SGLT2 inhibitors as a potential therapeutic option for pulmonary hypertension: mechanisms and clinical perspectives.

Pulmonary arterial hypertension (PAH), one subtype of pulmonary hypertension (PH), is a life-threatening condition characterized by pulmonary arterial remodeling, elevated pulmonary vascular resistance, and blood pressure in the pulmonary arteries, leading to right heart failure and increased mortality. The disease is marked by endothelial dysfunction, vasoconstriction, and vascular remodeling. The role of Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors, a class of medications originally developed for diabetes management, is increasingly being explored in the context of cardiovascular diseases, including PAH, due to their potential to modulate these pathophysiological processes. In this review, we systematically examine the burgeoning evidence from both basic and clinical studies that describe the effects of SGLT2 inhibitors on cardiovascular health, with a special emphasis on PAH. By delving into the complex interactions between these drugs and the potential pathobiology that underpins PH, this study seeks to uncover the mechanistic underpinnings that could justify the use of SGLT2 inhibitors as a novel therapeutic approach for PAH. We collate findings that illustrate how SGLT2 inhibitors may influence the normal function of pulmonary arteries, possibly alleviating the pathological hallmarks of PAH such as inflammation, oxidative stress, aberrant cellular proliferation, and so on. Our review thereby outlines a potential paradigm shift in PAH management, suggesting that these inhibitors could play a crucial role in modulating the disease's progression by targeting the potential dysfunctions that drive it. This comprehensive synthesis of existing research underscores the imperative need for further clinical trials to validate the efficacy of SGLT2 inhibitors in PAH and to integrate them into the therapeutic agents used against this challenging disease.

Antithrombotic therapy at discharge and prognosis in patients with chronic coronary syndrome and atrial fibrillation who underwent PCI: a real-world study.

BACKGROUND: This study aimed to describe the status of antithrombotic therapy at discharge and prognosis in patients with atrial fibrillation (AF) and chronic coronary syndrome (CCS) who underwent percutaneous coronary intervention (PCI). METHODS: This was an observational, prospective study. The primary endpoint was major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction, stroke/transient ischemic attach (TIA), systemic embolism or ischemia-driven revascularization. Bleeding events were collected according to the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: Between 2017 and 2019, a cohort of 516 patients (mean age 66, [SD 9], of whom 18.4% were female) with AF and CCS who underwent PCI were evaluated, with a median followed-up time of 36 months (Interquartile range: 22-45). MACE events occurred in 13.0% of the patients, while the TIMI bleeding events were observed in 17.4%. Utilization of TAT (triple antithrombotic therapy) (P < 0.001) and oral anticoagulation (OAC) therapy (P < 0.001) increased through years. History of heart failure (HF) (Hazard ratio [HR], 1.744; 95% confidence interval [CI], 1.011-3.038) and TAT (HR, 2.708; 95%CI, 1.653-4.436) had independent associations with MACE events. OAC (HR, 10.378; 95%CI, 6.136-17.555) was identified as a risk factor for bleeding events. A higher creatine clearance (HR, 0.986; 95%CI, 0.974-0.997) was associated with a lower incidence of bleeding events. CONCLUSIONS: Antithrombotic therapy has been improved among patients with AF and CCS who underwent PCI these years. History of HF and TAT were independently associated with MACE events. Higher creatine clearance was protective factor of bleeding events, while OAC was a risk factor for TIMI bleeding events.

Causal impact of gut microbiota and associated metabolites on pulmonary arterial hypertension: a bidirectional Mendelian randomization study.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. METHODS: Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. RESULTS: Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI] 1.100-4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019-2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358-0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245-0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367-0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231-0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide [TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids (SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increased the levels of Butyricicoccus and Holdemania, while decreasing the levels of Clostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. CONCLUSIONS: Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically.

Causal relationships of circulating amino acids with cardiovascular disease: a trans-ancestry Mendelian randomization analysis.

