WEIGHT 6a (GW6a) determines grain size and yield in rice. However, the gene regulatory network underlying GW6a-mediated regulation of grain size has remained elusive. In this study, we show that GW6a interacts with HOMOLOG OF DA1 ON RICE CHROMOSOME 3 (HDR3), a ubiquitin-interacting motif-containing ubiquitin receptor. Transgenic rice plants overexpressing HDR3 produced larger grains, whereas HDR3 knockout lines produce smaller grains compared to the control. Cytological data suggest that HDR3 modulates grain size in a similar manner to GW6a, by altering cell proliferation in spikelet hulls. Mechanistically, HDR3 physically interacts with and stabilizes GW6a in an ubiquitin-dependent manner, delaying protein degradation by the 26S proteasome. The delay in GW6a degradation results in dramatic enhancement of the local acetylation of H3 and H4 histones. Furthermore, RNA sequencing analysis and chromatin immunoprecipitation assays reveal that HDR3 and GW6a bind to the promoters of and modulate a common set of downstream genes. In addition, genetic analysis demonstrates that HDR3 functions in the same genetic pathway as GW6a to regulate the grain size. Therefore, we identified the grain size regulatory module HDR3-GW6a as a potential target for crop yield improvement.

Development and validation of a nomogram for predicting overall survival in patients with sinonasal mucosal melanoma.

BACKGROUND: Sinonasal mucosal melanoma (SNMM) is a relatively rare malignant tumour with a poor prognosis. This study was designed to identify prognostic factors and establish a nomogram model to predict the overall survival (OS) of patients with SNMM. METHODS: A total of 459 patients with SNMM were selected from the Surveillance, Epidemiology, and End Results (SEER) database as the training cohort. Univariate and multivariate Cox regression analyses were used to screen for independent factors associated with patient prognosis and develop the nomogram model. In addition, external validation was performed to evaluate the effectiveness of the nomogram with a cohort of 34 patients with SNMM from Peking Union Medical College Hospital. RESULTS: The median OS in the cohort from the SEER database was 28 months. The 1-year, 3-year and 5-year OS rates were 69.8%, 40.4%, and 30.0%, respectively. Multivariate Cox regression analysis indicated that age, T stage, N stage, surgery and radiotherapy were independent variables associated with OS. The areas under the receiver operating characteristic curves (AUCs) of the nomograms for predicting 1-, 3- and 5-year OS were 0.78, 0.71 and 0.71, respectively, in the training cohort. In the validation cohort, the area under the curve (AUC) of the nomogram for predicting 1-, 3- and 5-year OS were 0.90, 0.75 and 0.78, respectively. Patients were classified into low- and high-risk groups based on the total score of the nomogram. Patients in the low-risk group had a significantly better survival prognosis than patients in the high-risk group in both the training cohort (P < 0.0001) and the validation cohort (P = 0.0016). CONCLUSION: We established and validated a novel nomogram model to predict the OS of SNMM patients stratified by age, T stage, N stage, surgery and radiotherapy. This predictive tool is of potential importance in the realms of patient counselling and clinical decision-making.

The effect of metformin on urate metabolism: Findings from observational and Mendelian randomization analyses.

AIM: To evaluate the effect of metformin on urate metabolism. MATERIALS AND METHODS: Using the UK Biobank, we first performed association analyses of metformin use with urate levels, risk of hyperuricaemia and incident gout in patients with diabetes. To explore the causal effect of metformin on urate and gout, we identified genetic variants proxying the glycated haemoglobin (HbA1c)-lowering effect of metformin targets and conducted a two-sample Mendelian randomization (MR) utilizing the urate and gout genetic summary-level data from the CKDGen (n = 288 649) and the FinnGen cohort. We conducted two-step MR to explore the mediation effect of body mass index and systolic blood pressure. We also performed non-linear MR in the UK Biobank (n = 414 055) to show the results across HbA1c levels. RESULTS: In 18 776 patients with type 2 diabetes in UK Biobank, metformin use was associated with decreased urate [ß = -4.3 µmol/L, 95% confidence interval (CI) -7.0, -1.7, p = .001] and reduced hyperuricaemia risk (odds ratio = 0.87, 95% CI 0.79, 0.96, p = .004), but not gout. Genetically proxied averaged HbA1c-lowering effects of metformin targets, equivalent to a 0.62% reduction in HbA1c, was associated with reduced urate (ß = -12.5 µmol/L, 95% CI -21.4, -4.2, p = .004). Body mass index significantly mediated this association (proportion mediated = 33.0%, p = .002). Non-linear MR results suggest a linear trend of the effect of metformin on urate reduction across various HbA1c levels. CONCLUSIONS: The effect of metformin may reduce urate levels but not incident gout in the general population.

