Does COVID-19 impact the QT interval prolongation? Answers from genetic causal inference.

During the COVID-19 pandemic, there has been heightened interest in the QT interval, a crucial indicator of ventricular electrical activity. Mendelian randomization (MR) is used here to investigate the genetic causation between QT interval alterations and COVID-19. Genetic proxies representing three COVID-19 phenotypes-severe, hospitalized, and COVID-19-were identified in over 1,000,000 individuals of European ancestry.

Integrated analysis of disulfidptosis-related genes SLC7A11, SLC3A2, RPN1 and NCKAP1 across cancers.

Disulfidptosis, a newly identified form of regulated cell death associated with disruption of disulfide bond formation in the endoplasmic reticulum, involves the dysregulation of disulfidptosis-related genes (DRGs) that may contribute to cancer development and progression. However, the molecular mechanisms and clinical implications of DRGs in different cancer types remain poorly characterized. Therefore, in this comprehensive study, we investigated the expression, prognostic value, and functional roles of four recently identified DRGs (SLC7A11, SLC3A2, RPN1, and NCKAP1) across various cancers.

Identification of immune feature genes and intercellular profiles in diabetic cardiomyopathy.

Background: Diabetic cardiomyopathy (DCM) is a multifaceted cardiovascular disorder in which immune dysregulation plays a pivotal role. The immunological molecular mechanisms underlying DCM are poorly understood.

Aim: To examine the immunological molecular mechanisms of DCM and construct diagnostic and prognostic models of DCM based on immune feature genes (IFGs).

Genetically predicted Caspase 8 levels mediates the causal association between CD4+ T cell and breast cancer.

Background: Breast cancer (BC) remains a significant contributor to female mortality globally, with inflammation and the immune system implicated in its pathogenesis. To elucidate potential causal relationships, we evaluated the relationship among 731 immune cell phenotypes and BC be at risk by using Mendelian randomization (MR), while also exploring inflammatory proteins as mediators in this association.

Methods: We obtained immune cell genome-wide association study (GWAS) summary data and 91 inflammatory factors from the GWAS Catalog.

Mendelian randomization of plasma lipidome, inflammatory proteome and heart failure.

Aims: Heart failure (HF) is a global health issue, with lipid metabolism and inflammation critically implicated in its progression. This study harnesses cutting-edge, expanded genetic information for lipid and inflammatory protein profiles, employing Mendelian randomization (MR) to uncover genetic risk factors for HF.

Methods: We assessed genetic susceptibility to HF across 179 lipidomes and 91 inflammatory proteins using instrumental variables (IVs) from recent genome-wide association studies (GWASs) and proteome-wide quantitative trait loci (pQTL) studies.

Causal links between serum micronutrients and epilepsy: a Mendelian randomization analysis.

Background: Micronutrient levels play a critical role in epilepsy. This study investigates the impact of micronutrient levels on epilepsy via Mendelian randomization (MR).

Methods: A two-sample MR framework evaluated the genetic association between 15 serum micronutrients and epilepsy phenotypes.

Safety of RNA-Dependent RNA Polymerase Inhibitors, Molnupiravir and VV116, for Oral Treatment of COVID-19: A Meta-Analysis.

Background: The RNA-dependent RNA polymerase (RdRp) inhibitors, molnupiravir and VV116, have the potential to maximize clinical benefits in the oral treatment of COVID-19. Subjects who consume these drugs may experience an increased incidence of adverse events. This study aimed to evaluate the safety profile of molnupiravir and VV116.

A causal relationship between appendicular lean mass and atrial fibrillation: A two sample Mendelian randomization study.

Background And Aim: The relationship between appendicular lean mass (ALM) and most cardiovascular events has been established, but the direct association between ALM and atrial fibrillation (AF) remains uncertain.

Methods And Results: Herein, we identified 494 single-nucleotide polymorphisms (SNPs) strongly associated with ALM as instrumental variables (P < 5E-8) based on a genome-wide association study (GWAS) with 450,243 European participants. Then, we employed five Mendelian randomization (MR) analysis methods to investigate the causal relationship between ALM and AF.

Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.

The prevalence of diabetic cardiomyopathy (DCM) increases year by year with the increase in the prevalence of diabetes mellitus (DM), which is one of the most serious cardiovascular complications of DM and a major cause of death in diabetic patients. Although the pathological molecular features of DCM have not been fully elucidated, increasing evidence suggests that impaired autophagy in cardiomyocytes plays a nonnegligible role in the development of DCM. It has been shown that SUMOylation [SUMO = small ubiquitin-like modifier], a post-translational modification of proteins, and its associated ubiquitin-proteasome system mediates protein quality control in the heart and plays an important role in the proteotoxic environment of the heart.

Genetic and immunological insights into COVID-19 with acute myocardial infarction: integrated analysis of mendelian randomization, transcriptomics, and clinical samples.

Background: Globally, most deaths result from cardiovascular diseases, particularly ischemic heart disease. COVID-19 affects the heart, worsening existing heart conditions and causing myocardial injury. The mechanistic link between COVID-19 and acute myocardial infarction (AMI) is still being investigated to elucidate the underlying molecular perspectives.