BACKGROUND: Epidemiological studies demonstrated that multiple amino acids (AAs) were associated with cardiovascular diseases (CVDs), but whether these associations were causal remains unclear. This study aims to investigate the causal relationships between circulating levels of 20 AAs and 10 CVDs in European and East Asian populations by Mendelian randomization (MR). METHODS: This MR study utilized single-nucleotide polymorphisms that were significantly associated with AAs as instrumental variables. Summary-level data for AAs and CVDs were obtained from public genome-wide association studies. The causal effects were primarily estimated by inverse variance weighting with multiplicative random effect method. Sensitivity analyses, including weighted median, weighted mode, and MR Egger regression, were used to test the robustness of our results. RESULTS: In the European population, alanine and serine were inversely associated with angina pectoris (AP) and chronic heart failure, respectively. With each unit increase of leucine, the risk of ischemic stroke increased by 10%. Moreover, tyrosine was positively associated with AP and deep vein thrombosis. In the East Asian population, each unit increase in glycine was associated with 4.1% and 9.0% decreased risks of coronary artery disease (CAD) and myocardial infarction (MI), respectively. A unit increase in serine was associated with 13.1%, 12.6% and 15.5% decreased risks of AP, CAD and MI, respectively. Sensitivity analyses supported the robustness of our results. CONCLUSIONS: This MR study demonstrated significant causal effects of circulating levels of AAs on CVDs, indicating the potential use of AAs as biomarkers or as therapeutic targets for CVD in clinical scenarios.

Individual or familial diabetes in relation to eight cardiovascular diseases: A two-sample Mendelian randomization study.

BACKGROUND AND AIMS: Diabetes is associated with increased risk of certain cardiovascular diseases, yet the causality remains to be determined. Meanwhile, given that first-degree relatives share 50% of genes, the effect of familial diabetes is also worthy of attention. Therefore, we sought to investigate the causal relations of individual or familial diabetes with eight cardiovascular diseases, including myocardial infarction, hypertension, atrial fibrillation, heart failure, cardiac death, pulmonary embolism, transient ischemic attack, and ischemic stroke. METHODS AND RESULTS: Applying two-sample Mendelian randomization, we selected instruments for genetic predisposition to individual or familial diabetes based on published genome-wide association studies. The primary analyses were conducted using the random-effects inverse-variance weighted method. We found that genetically predicted individual diabetes was causally associated with higher risks of myocardial infarction (odd ratio [OR] = 1.09; 95% confidence interval [CI]: 1.05-1.13; P < 0.0001), hypertension (OR = 1.08; 95% CI: 1.03-1.13; P = 0.0006), and ischemic stroke (OR = 1.10; 95% CI: 1.05-1.15; P < 0.0001). Genetically predicted paternal diabetes could increase the risk of ischemic stroke (OR = 1.16; 95% CI: 1.04-1.30; P = 0.0061). Genetically predicted maternal diabetes could increase the risk of myocardial infarction (OR = 1.18; 95% CI: 1.09-1.29; P = 0.0001). Genetically predicted siblings' diabetes was causally associated with higher risks of myocardial infarction (OR = 1.17; 95% CI: 1.08-1.27; P = 0.0001) and hypertension (OR = 1.19; 95% CI: 1.06-1.34; P = 0.0036). No significant differences were observed in other outcomes. CONCLUSION: This study supports causal effects of not only individual but also familial diabetes on the development of cardiovascular diseases, which will help realize the potential effect of family history in the prevention of cardiovascular diseases.

De-escalation of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome: An Updated Meta-analysis and Trial Sequential Analysis of 21 Studies and 38,741 Patients.