Sex-specific causality of MRI-derived body compositions on glycaemic traits: Mendelian randomization and observational study.

AIM: To investigate the sex-specific causality of body compositions in type 2 diabetes and related glycaemic traits using Mendelian randomization (MR). MATERIALS AND METHODS: We leveraged sex-specific summary-level statistics from genome-wide association studies for three adipose deposits adjusted for body mass index and height, including abdominal subcutaneous adipose tissue, visceral adipose tissue (VATadj) and gluteofemoral adipose tissue (GFATadj), measured by MRI (20 038 women; 19 038 men), and fat mass-adjusted appendicular lean mass (ALMadj) (244 730 women; 205 513 men) in the UK Biobank. Sex-specific statistics of type 2 diabetes were from the Diabetes Genetics Replication and Meta-analysis Consortium and those for fasting glucose and insulin were from the Meta-analyses of Glucose and Insulin-related Traits Consortium. Univariable and multivariable MR (MVMR) were performed. We also performed MR analyses of anthropometric traits and genetic association analyses using individual-level data of body composition as validation. RESULTS: Univariable MR analysis showed that, in women, higher GFATadj and ALMadj exerted a causally protective effect on type 2 diabetes (GFATadj: odds ratio [OR] 0.59, 95% confidence interval [CI; 0.50, 0.69]; ALMadj: OR 0.84, 95% CI [0.77, 0.91]) and VATadj to be riskier in glycaemic traits. MVMR showed that GFATadj retained a robust effect on type 2 diabetes (OR 0.57, 95% CI [0.42, 0.77]; P = 2.6 × 10-4 ) in women, while it was nominally significant in men (OR 0.58, 95% CI [0.35, 0.96]; P = 3.3 × 10-2 ), after adjustment for ASATadj and VATadj. MR analyses of anthropometric measures and genetic association analyses of glycaemic traits confirmed the results. CONCLUSIONS: Body composition has a sex-specific effect on type 2 diabetes, and higher GFATadj has an independent protective effect on type 2 diabetes in both sexes.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

Association between updated cardiovascular health construct and risks of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: The American Heart Association (AHA) updated the construct and algorithm of cardiovascular health (CVH) recently. We aimed to explore the relationship between the new CVH score and the development of non-alcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: 3266 adults free of NAFLD identified via ultrasound were recruited in this prospective study. A modified AHA "Life's Essential 8" (mLE8, i.e., physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) were collected to evaluate the CVH score. Then participants were categorized into low, moderate, and high CVH subgroups based on overall mLE8 CVH score. According to modified Life's Simple 7 (mLS7) CVH construct, participants were also subdivided into poor, intermediate, and ideal CVH subgroups. During a median 4.3 years follow-up, 623 incident cases of NAFLD were recorded. Compared to those with high CVH, participants with low CVH (adjusted OR = 2.56, 95% CI 1.55-4.24) and moderate CVH (adjusted OR = 1.83, 95% CI 1.17-2.85) had a significantly increased risk of incident NAFLD. Participants with poor CVH (mLS7) but without low CVH (mLE8) did not show a significant elevated risk of incident NAFLD (P = 0.1053). A significant trend was found between increased changes in mLE8 score and a lower risk of NAFLD occurrence. CONCLUSION: Our findings suggested high mLE8 CVH score was associated with a lower risk of NAFLD incidence. The new CVH construct showed a more reasonable classification of CVH status and was more robust in association with NAFLD risks compared with the original one.

Impact of baseline and trajectory of the atherogenic index of plasma on incident diabetic kidney disease and retinopathy in participants with type 2 diabetes: a longitudinal cohort study.