4-phenylbutyric acid re-trafficking hERG/G572R channel protein by modulating the endoplasmic reticulum stress-associated chaperones and endoplasmic reticulum-associated degradation gene.

Background: Long QT syndrome type 2 (LQT2) is caused by mutations in the /human ether-à-go-go-related gene (hERG). Some hERG genetic mutation-associated diseases are alleviated by hERG-specific drug chaperones (glycerol, dimethyl sulfoxide, trimethylamine N-oxide, thapsigargin), delayed rectifier K current (IKr) blockers methanesulfonanilide E4031, the antihistamine astemizole, or the prokinetic drug cisapride, and the anti-arrhythmic drug quinidine. Meanwhile, many and studies have reported the efficacy of 4-phenylbutyric acid (4-PBA) in diseases with inherited genetic mutations.

Synaptopodin-2: a potential tumor suppressor.

Initially identified as an actin-binding protein containing a PSD95-DLG-ZO1 Domain (PZD domain), Synaptopodin 2 (SYNPO2) has long been considered a structural protein ubiquitously expressed in muscular tissues. However, emerging evidence suggests that SYNPO2 performs diverse functions in cancers in addition to its role in microfilament assembly. In most cancers, high SYNPO2 expression is positively correlated with a good prognosis, suggesting its role as a novel tumor suppressor.

Immune-mediated inflammatory diseases and the risk of valvular heart disease: a Mendelian randomization study.

Background: Observational studies have suggested that immune-mediated inflammatory diseases (IMIDs) are associated with a higher risk of valvular heart disease (VHD). But the potential causal association is not clear. Therefore, we used Mendelian randomization (MR) analysis to assess the causal association of IMIDs with VHD risk.

Deciphering HERG mutation in long QT syndrome type 2 using antisense oligonucleotide-mediated techniques: Lessons from cystic fibrosis.

Long QT syndrome type 2 (LQT2) is a genetic disorder caused by mutations in the KCNH2 gene, also known as the human ether-a-go-go-related gene (HERG). More than 30% of HERG mutations result in a premature termination codon that triggers a process called nonsense-mediated messenger RNA (mRNA) decay (NMD), where the mRNA transcript is degraded. NMD is a quality control mechanism that removes faulty mRNA to prevent the translation of truncated proteins.

Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers.

KCNH2 encodes the human ether-a-go-go-related gene (hERG) potassium channel and is an important repolarization reserve for regulating cardiac electrical activity. Increasing evidence suggests that it is involved in the development of various tumours, yet a thorough analysis of the underlying process has not been performed. Here, we have comprehensively examined the role of KCNH2 in multiple cancers by assessing KCNH2 gene expression, diagnostic and prognostic value, genetic alterations, immune infiltration correlations, RNA modifications, mutations, clinical correlations, interacting proteins, and associated signalling pathways.

The Advantages, Challenges, and Future of Human-Induced Pluripotent Stem Cell Lines in Type 2 Long QT Syndrome.

Type 2 long QT syndrome (LQT2) is the second most common subtype of long QT syndrome and is caused by mutations in KCHN2 encoding the rapidly activating delayed rectifier potassium channel vital for ventricular repolarization. Sudden cardiac death is a sentinel event of LQT2. Preclinical diagnosis by genetic testing is potentially life-saving.

Chronic Administration of COVID-19 Drugs Fluvoxamine and Lopinavir Shortens Action Potential Duration by Inhibiting the Human Ether-à-go-go-Related Gene and Cav1.2.

Old drugs for new indications in the novel coronavirus disease of 2019 (COVID-19) pandemic have raised concerns regarding cardiotoxicity, especially the development of drug-induced QT prolongation. The acute blocking of the cardiac hERG potassium channel is conventionally thought to be the primary mechanism of QT prolongation induced by COVID-19 drugs fluvoxamine (FLV) and lopinavir (LPV). The chronic impact of these medications on the hERG expression has yet to be determined.

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein.

Long QT syndrome type 2 is caused by a mutation in the human‑ether‑a‑go‑go‑related gene (HERG) gene encoding the rapidly activating delayed rectifier K‑current. HERG is a key cell membrane glycoprotein; however, whether the maturation process of HERG protein involves key molecules derived from the calnexin (CNX)/calreticulin (CRT) cycle and how these molecules work remains unknown. Using western blotting, the present study screened the key molecules CNX/CRT/endoplasmic reticulum protein 57 (ERP57) involved in this cycle, and it was revealed that the protein expression levels of CNX/CRT/ERP57 in wild‑type (WT)/A561V cells were increased compared with those in WT cells (n=3; P<0.

Molecular Insights Into the Gating Kinetics of the Cardiac hERG Channel, Illuminated by Structure and Molecular Dynamics.

The rapidly activating delayed rectifier K current generated by the cardiac hERG potassium channel encoded by is the most important reserve current for cardiac repolarization. The unique inward rectification characteristics of the hERG channel depend on the gating regulation, which involves crucial structural domains and key single amino acid residues in the full-length hERG channel. Identifying critical molecules involved in the regulation of gating kinetics for the hERG channel requires high-resolution structures and molecular dynamics simulation models.