ABSTRACT: Dual antiplatelet therapy (DAPT) is recommended among patients with established acute coronary syndrome. In this meta-analysis, we sought to compare the clinical outcomes between de-escalation versus unchanged DAPT based on both randomized controlled trials (RCTs) and observational studies. The primary outcomes were major adverse cardiovascular events for observational studies and net clinical events for RCTs. Four RCTs and 17 observational studies with a total of 38,741 patients were included. Net clinical events were more common with unchanged DAPT than with de-escalation in RCTs [odd ratio (OR): 1.71; 95% confidence interval (CI), 1.21-2.43; I2 = 69.4%], which was mainly due to higher risks of any bleeding (OR: 1.81; 95% CI, 1.14-2.88; I2 = 75.5%) and major bleeding (OR: 1.58; 95% CI, 1.02-2.46; I2 = 0), without significant differences in ischaemic events. However, trial sequential analysis revealed that sufficient information was obtained just for net clinical events, not for respective ischaemic or bleeding events in RCTs. In the analysis based on real-world observational studies, the risks of myocardial infarction (OR: 0.77; 95% CI, 0.61-0.98; I2 = 0) and stroke (OR: 0.42; 95% CI, 0.22-0.81; I2 = 0) were lower with the unchanged DAPT group. Therefore, de-escalation of DAPT led to a marked reduction in net clinical events compared with unchanged DAPT in RCTs, which was mainly due to reduced bleeding events. However, sufficient information for ischaemic events was not obtained. In the analysis based on real-world observational studies, myocardial infarction and stroke were more common with de-escalation, which should arise our attention.

Clinical characteristics and thrombotic risk of atrial fibrillation with obstructive sleep apnea: results from a multi-center atrial fibrillation registry study.

BACKGROUND: Sleep apnea is a risk factor for atrial fibrillation (AF) but it is underdiagnosed. Whether obstructive sleep apnea (OSA) is correlated with thrombotic risk in AF remains unclear. The aim of the present study was to analyze the clinical characteristics and assess the thrombotic risk of AF with OSA. METHODS: In the present registry study,1990 consecutive patients with AF from 20 centers were enrolled. The patients were divided into 2 groups depending on whether they presented with both AF and OSA. All the patients were followed up for 1 year to evaluate the incidences of stroke and non-central nervous system (CNS) embolism. RESULTS: Of the 1990 AF patients, 70 (3.5%) and 1920 (96.5%) patients were in the OSA group and non-OSA group, respectively. The results of the multivariate logistic model analysis showed that male sex, body mass index (BMI), smoking, and major bleeding history were independent risk factors for patients with AF and OSA. The comparison of the Kaplan-Meier curves using the log-rank test revealed that AF with OSA was correlated with an increased risk of non-CNS embolism (p < 0.01). After multivariate adjustments were performed, OSA remained an independent risk factor for non-CNS embolism (HR 5.42, 95% CI 1.34-22.01, p = 0.02), but was not correlated with the risk of stroke in patients with AF. CONCLUSIONS: The present study revealed that male sex, high BMI values, smoking, and major bleeding history were independent risk factors for patients with AF and OSA. Moreover, OSA was an independent risk factor for non-CNS embolism in AF. Our results indicate that non-CNS embolism requires focus in patients with AF and OSA.

The long-term survival in patients with chronic thromboembolic pulmonary hypertension: experience from a single center in China.

The long-term prognosis of patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving different treatments is deserved to be analyzed in modern era of CTEPH treatment. From 2013 to 2019, a total of 364 patients diagnosed with CTEPH were retrospectively included, 14 patients were lost during follow-up. Among 350 patients included in the final analysis: 123 underwent pulmonary endarterectomy (PEA), 121 received balloon pulmonary angioplasty (BPA), and 106 treated with targeted drug alone. The median period of follow-up was 51.2 months, the estimated survival at 1-, 3-, 5- and 7-year was 97.1%, 93.3%, 86.9%, and 82.0% for the whole cohort; 100%, 99.20%, 96.5% and 92.5% in PEA group; 98.4%, 97.4%, 95.3% and 89.3% in BPA group;92.5%, 81.9%, 70.1% and 66.8% in patients who received targeted drug alone. In comparing with targeted treatment along, results of multivariate Cox analysis after adjusting the confounders showed that receiving PEA decreased the risk of death by 83% (HR [hazard ratio] 0.17, 95% CI [Confidence interval] 0.07-0.44) and receiving BPA decreased the risk of death by 89% (HR 0.11, 95% CI 0.04-0.29). In conclusion, the estimated survival of CTEPH patients at 1-, 3-, 5- and 7-year was 97.1%, 93.3%, 86.9%, and 82.0% respectively. The intervention of revascularization, including PEA and BPA, were preferred than treating with targeted drug alone in the view of long-term prognosis of CTEPH.

Diabetes mellitus, glycemic traits, SGLT2 inhibition, and risk of pulmonary arterial hypertension: A Mendelian randomization study.

This study aimed to investigate the causal role of diabetes mellitus (DM), glycemic traits, and sodium-glucose cotransporter 2 (SGLT2) inhibition in pulmonary arterial hypertension (PAH). Utilizing a two-sample two-step Mendelian randomization (MR) approach, we determined the causal influence of DM and glycemic traits (including insulin resistance, glycated hemoglobin, and fasting insulin and glucose) on the risk of PAH. Moreover, we examined the causal effects of SGLT2 inhibition on the risk of PAH. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Results showed that genetically inferred DM demonstrated a causal correlation with an increased risk of PAH, exhibiting an odds ratio (OR) of 1.432, with a 95% confidence interval (CI) of 1.040-1.973, and a p-value of 0.028. The multivariate MR analysis revealed comparable outcomes after potential confounders (OR = 1.469, 95%CI = 1.021-2.115, p = 0.038). Moreover, genetically predicted SGLT2 inhibition was causally linked to a reduced risk of PAH (OR = 1.681*10-7, 95%CI = 7.059*10-12-0.004, p = 0.002). Therefore, our study identified the suggestively causal effect of DM on the risk of PAH, and SGLT2 inhibition may be a potential therapeutic target in patients with PAH.

Genetically predicted waist circumference and risk of atrial fibrillation.

INTRODUCTION: Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis. METHODS: In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10 -8 ). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR-Egger, and weighted median regression) were used to ensure that our results more reliable. RESULTS: All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30-1.58, P = 2.51 × 10 -13 ). The results of MR-Egger and weighted median regression exhibited similar trends (MR-Egger OR = 1.40 [95% CI, 1.08-1.81], P = 1.61 × 10 -2 ; weighted median OR = 1.39 [95% CI, 1.21-1.61], P = 1.62 × 10 -6 ). MR-Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. CONCLUSIONS: Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.

Direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension patients: A retrospective cohort study.

INTRODUCTION: Direct oral anticoagulants (DOACs) are increasingly prescribed for life-long anticoagulation in chronic thromboembolic pulmonary hypertension (CTEPH) patients, despite not being recommended in the guidelines. This study aims to evaluate the efficacy and safety of DOACs in CTEPH patients. METHODS: From May 2013 to December 2022, patients who were first diagnosed with CTEPH in Fuwai Hospital and started long-term anticoagulation treatment with warfarin or DOACs were retrospectively included and followed up until (1) death, (2) transition to other kinds of anticoagulants, or (3) discontinuation of anticoagulation. Propensity score matching was used to balance confounding bias of baseline characteristics. All-cause death, major bleeding, clinically relevant nonmajor bleeding and venous thromboembolism (VTE) recurrence were obtained and analysed. RESULTS: After propensity score matching, 115 patients taking warfarin and 206 patients taking DOACs were included in our study and followed up for 5.5 [3.4, 7.1] years. There was no significant difference of survival between the warfarin and the DOAC group (p = 0.77). The exposure adjusted event rate of major bleeding (0.3 %/person-year vs 0.4 %/person-year, p = 0.705) and clinically relevant nonmajor bleeding (3.1 %/person-year vs 3.2 %/person-year, p > 0.999) was similar between two groups. The exposure adjusted rate of VTE recurrence was significantly higher in the DOAC group (1.5 %/person-year vs 0.3 %/person-year, p = 0.030). CONCLUSION: In anticoagulation of CTEPH patients, DOACs have similar survival rate, similar risk of bleeding but higher risk of VTE recurrence than warfarin.

Rate control or rhythm control in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention.

Background: Restoring and maintaining sinus rhythm in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) has been studied in clinical trials to reduce symptoms and improve quality of life. Limited data exist on the effectiveness of rate or rhythm control therapy in these patients. Methods: Consecutive patients with AF and ACS or referred for PCI were prospectively recruited in Fuwai Hospital during 2017-2020. The primary endpoints were all-cause death and major adverse cardiovascular and cerebrovascular events (MACCEs), including cardiovascular mortality, myocardial infarction, ischemic stroke, non-central nervous system embolism and ischemia-driven revascularization. Kaplan-Meier curves and Cox regressions were performed to evaluate the association between rhythm/rate control and subsequent outcomes. For the primary endpoints, we used the Benjamini-Hochberg correction for multiple comparisons. Results: A total of 1499 patients with AF and ACS or undergoing PCI were included, with a median follow-up of 34.7 months. Compared to non-rate control, rate control strategy reduced the risk of subsequent MACCEs (adjusted HR, 0.320; 95 % CI 0.220-0.466; p <0.001; *p <0.002) and all-cause death (adjusted HR, 0.148; 95 % CI 0.093-0.236; p <0.001; *p <0.002). Similar trends were observed across all predefined subgroups (p <0.001). In the final multivariate model, rhythm control was not associated with a lower subsequent MACCEs but significantly improved all-cause mortality compared to non-rhythm control (adjusted HR, 0.546; 95 % CI 0.313-0.951; p =0.033; *p =0.044). Conclusions: In this real-world study, rate control strategy was associated with lower risk of MACCEs and all-cause death in AF and ACS or undergoing PCI. Besides, management with rhythm control strategy may improve all-cause mortality.

Exploring the association between COVID-19 and male genital cancer risk in European population: evidence from mendelian randomization analysis.

BACKGROUND: Recently accumulated evidence indicates a potential association between COVID-19 and elevated susceptibility to cancer, including male genital cancer. However, the causal nature of this relationship remains unclear. METHODS: In this Mendelian randomization (MR) study, we investigated the potential causal relationship between COVID-19 and male genital cancer using genetic variants as instrumental variables. We utilized summary statistics from two large-scale genome-wide association studies of COVID-19 hospitalized Vs. controls, as well as data from a population-based male genital cancer database based on European ancestry. We applied stringent quality control measures to select instrumental variables, including checking for linkage disequilibrium, removing low-quality variants, and assessing the strength of the instruments using the F-statistic. We conducted the MR  analysis using the inverse-variance weighted method and several sensitivity analyses (including MR Egger and Weighted Median MR analysis) to test the robustness of our results. RESULTS: Our MR analysis revealed no causal associations between COVID-19 hospitalization and the incidence of male genital cancer. In the inverse-variance weighted analysis, no causal associations were observed between patients with COVID-19 hospitalization and the incidence of male genital cancer (odds ratio = 1.000 and 95% confidence interval = 0.998-1.001, p = 0.668). The estimated causal effect was consistent across all sensitivity analyses (including the Weighted Median, the MR Egger analysis, and the MR PROSSO analysis). The leave-one-out analysis showed that there was no any sing Single-nucleotide polymorphism significantly influencing our results. CONCLUSIONS: Our study provides evidence that there is no causal association between COVID-19 hospitalization and male genital cancer.

Association of serum uric acid with benefits of intensive blood pressure control.

INTRODUCTION AND OBJECTIVES: Intensive systolic blood pressure (SBP) control improved outcomes in the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Whether the serum uric acid concentration at baseline alters the benefits of intensive SBP control is unknown. METHODS: The STEP trial was a randomized controlled trial that compared the effects of intensive (SBP target of 110 to<130mmHg) and standard (SBP target of 130 to <150mmHg) SBP control in Chinese patients aged 60 to 80 years with hypertension. The primary outcome was a composite of cardiovascular disease events. This post hoc analysis was performed to examine whether the effects of intensive SBP intervention differed by the baseline uric acid concentration using 2 models: restricted cubic spline curves and subgroup analyses, both based on the Fine-Gray subdistribution hazard model in the analysis of the primary outcome and secondary outcomes (excluding all-cause death). In the analysis of all-cause death, the Cox regression model was used. We also examined the change in the follow-up uric acid concentrations. RESULTS: Overall, the risk of the primary outcome rose as the cumulative uric acid concentration increased in both the intensive and standard treatment groups. Patients with intensive treatment had a lower multivariable-adjusted subdistribution hazard ratio for the primary outcome, but with a wide overlap of 95%CI. Next, we stratified patients according to their baseline uric acid concentration (tertile 1 [T1], <303.0µmol/L; tertile 2 [T2], 303.0 to <375.8µmol/L; and tertile 3 [T3], ≥375.8µmol/L). Subgroup analyses using tertiles provided HRs and 95%CI in T1 (HR, 0.55; 95%CI, 0.36-0.86; P=.008), T2 (HR, 0.80; 95%CI, 0.56-1.14; P=.22) and T3 (HR, 0.86; 95%CI, 0.60-1.21; P=.39), with an interaction P value of .29. The results for most of the secondary outcomes followed the same trends. CONCLUSIONS: There was no evidence that the benefit of the intensive SBP control differed by baseline uric acid concentrations. This trial was registered at ClinicalTrial.gov (Identifier: NCT03015311).