BACKGROUND: Some studies have assessed the predictive role of the atherogenic index of plasma (AIP) for macrovascular diseases. This prospective investigation aimed to elucidate whether AIP is associated with diabetic kidney disease (DKD) and diabetic retinopathy (DR) incidence. METHODS: The data were extracted from 4831 participants, of whom 2943 and 3360 participants with type 2 diabetes (T2D) were included in the DKD and DR follow-up analyses, respectively. Cox regression models were performed to test the relationships of AIP value at baseline with the risk of incident DKD and DR. Group-based trajectory modelling was utilized to discern AIP trajectories during the follow-up period. Subsequently, logistic regressions were applied to ascertain the influence of AIP trajectories on the incidence of DKD and DR. RESULTS: During the follow-up period, 709 (24.1%) and 193 (5.7%) participants developed DKD and DR, respectively. The median (interquartile range) follow-up time was 24.2 (26.3) months for DKD and 25.7 (27.0) months for DR. According to the multivariate Cox regression models, baseline AIP was positively and linearly related to the occurrence of DKD, with a hazard ratio of 1.75 (95% confidence interval [CI] 1.36-2.26). Three distinct trajectories of AIP were identified throughout the follow-up time: Low (31.4%), Median (50.2%), and High (18.3%). Compared to participants with the Low AIP trajectory, those with High and Median AIP trajectories presented 117% (95% CI: 1.62-2.91) and 84% (95% CI 1.46-2.32) greater odds of developing DKD, respectively. However, neither baseline levels nor trajectories of AIP were shown to be related to DR after adjusting for confounding factors. CONCLUSIONS: Baseline levels and trajectories of AIP were independently related to elevated DKD risk, indicating that AIP could be used as a predictor for identifying T2D participants at higher risk of DKD. No association between AIP and DR was detected.

Hypertriglyceridemic hyperapoB and the development and resolution of nonalcoholic fatty liver disease: a cohort study.

Hypertriglyceridemic hyperapoB is an adverse lipoprotein phenotype characterized by low high density lipoprotein (HDL) cholesterol, high triglycerides, high apolipoprotein B (ApoB), and low low density lipoprotein (LDL) cholesterol to ApoB ratio. We investigated whether and to what extent hypertriglyceridemic hyperapoB associates with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD). This prospective cohort study included 9,019 Chinese participants 40 years or older, from 2010 to 2015. Logistic regression models were used to examine the odds ratios (ORs) for the incidence and resolution of NAFLD associated with the hypertriglyceridemic hyperapoB lipoprotein phenotype and individual lipid and lipoprotein parameters. During a median 4.3 years of follow-up, compared with participants with optimal phenotype, the fully adjusted ORs (95% CIs) for participants with hypertriglyceridemic hyperapoB were 2.75 (1.91, 3.95) and 0.57 (0.33, 1.00) for incidence and resolution of NAFLD, respectively. These associations were consistent across subgroup participants with varied demographic, lifestyle, and metabolic status. Individually, each unit increase in HDL cholesterol (OR: 0.98; 95% CI: 0.97, 0.99), natural logarithm-transformed triglycerides (1.89; 1.52, 2.36), and ApoB (1.006; 1.002, 1.011) was independently associated with NAFLD incidence, and only triglycerides (0.77; 0.60, 0.99) was independently associated with NAFLD resolution. Our findings suggest that Chinese adults with hypertriglyceridemic hyperapoB have a higher risk of NAFLD incidence and a lower likelihood of NAFLD resolution. These associations were stable among adults with different demographic, lifestyle, and metabolic status, supporting hypertriglyceridemic hyperapoB as a valuable clinical marker for the prevention and control of NAFLD.

Outdoor light at night in relation to glucose homoeostasis and diabetes in Chinese adults: a national and cross-sectional study of 98,658 participants from 162 study sites.

AIMS/HYPOTHESIS: Exposure to artificial light at night (LAN) disrupts the circadian timing system and might be a risk factor for diabetes. Our aim was to estimate the associations of chronic exposure to outdoor LAN with glucose homoeostasis markers and diabetes prevalence based on a national and cross-sectional survey of the general population in China. METHODS: The China Noncommunicable Disease Surveillance Study was a nationally representative study of 98,658 participants aged ≥18 years who had been living in their current residence for at least 6 months recruited from 162 study sites across mainland China in 2010. Diabetes was defined according to ADA criteria. Outdoor LAN exposure in 2010 was estimated from satellite data and the participants attending each study site were assigned the same mean radiance of the outdoor LAN at the study site. The linear regression incorporating a restricted cubic spline function was used to explore the relationships between LAN exposure and markers of glucose homoeostasis. Cox regression with a constant for the time variable assigned to all individuals and with robust variance estimates was used to assess the associations between the levels of outdoor LAN exposure and the presence of diabetes by calculating the prevalence ratios (PRs) with adjustment for age, sex, education, smoking status, drinking status, physical activity, family history of diabetes, household income, urban/rural areas, taking antihypertensive medications, taking lipid-lowering medications, and BMI. RESULTS: The mean age of the study population was 42.7 years and 53,515 (weighted proportion 49.2%) participants were women. Outdoor LAN exposure levels were positively associated with HbA1c, fasting and 2 h glucose concentrations and HOMA-IR and negatively associated with HOMA-B. Diabetes prevalence was significantly associated with per-quintile LAN exposure (PR 1.07 [95% CI 1.02, 1.12]). The highest quintile of LAN exposure (median 69.1 nW cm-2 sr-1) was significantly associated with an increased prevalence of diabetes (PR 1.28 [95% CI 1.03, 1.60]) compared with the lowest quintile of exposure (median 1.0 nW cm-2 sr-1). CONCLUSIONS/INTERPRETATION: There were significant associations between chronic exposure to higher intensity of outdoor LAN with increased risk of impaired glucose homoeostasis and diabetes prevalence. Our findings contribute to the growing evidence that LAN is detrimental to health and point to outdoor LAN as a potential novel risk factor for diabetes.

Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study.

BACKGROUND: Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. METHODS: Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. RESULTS: Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45-0.59), and decreased HOMA-IR (ß = - 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06-1.15), and decreased HOMA-B (ß = - 0.04, SE = 0.01, P = 4.52 × 10-5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. CONCLUSIONS: This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

Visit-to-visit HbA1c variability is associated with aortic stiffness progression in participants with type 2 diabetes.

BACKGROUND: Glycemic variability plays an important role in the development of cardiovascular disease (CVD). This study aims to determine whether long-term visit-to-visit glycemic variability is associated with aortic stiffness progression in participants with type 2 diabetes (T2D). METHODS: Prospective data were obtained from 2115 T2D participants in the National Metabolic Management Center (MMC) from June 2017 to December 2022. Two brachial-ankle pulse wave velocity (ba-PWV) measurements were performed to assess aortic stiffness over a mean follow-up period of 2.6 years. A multivariate latent class growth mixed model was applied to identify trajectories of blood glucose. Logistic regression models were used to determine the odds ratio (OR) for aortic stiffness associated with glycemic variability evaluated by the coefficient of variation (CV), variability independent of the mean (VIM), average real variability (ARV), and successive variation (SV) of blood glucose. RESULTS: Four distinct trajectories of glycated hemoglobin (HbA1c) or fasting blood glucose (FBG) were identified. In the U-shape class of HbA1c and FBG, the adjusted ORs were 2.17 and 1.21 for having increased/persistently high ba-PWV, respectively. Additionally, HbA1c variability (CV, VIM, SV) was significantly associated with aortic stiffness progression, with ORs ranging from 1.20 to 1.24. Cross-tabulation analysis indicated that the third tertile of the HbA1c mean and VIM conferred a 78% (95% confidence interval [CI] 1.23-2.58) higher odds of aortic stiffness progression. Sensitivity analysis demonstrated that the SD of HbA1c and the highest HbA1c variability score (HVS) were significantly associated with the adverse outcomes independent of the mean of HbA1c during the follow-up. CONCLUSIONS: Long-term visit-to-visit HbA1c variability was independently associated with aortic stiffness progression, suggesting that HbA1c variability was a strong predictor of subclinical atherosclerosis in T2D participants.

Opposite causal effects of birthweight on myocardial infarction and atrial fibrillation and the distinct mediating pathways: a Mendelian randomization study.

BACKGROUND: Previous observational studies have documented an inverse association of birthweight with myocardial infarction (MI) but a positive association with atrial fibrillation (AF). However, the causality of these associations and the underlying mediating pathways remain unclear. We aimed to investigate the causal effects of birthweight, incorporating both fetal and maternal genetic effects, on MI and AF, and identify potential mediators in their respective pathways. METHODS: We performed Mendelian randomization (MR) analyses using genome-wide association study summary statistics for birthweight (N = 297,356 for own birthweight and 210,248 for offspring birthweight), MI (Ncase=61,000, Ncontrol=577,000), AF (Ncase=60,620, Ncontrol=970,216), and 52 candidate mediators (N = 13,848-1,295,946). Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the associations of birthweight with MI and AF, respectively. As a complement, we replicated analyses for fetal-specific birthweight and maternal-specific birthweight. RESULTS: Genetically determined each 1-SD lower birthweight was associated with a 40% (95% CI: 1.22-1.60) higher risk of MI, whereas each 1-SD higher birthweight was causally associated with a 29% (95% CI: 1.16-1.44) higher risk of AF. Cardiometabolic factors, including lipids and lipoproteins, glucose and insulin, blood pressure, and fatty acids, each mediated 4.09-23.71% of the total effect of birthweight on MI, followed by body composition and strength traits (i.e., appendicular lean mass, height, and grip strength) and socioeconomic indicators (i.e., education and household income), with the mediation proportion for each factor ranging from 8.08 to 16.80%. By contrast, appendicular lean mass, height, waist circumference, childhood obesity, and body mass index each mediated 15.03-45.12% of the total effect of birthweight on AF. Both fetal-specific birthweight and maternal-specific birthweight were inversely associated with MI, while only fetal-specific birthweight was positively associated with AF. Psychological well-being and lifestyle factors conferred no mediating effect in either association. CONCLUSIONS: Cardiometabolic factors mainly mediated the association between lower birthweight and MI, while body composition and strength traits mediated the association between higher birthweight and AF. These findings provide novel evidence for the distinct pathogenesis of MI and AF and advocate adopting a life-course approach to improving fetal development and subsequent causal mediators to mitigate the prevalence and burden of cardiovascular diseases.

Roles of gut microbiota in atrial fibrillation: insights from Mendelian randomization analysis and genetic data from over 430,000 cohort study participants.

BACKGROUND: Gut microbiota imbalances have been suggested as a contributing factor to atrial fibrillation (AF), but the causal relationship is not fully understood. OBJECTIVES: To explore the causal relationships between the gut microbiota and AF using Mendelian randomization (MR) analysis. METHODS: Summary statistics were from genome-wide association studies (GWAS) of 207 gut microbial taxa (5 phyla, 10 classes, 13 orders, 26 families, 48 genera, and 105 species) (the Dutch Microbiome Project) and two large meta-GWASs of AF. The significant results were validated in FinnGen cohort and over 430,000 UK Biobank participants. Mediation MR analyses were conducted for AF risk factors, including type 2 diabetes, coronary artery disease (CAD), body mass index (BMI), blood lipids, blood pressure, and obstructive sleep apnea, to explore the potential mediation effect of these risk factors in between the gut microbiota and AF. RESULTS: Two microbial taxa causally associated with AF: species Eubacterium ramulus (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.04-1.12, P = 0.0001, false discovery rate (FDR) adjusted p-value = 0.023) and genus Holdemania (OR 1.15, 95% CI 1.07-1.25, P = 0.0004, FDR adjusted p-value = 0.042). Genus Holdemania was associated with incident AF risk in the UK Biobank. The proportion of mediation effect of species Eubacterium ramulus via CAD was 8.05% (95% CI 1.73% - 14.95%, P = 0.008), while the proportion of genus Holdemania on AF via BMI was 12.01% (95% CI 5.17% - 19.39%, P = 0.0005). CONCLUSIONS: This study provided genetic evidence to support a potential causal mechanism between gut microbiota and AF and suggested the mediation role of AF risk factors.

Causal impacts of educational attainment on chronic liver diseases and the mediating pathways: Mendelian randomization study.

BACKGROUND AND AIMS: Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways. METHODS: We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association. RESULTS: Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%). CONCLUSIONS: Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education.

Causal effect of lower birthweight on non-alcoholic fatty liver disease and mediating roles of insulin resistance and metabolites.

BACKGROUND & AIMS: The causal association of lower birthweight with non-alcoholic fatty liver disease (NAFLD) and the mediating pathways remain unclear. We aimed to investigate the causal, independent association of lower birthweight with NAFLD and identify potential metabolic mediators and their mediation effects in this association. METHODS: We performed two-step, two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics for birthweight from the Early Growth Genetics Consortium of 298 142 Europeans, NAFLD from a GWAS meta-analysis of 8434 NAFLD cases and 770 180 controls of Europeans, and 25 candidate mediators from corresponding reliable GWASs. RESULTS: Genetically determined each 1-SD lower birthweight was associated with a 45% (95% CI: 1.25-1.69) increased risk of NAFLD, and this causal association persisted after adjusting for childhood obesity or adult adiposity traits in multivariable MR. Two-step MR identified 6 of 25 candidate mediators partially mediate the effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.05%), leucine (17.29%), isoleucine (13.55%), valine (11.37%), alanine (10.01%) and monounsaturated fatty acids (MUFA; 7.23%). Bidirectional MR suggested a unidirectional effect of insulin resistance on isoleucine, leucine and valine and a unidirectional effect of alanine on insulin resistance. CONCLUSIONS: This MR study elucidated the causal impact of lower birthweight on subsequent risk of NAFLD, independently of later-life adiposity and identified mediators including insulin resistance, branched-chain amino acids, alanine and MUFA in this association pathway. Our findings shed light on the pathogenesis of NAFLD and imply additional targets for prevention and intervention of NAFLD attributed to low birthweight.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.