High genetic risk for depression as an independent risk factor for mortality in patients referred for coronary angiography

BackgroundDifferent observations have suggested that patients with depression have a higher risk for a number of comorbidities and mortality. The underlying causes have not been fully understood yet.AimsThe aim of our study was to investigate the association of a genetic depression risk score (GDRS) with mortality [all-cause and cardiovascular (CV)] and markers of depression (including intake of antidepressants and a history of depression) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study involving 3,316 patients who had been referred for coronary angiography.Methods and resultsThe GDRS was calculated in 3,061 LURIC participants according to a previously published method and was found to be associated with all-cause (p = 0.016) and CV mortality (p = 0.0023). In Cox regression models adjusted for age, sex, body mass index, LDL-cholesterol, HDL-cholesterol, triglycerides, hypertension, smoking, and diabetes mellitus, the GDRS remained significantly associated with all-cause [1.18 (1.04–1.34, p = 0.013)] and CV [1.31 (1.11–1.55, p = 0.001)] mortality. The GDRS was not associated with the intake of antidepressants or a history of depression. However, this cohort of CV patients had not specifically been assessed for depression, leading to marked underreporting. We were unable to identify any specific biomarkers correlated with the GDRS in LURIC participants.ConclusionA genetic predisposition for depression estimated by a GDRS was independently associated with all-cause and CV mortality in our cohort of patients who had been referred for coronary angiography. No biomarker correlating with the GDRS could be identified

Diagnostic Performance of Rapid Antigen Testing for SARS-CoV-2: The COVid-19 AntiGen (COVAG) study

Background Rapid diagnostic testing for SARS-Cov-2 antigens is used to combat the ongoing pandemic. In this study we aimed to compare two RDTs, the SD Biosensor Q SARS-CoV-2 Rapid Antigen Test (Roche) and the Panbio COVID-19 Ag Rapid Test (Abbott), against rRT-PCR. Methods We included 2,215 all-comers at a diagnostic center between February 1 and March 31, 2021. rRT-PCR-positive samples were examined for SARS-CoV-2 variants. Findings Three hundred and thirty eight participants (15%) were rRT-PCR-positive for SARS-CoV-2. The sensitivities of Roche-RDT and Abbott-RDT were 60.4 and 56.8% ( P < 0.0001) and specificities 99.7% and 99.8% ( P = 0.076). Sensitivity inversely correlated with rRT-PCR-Ct values. The RDTs had higher sensitivities in individuals referred by treating physicians (79.5%, 78.7%) than in those referred by health departments (49.5%, 44.3%) or tested for other reasons (50%, 45.8%), in persons without any comorbidities (74.4%, 71%) compared to those with comorbidities (38.2%, 34.4%), in individuals with COVID-19 symptoms (75.2%, 74.3%) compared to those without (31.9%, 23.3%), and in the absence of SARS-CoV-2 variants (87.7%, 84%) compared to Alpha variant carriers (77.1%, 72.3%). If 10,000 symptomatic individuals are tested of which 500 are truly positive, the RDTs would generate 38 false-positive and 124 false-negative results. If 10,000 asymptomatic individuals are tested, including 50 true positives, 18 false-positives and 34 false-negatives would be generated. Interpretation The sensitivities of the two RDTs for asymptomatic SARS-CoV-2 carriers are unsatisfactory. Their widespread use may not be effective in the ongoing SARS-CoV-2 pandemic. The virus genotype influences the sensitivity of the two RDTs. RDTs should be evaluated for different SARS-CoV-2 variants

Are soluble ST2 levels influenced by vitamin D and/or the seasons?

Objective: Cardiovascular disease manifestation and several associated surrogate markers, such as vitamin D, have shown substantial seasonal variation. A promising cardiovascular biomarker, soluble ST2 (sST2), has not been investigated in this regard – we therefore determined if systemic levels of sST2 are affected by seasonality and/or vitamin D in order to investigate their clinical interrelation and usability. Design: sST2 levels were measured in two cohorts involving hypertensive patients at cardiovascular risk, the Styrian Vitamin D Hypertension Trial (study A; RCT design, 8 weeks 2800 IU cholecalciferol daily) and the Ludwigshafen Risk and Cardiovascular Health Study (LURIC; study B; cross-sectional design). Methods: The effects of a vitamin D intervention on sST2 levels were determined in study A using ANCOVA, while seasonality of sST2 levels was determined in study B using ANOVA. Results: The concentrations of sST2 remained unchanged by a vitamin D intervention in study A, with a mean treatment effect (95% confidence interval) of 0.1 (−0.6 to 0.8) ng/mL; P = 0.761), despite a rise in 25(OH)D (11.3 (9.2–13.5) ng/mL; P < 0.001) compared to placebo. In study B, seasonal variations were present in 25(OH)D levels in men and women with or without heart failure (P < 0.001 for all subgroups), while sST2 levels remained unaffected by the seasons in all subgroups. Conclusions: Our study provides the first evidence that systemic sST2 levels are not interrelated with vitamin D levels or influenced by the seasons in subjects at cardiovascular risk

Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

Does hepatotoxicity interfere with endocrine activity in zebrafish (Danio rerio)?

Vitellogenin (VTG), a well-established biomarker for the diagnosis of endocrine activity in fish, is used in multiple OECD test guidelines (TG) to identify activities of chemicals on hormonal pathways. However, the synthesis of VTG may not only be modified by typical endocrine-related pathways, but also through non-endocrine-mediated processes. In particular, hepatotoxicity, i.e. toxicant-induced impairment of liver structure and function, might influence VTG as a biomarker, since VTG is synthesized in hepatocytes. An intimate understanding of the interplay between endocrine-related and non-endocrine-related pathways influencing VTG production is crucial for the avoidance of erroneous diagnoses in hazard assessment for regulatory purposes of chemical compounds. In order to investigate whether hepatotoxicity may interfere with hepatic VTG synthesis, adult zebrafish (Danio rerio) were exposed to three well-known hepatotoxicants, acetaminophen, isoniazid and acetylsalicylic acid, according to OECD TG 230. Various hepatotoxicity- and endocrine system-related endpoints were recorded: mRNA expression of selected endocrine- and hepatotoxicity-related marker genes in the liver; VTG levels in head/tail homogenates; and liver histopathology. All three test compounds induced significant, but mild single cell necrosis of hepatocytes and transcriptional changes of hepatotoxicity-related marker genes, thus confirming hepatotoxic effects. A positive correlation between hepatotoxicity and reduced hepatic VTG synthesis was not observed, with the single exception of a weak increase in female zebrafish exposed to APAP. This suggests that - in studies conducted according to OECD TG 229 or 230 - it is unlikely that hepatotoxic chemicals will interfere with the hepatic capacity for VTG synthesis

Clusters of prediabetes and type 2 diabetes stratify all-cause mortality in a cohort of participants undergoing invasive coronary diagnostics

Abstract Background Heterogeneous metabolic clusters have been identified in diabetic and prediabetic states. It is not known whether such pathophysiologic clusters impact survival in at-risk persons being evaluated for coronary heart disease. Methods The LURIC Study recruited patients referred for coronary angiography at a median age of 63 (IQR 56–70) with a follow-up of 16.1 (IQR 9.6, 17.7) years. Clustering of 1269 subjects without diabetes was performed with oGTT-derived glucose and insulin; fasting triglyceride, high-density lipoprotein, BMI, waist and hip circumference. Patients with T2D (n = 794) were clustered using age, BMI, glycemia, homeostasis model assessment, and islet autoantibodies. Associations of clusters with mortality were analysed using Cox regression. Results Individuals without diabetes were classified into six subphenotypes, with 884 assigned to subjects at low-risk (cluster 1,2,4) and 385 at high-risk (cluster 3,5,6) for diabetes. We found significantly increased mortality in clusters 3 (hazard ratio (HR)1.42), 5 (HR 1.43), and 6 (HR 1.46) after adjusting for age, BMI, HbA1c and sex. In the T2D group, 508 were assigned to mild age-related diabetes (MARD), 183 to severe insulin-resistant diabetes (SIRD), 84 to mild obesity-related diabetes (MOD), 19 to severe insulin-deficient diabetes (SIDD). Compared to the low-risk non-diabetes group, crude mortality was not different in MOD. Increased mortality was found for MARD (HR 2.2), SIRD (HR 2.2), and SIDD (HR 2.5). Conclusions Metabolic clustering successfully stratifies survival even among persons undergoing invasive coronary diagnostics. Novel clustering approaches based on glucose metabolism can identify persons who require special attention as they are at risk of increased mortality

Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10$^{-8}$), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease

Arterioscler Thromb Vasc Biol

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of AT included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels