Genetic liability between COVID-19 and heart failure: Evidence from a bidirectional mendelian randomization study

Background: Previous studies have observed inconsistent associations between coronavirus disease 2019 (COVID-19) and heart failure (HF), but these studies were prone to bias based on reverse causality and residual confounding factors. We aimed to investigate genetic liability between COVID-19 and heart failure using a bidirectional Mendelian randomization study. Methods: The causal relationship between COVID-19 (including COVID-19, hospitalized COVID-19 compared with the general population, and severe COVID-19) and HF are determined by using a bidirectional Mendelian randomization analysis. We drew on summary statistics from the largest HF genome-wide association study (GWAS) meta-analysis on individuals of European ancestry, which included 47,309 HF patients and 930,014 controls. The inverse variance weighted (IVW), an adaption of the Egger regression (MR-Egger), the weighted median, and weighted model were conducted for the Mendelian randomization analysis to estimate a causal effect. To confirm the stability, we performed a “leave-one-out” approach for the sensitivity analysis. Results: Genetically predicted severe COVID-19 was not significantly associated with the risk of HF [odds ratio (OR), 1.003; 95% confidence interval (CI), 0.969–1.037; p = 0.867]. The IVW demonstrated that there was no association between genetically hospitalized COVID-19 infection and HF risk [OR, 1.009; 95% CI, 0.939–1.085; p = 0.797]. There was no evidence to support the association between genetically determined COVID-19 and the risk of HF [OR, 1.066; 95% CI, 0.955–1.190; p = 0.253]. In addition, genetically predicted HF was also not causally associated with COVID-19 [OR, 1.162; 95% CI, 0.824–1.639; p = 0.393]. MR-Egger analysis indicated no evidence of directional pleiotropy. Conclusion: The current bidirectional Mendelian randomization analysis overcomes the limitations of observational studies. Our findings indicated that there is no causal association between COVID-19 and HF

No casual relationship between T2DM and the risk of infectious diseases: A two-sample mendelian randomization study

Background: In epidemiological studies, it has been proven that the occurrence of type 2 diabetes mellitus (T2DM) is related to an increased risk of infectious diseases. However, it is still unclear whether the relationship is casual. Methods: We employed a two-sample Mendelian randomization (MR) to clarify the causal effect of T2DM on high-frequency infectious diseases: sepsis, skin and soft tissue infections (SSTIs), urinary tract infections (UTIs), pneumonia, and genito-urinary infection (GUI) in pregnancy. And then, we analyzed the genome-wide association study (GWAS) meta-analysis of European-descent individuals and conducted T2DM-related single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) that were associated with genome-wide significance (p \u3c 5 × 10–8). MR estimates were obtained using the inverse variance-weighted (IVW), the MR-Egger regression, the simple mode (SM), weighted median, and weighted mode. Results: The UK Biobank (UKB) cohort (n \u3e 500,000) provided data for GWASs on infectious diseases. MR analysis showed little evidence of a causal relationship of T2DM with five mentioned infections’ (sepsis, SSTI, UTI, pneumonia, and GUI in pregnancy) susceptibility [odds ratio (OR) = 0.99999, p = 0.916; OR = 0.99986, p = 0.233; OR = 0.99973, p = 0.224; OR = 0.99997, p = 0.686; OR, 1.00002, p = 0.766]. Sensitivity analysis showed similar results, indicating the robustness of causality. There were no heterogeneity and pleiotropic bias. Conclusion: T2DM would not be causally associated with high-frequency infectious diseases (including sepsis, SSTI, UTI, pneumonia, and GUI in pregnancy)

Proposing an avenue for suboptimal health research through the lens of tourism

The COVID-19 outbreak has posed tremendous threats to both global health and individuals’ psychological and physiological well-being. Scholars across the social and medical sciences are calling for multidisciplinary research regarding how the COVID-19 pandemic has affected global health [1]. As daily stressors continue to accumulate, the number of people reporting health complaints that cannot be detected by laboratory measures is on the rise [2,3]. These conditions can be complex and challenging to define but are generally deemed as “suboptimal health” [4]. Suboptimal health status (SHS) refers to a reversible state between health and illness [2]. It is characterized by health concerns (eg, back pain, headache, chronic fatigue) and constellations of symptoms (eg, anxiety, depression) that can affect one’s cardiovascular system [3,5,6], digestive system [7], immune system [4,8], and mental status [9,10]. Guidance from traditional Chinese medicine as reported by the China Association of Chinese Medicine suggests that SHS also hinders one’s adaptability, physiological state, and vitality [11]

The association between FGF21 and diabetic erectile dysfunction: Evidence from clinical and animal studies

Erectile dysfunction (ED), a complication of diabetes mellitus (DM), affects 50–75% of men with diabetes. Fibroblast growth factor 21 (FGF21) is a liver-derived metabolic regulator which plays a role in insulin-independent glucose uptake in adipocytes. We designed a clinical study and an animal experiment to investigate the relationship between FGF21 and DM-induced ED. The clinical study enrolled 93 participants aged \u3e 18 years (61 patients with type 2 DM and 32 healthy controls) from Taian City Central Hospital (TCCH) in Shandong Province, China, amongst whom the association between serum FGF21 and diabetic ED was analyzed. To further validate this association, we developed animal model of diabetic ED using Sprague-Dawley (SD) rats. Serum FGF21 concentration and FGF21 mRNA expression in penile samples of the rats were determined with Western blotting and quantitative real-time PCR. Among the 93 participants, the level of serum FGF21 was negatively correlated with the IIEF-5 score (r = -0.74, P \u3c 0.001). The analysis on the performance of FGF21 for ED diagnosis showed that the area under the receiver operating characteristic (ROC) curve was 0.875 (95% confidence interval [CI]: 0.803 to 0.946). In the animal experiment, the levels of serum FGF21, 2-Δ Δ Ct values of FGF21 mRNA expression, and relative levels of FGF21 in penile samples were higher in the ED group compared to the DM and control groups. Our findings demonstrated an association between the FGF21 level and diabetic ED, indicating the potential of this cytokine in predicting diabetic ED

MAPK1 promotes the metastasis and invasion of gastric cancer as a bidirectional transcription factor

Background: The Mitogen-activated protein kinase 1 (MAPK1) has both independent functions of phosphorylating histones as a kinase and directly binding the promoter regions of genes to regulate gene expression as a transcription factor. Previous studies have identified elevated expression of MAPK1 in human gastric cancer, which is associated with its role as a kinase, facilitating the migration and invasion of gastric cancer cells. However, how MAPK1 binds to its target genes as a transcription factor and whether it modulates related gene expressions in gastric cancer remains unclear. Results: Here, we integrated biochemical assays (protein interactions and chromatin immunoprecipitation (ChIP)), cellular analysis assays (cell proliferation and migration), RNA sequencing, ChIP sequencing, and clinical analysis to investigate the potential genomic recognition patterns of MAPK1 in a human gastric adenocarcinoma cell-line (AGS) and to uncover its regulatory effect on gastric cancer progression. We confirmed that MAPK1 promotes AGS cells invasion and migration by regulating the target genes in different directions, up-regulating seven target genes (KRT13, KRT6A, KRT81, MYH15, STARD4, SYTL4, and TMEM267) and down-regulating one gene (FGG). Among them, five genes (FGG, MYH15, STARD4, SYTL4, and TMEM267) were first associated with cancer procession, while the other three (KRT81, KRT6A, and KRT13) have previously been confirmed to be related to cancer metastasis and migration. Conclusion: Our data showed that MAPK1 can bind to the promoter regions of these target genes to control their transcription as a bidirectional transcription factor, promoting AGS cell motility and invasion. Our research has expanded the understanding of the regulatory roles of MAPK1, enriched our knowledge of transcription factors, and provided novel candidates for cancer therapeutics

Thirty-six months recurrence after acute ischemic stroke among patients with comorbid type 2 diabetes: A nested case-control study

Background: Stroke patients have to face a high risk of recurrence, especially for those with comorbid T2DM, which usually lead to much more serious neurologic damage and an increased likelihood of death. This study aimed to explore determinants of stroke relapse among patients with comorbid T2DM. Materials and methods: We conducted this case-control study nested a prospective cohort of ischemic stroke (IS) with comorbid T2DM. During 36-month follow-up, the second stroke occurred in 84 diabetic IS patients who were allocated into the case group, while 613 patients without recurrence were the controls. We collected the demographic data, behaviors and habits, therapies, and family history at baseline, and measured the variables during follow-up. LASSO and Logistic regression analyses were carried out to develop a prediction model of stroke recurrence. The receiver operator characteristic (ROC) curve was employed to evaluate the performance of the prediction model. Results: Compared to participants without recurrence, the higher levels of pulse rate (78.29 ± 12.79 vs. 74.88 ± 10.93) and hypertension (72.6 vs. 61.2 %) were recorded at baseline. Moreover, a lower level of physical activity (77.4 vs. 90.4 %), as well as a higher proportion of hypoglycemic therapy (36.9 vs. 23.3 %) was also observed during 36-month follow-up. Multivariate logistic regression revealed that higher pulse rate at admission (OR = 1.027, 95 % CI = 1.005 – 1.049), lacking physical activity (OR = 2.838, 9 5 % CI = 1.418 – 5.620) and not receiving hypoglycemic therapy (OR = 1.697, 95 % CI = 1.013 – 2.843) during follow-up increased the risk of stroke recurrence. We developed a prediction model using baseline pulse rate, hypoglycemic therapy, and physical activity, which produced an area under ROC curve (AUC) of 0.689. Conclusion: Physical activity and hypoglycemic therapy play a protective role for IS patients with comorbid diabetes. In addition to targeted therapeutics, the improvement of daily-life habit contributes to slowing the progress of the IS

IgG N-glycosylation cardiovascular age tracks cardiovascular risk beyond calendar age

The use of an altered immunoglobulin G (IgG) N-glycan pattern as an inflammation metric has been reported in subclinical atherosclerosis and metabolic disorders, both of which are important risk factors in cardiovascular health. However, the usable capacity of IgG N-glycosylation profiles for the risk stratification of cardiovascular diseases (CVDs) remains unknown. This study aimed to develop a cardiovascular aging index for tracking cardiovascular risk using IgG N-glycans. This cross-sectional investigation enrolled 1465 individuals aged 40–70 years from the Busselton Healthy and Ageing Study. We stepwise selected the intersection of altered N-glycans using feature-selection methods in machine learning (recursive feature elimination and penalized regression algorithms) and developed an IgG N-glycosylation cardiovascular age (GlyCage) index to reflect the deviation from calendar age attributable to cardiovascular risk. The strongest contributors to GlyCage index were fucosylated N-glycans with bisecting N-acetylglucosamine (GlcNAc) (glycan peak 6 (GP6), FA2B,) and digalactosylated N-glycans with bisecting GlcNAc (GP13, A2BG2). A one-unit increase of GlyCage was significantly associated with a higher Framingham ten-year cardiovascular risk (odds ratio (OR), 1.09; 95% confidence interval (95% CI): 1.05–1.13) and probability of CVDs (OR, 1.07; 95% CI: 1.01–1.13) independent of calendar age. Individuals with excessive GlyCage (exceeding a calendar age \u3e 3 years) had an increased cardiovascular risk and probability of CVDs, with adjusted ORs of 2.22 (95% CI: 1.41–3.53) and 2.71 (95% CI: 1.25–6.41), respectively. The area under curve (AUC) values of discriminating high cardiovascular risk and events were 0.73 and 0.65 for GlyCage index, and 0.65 and 0.63 for calendar age. The GlyCage index developed in this study can thus be used to track cardiovascular health using IgG N-glycosylation profiles. The distance between GlyCage and calendar age independently indicates the cardiovascular risk, suggesting that IgG N-glycosylation plays a role in the pathogenesis of CVDs. The generalization of the observed associations and the predictive capability of GlyCage index require external and longitudinal validation in other populations