An inverse causal association between genetically predicted vitamin D and chronic obstructive pulmonary disease risk.

Aim: Observational studies have reported that levels of vitamin D were associated with the incidence of chronic obstructive pulmonary disease (COPD), but the relationship between them may have been confounded in previous studies. In this study, we aimed to determine the relationship between the levels of 25-hydroxyvitamin D (25OHD) and the risk of COPD by two-sample Mendelian randomization (MR) analysis. Methods: Summary statistics for 25OHD and COPD in this study were obtained from the EBI (n = 496,946) consortium and Finn (n = 187,754) consortium. MR was adopted to explore the effect of the genetically predicted levels of 25OHD on the risk of COPD. Based on three assumptions of MR analysis, inverse variance weighting was used as the main analysis. To make our results more robust and reliable, MR Egger's intercept test, Cochran's Q test, funnel plot, and "leave-one-out" sensitivity analysis were used to assess the potential pleiotropy and heterogeneity in this study. Then, colocalization analysis and MR Steiger approaches were used to estimate the possible directions of estimates between them. Finally, we analyzed the causal associations between the four core genes (DHCR7, GC, CYP2R1, and CYP24A1) of vitamin D and the levels of 25OHD or the risk of COPD. Results: Our results showed that each 1 standard deviation (SD) increase in the genetically predicted 25OHD level was associated with a 57.2% lower relative risk of COPD [odds ratio (OR): 0.428, 95% Cl: 0.279-0.657, p = 1.041 × 10-4], and the above association was also verified by maximum likelihood (OR: 0.427, 95% Cl: 0.277-0.657, p = 1.084 × 10-4), MR-Egger (OR: 0.271, 95% CI: 0.176-0.416, p = 2.466 × 10-4), MR-PRESSO (OR: 0.428, 95% Cl: 0.281-0.652, p = 1.421 × 10-4) and MR-RAPS (OR: 0.457, 95% Cl: 0.293-0.712, p = 5.450 × 10-4). Furthermore, colocalization analyses (rs3829251, PP.H4 = 0.99) and MR Steiger ("TRUE") also showed a reverse association between them. Besides, the core genes of vitamin D also showed similar results except for CYP24A1. Conclusion: Our findings provide evidence for a reverse association between genetically predicted 25OHD levels and COPD risk. Taking measures to supplement 25OHD may help reduce the incidence of COPD.

Roles of obesity in mediating the causal effect of attention-deficit/hyperactivity disorder on diabetes.

AIMS: Previous observational studies have reported potential associations among attention-deficit/hyperactivity disorder (ADHD), obesity, and diabetes (including type 1 and type 2 diabetes mellitus [T1DM/T2DM]). However, whether the association between ADHD and diabetes is mediated by obesity is unknown. METHODS: With two-sample Mendelian randomization, we analysed the causal effect of ADHD on T1DM and T2DM and six obesity-related traits [including body mass index, waist circumference (WC), hip circumference, waist-to-hip ratio (WHR), body fat percentage and basal metabolic rate] and the causal effect of these obesity-related traits on T1DM/T2DM. Finally, with multivariable Mendelian randomization, we explored and quantified the possible mediation effects of obesity-related traits on the causal effect of ADHD on T1DM/T2DM. RESULTS: Our results showed that ADHD increased the risk of T2DM by 14% [odds ratio (OR) = 1.140, 95% confidence interval (CI) = 1.005-1.293] but with no evidence of an effect on T1DM (OR = 0.916, 95% CI = 0.735-1.141, P = 0.433.). In addition, ADHD had a 6.1% increased causal effect on high WC (OR = 1.061, 95% CI = 1.024-1.099, P = 0.001) and an 8.2% increased causal effect on high WHR (OR = 1.082, 95% CI = 1.035-1.131, P = 0.001). In addition, a causal effect of genetically predicted high WC (OR = 1.870, 95% CI = 1.594-2.192, P < 0.001) on a higher risk of T2DM was found. In further analysis, WC mediated approximately 26.75% (95% CI = 24.20%-29.30%) of the causal association between ADHD and T2DM. CONCLUSIONS: WC mediates a substantial proportion of the causal effect of ADHD on the risk of T2DM, which indicated that the risk of T2DM induced by ADHD could be indirectly reduced by controlling WC as a main risk factor.

The Causality between Diabetes and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: Diabetes was considered as a risk factor for venous thromboembolism (VTE), but conflicting findings have been reported from observational studies. This study aimed at investigating the causal associations of type 1 and type 2 diabetes with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: We designed a bidirectional two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. Inverse variance weighting with multiplicative random effect method was used to obtain the primary causal estimates, and weighted median, weighted mode, and MR egger regression were replenished as sensitivity analyses to test the robustness of the results. RESULTS: We found no significant causal effects of type 1 diabetes on VTE (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-1.00, p = 0.043), DVT (OR: 0.98, 95% CI: 0.95-1.00, p = 0.102), and PE (OR: 0.98, 95% CI: 0.96-1.01, p = 0.160). Similarly, no significant associations of type 2 diabetes with VTE (OR: 0.97, 95% CI: 0.91-1.03, p = 0.291), DVT (OR: 0.96, 95% CI: 0.89-1.03, p = 0.255), and PE (OR: 0.97, 95% CI: 0.90-1.04, p = 0.358) were also observed. Results from multivariable MR analysis were consistent with the findings in univariable analysis. In the other direction, the results showed no significant causal effects of VTE on type 1 and type 2 diabetes. CONCLUSION: This MR analysis demonstrated no significant causal associations of type 1 and type 2 diabetes with VTE in both directions, in conflict with previous observational studies reporting positive association, which provided clues for understanding the underlying pathogenesis of diabetes and VTE.

Untargeted metabolomics reveal the metabolic profile of normal pulmonary circulation.

BACKGROUND: As an important place of material exchange, the homeostasis of the pulmonary circulation environment and function lays an essential foundation for the normal execution of various physiological functions of the body. Small metabolic molecules in the circulation can reflect the corresponding state of the pulmonary circulation. METHODS: We enrolled patients with Patent Foramen Ovale and obtained blood from the pulmonary arteries and veins through heart catheterization. UPLC-MS based untargeted metabolomics was used to compare the changes and metabolic differences of plasma between pulmonary vein and pulmonary artery. RESULTS: The plasma metabolomics revealed that pulmonary artery had a different metabolomic profile compared to venous. 1060 metabolites were identified, and 61 metabolites were differential metabolites. Purine, Amino acids, Nicotinamide, Tetradecanedioic acid and Bile acid were the most markedly. CONCLUSION: The differential metabolites are mostly related to immune inflammation and damage repaired. It is suggested that the pulmonary circulation is always in a steady state of injury and repair while pathological changes may be triggered when the homeostasis is broken. These changes play an important role in revealing the development process and etiology of lung homeostasis and related diseases. Relevant metabolites can be used as potential targets for further study of pulmonary circulation homeostasis.

Corrigendum: Genetic predisposition between COVID-19 and four mental illnesses: A bidirectional, two-sample Mendelian randomization study.

[This corrects the article DOI: 10.3389/fpsyt.2021.746276.].