Synlab (Germany)

Cholesterol is a main contributor to coronary artery disease (CAD). Although the genetic basis of blood cholesterol concentration is well studied, there is currently a lack of studies investigating the genetics of its precursors from de novo biosynthesis. We conducted a genome-wide association meta-analysis, combining data from KORA, LIFE-Heart, LIFE-Adult, LURIC, the Sorbs study, and YFS, resulting in up to 10,519 individuals. We investigated 14 traits related to serum concentrations of lanosterol, desmosterol, and cholesterol. Direct and indirect effects of lanosterol on CAD were investigated with a Mendelian randomisation mediation analysis. Our analysis revealed four genome-wide significant (p < 5 × 10-8) associations not previously reported in the GWAS catalogue. These include two loci without prior connection to cholesterol, associated with lanosterol (7q21.2, CYP51A1) and free cholesterol (11q14.1), and two associations with lanosterol at loci previously reported for cholesterol (5q13.3, HMGCR; 11q23.3, APO cluster). We also replicated eight loci previously reported for associations with cholesterol-related traits. Lanosterol exhibited significant total and indirect effects on CAD, but its direct effect was not significant. We demonstrate that the investigation of intermediate phenotypes can help to functionally fine map previously reported associations for cholesterol, improving our understanding of genetic regulation of cholesterol concentrations. Further, the effect of lanosterol on CAD is probably fully mediated by total cholesterol. This investigation was primarily funded by the ministry for science and health of the Rhineland-Palatinate through the CoAGE graduate programme. A complete list of funding organisations is provided in the acknowledgements.

Vitamin D status is influenced by genetic and environmental factors—primarily sun exposure. Using satellite weather data, we estimated an ambient UVB dose for each participant based on residential address and date of sampling. We conducted genome-wide tests in 338,977 UK Biobank White British participants, adjusted for age, sex, supplements, UVB dose, and 10 principal components to account for population structure. We applied three models to test for genetic effects: marginal only, main and interaction, and joint effects. We identified 307 variants associated with standardised log-transformed 25-hydroxyvitamin D (25OHD) concentration, 162 of which were not previously identified in GWAS. We identify an increase in SNP-heritability by increasing ambient UVB exposure quintiles (h2Q1 = 8.48% vs. h2Q5 = 15.56%). Downstream annotation implicated genes in the 25OHD pathway, including the circadian regulator, BMAL1. This and further findings suggest that vitamin D status and circadian rhythm may be entangled and that vitamin D metabolites may have a role as mediators of seasonal physiological fluctuations, including metabolism, and in turn explain the established associations with lipid metabolism pathways.

Background: Pulse pressure (PP), the difference between systolic (SBP) and diastolic blood pressure (DBP), is an essential marker of cardiovascular (CV) health and arterial stiffness. Elevated PP is linked to a higher risk of CV events, a major cause of global mortality. This study examines its association with key electrolytes – sodium, potassium, calcium, magnesium, phosphate, and vitamin D – in blood-pressure regulation and vascular function. Methods: We analysed data from 3,316 LURIC participants who underwent coronary angiography and had a median follow-up of 9.9 years. Fasting blood samples were collected at baseline. Associations between PP and electrolyte levels were assessed using Spearman correlation. Logistic regression models were used to calculate odds ratios (ORs) per standard deviation (SD) of PP and electrolyte concentrations for four clinical outcomes: all-cause mortality, CV mortality, reduced estimate the glomerular filtration rate (eGFR), and type 2 diabetes mellitus. Results: The cohort’s average age was 62.7 years, with 70% of participants being male. Higher PP was significantly associated with older age, increased body mass index, and the prevalence of coronary artery disease (CAD), carotid stenosis, and peripheral arterial disease. Potassium, phosphate, renin, 25-OH, and 1,25-OH vitamin D concentrations decreased significantly as PP increased, while sodium remained unchanged. Sodium-potassium ratio and aldosterone-renin ratio increased with higher PP. Women had a higher risk of CV mortality per SD of PP (OR 1.57; 95% confidence interval [CI]: 1.33–1.86), while men showed a greater risk of reduced eGFR (OR 1.59; 95% CI: 1.40–1.80). Conclusion: Specific electrolyte imbalances are closely linked to increased PP and arterial stiffness. Our findings highlight sex-specific CV risk and support further research into nutrient-based and hormonal interventions targeting PP modulation.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and current predictors such as lipoprotein (a) [Lp(a)] and risk scores have limitations. Automated machine learning (AutoML) offers the potential to improve CVD risk prediction by processing large datasets and developing tailored models without the need for extensive data science expertise. Using clinical datasets from the LURIC (n = 3316) and UMC/M (n = 423) studies, we built AutoML models to predict Lp(a), specific CVDs and CVD-related mortality in three phases. Phase 1 identified key CVD determinants such as age, Lp(a), troponin T, BMI and cholesterol with good accuracy (AUC 0.6249 to 0.9101). Phase 2 validated models in the UMC/M dataset and showed robust performance (AUC 0.7224 to 0.8417), with SHAP analysis highlighting predictors like statin therapy, age and NTproBNP. Phase 3 focused on cardiovascular mortality prediction, achieving high AUC values (0.74 to 0.85) and showed data drift, highlighting the need for model adjustment.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-24189-z.

BackgroundStudies examining the association of chronic kidney disease (CKD) with cancer risk have demonstrated conflicting results.MethodsThis was an individual participant data meta-analysis including 54 international cohorts contributing to the CKD Prognosis Consortium. Included cohorts had data on albuminuria [urine albumin-to-creatinine ratio (ACR)], estimated glomerular filtration rate (eGFR), overall and site-specific cancer incidence, and established risk factors for cancer. Included participants were aged 18 years or older, without previous cancer or kidney failure.ResultsAmong 1,319,308 individuals, the incidence rate of overall cancer was 17.3 per 1000 person-years. Higher ACR was positively associated with cancer risk [adjusted hazard ratio 1.08 (95% CI 1.06–1.10) per 8-fold increase in ACR]. No association of eGFR with overall cancer risk was seen. For site-specific cancers, lower eGFR was associated with urological cancer and multiple myeloma, whereas higher ACR was associated with many cancer types (kidney, head/neck, colorectal, liver, pancreas, bile duct, stomach, larynx, lung, hemolymphatic, leukaemia, and multiple myeloma). Results were similar in a 1-year landmark analysis.DiscussionAlbuminuria, but not necessarily eGFR, was independently associated with the subsequent risk of cancer. Our results warrant an investigation into mechanisms that explain the link between albuminuria and cancer.

Objective: To assess changes in disease activity in Multiple Sclerosis (MS) patients on various disease-modifying-drugs, as well as immunogenicity, safety and clinical tolerability following combined tetanus- and diphtheria-vaccination. Methods: We conducted a prospective, multicentre, non-randomised real-world observational study at specialised outpatient MS care centres in Germany. We enrolled multiple sclerosis patients receiving a combined tetanus- and diphtheria-vaccination who had a stable MS-treatment regimen for at least six months and had an indication for this vaccination. Serum samples were obtained before and four weeks after vaccination for specific antibody response. Antibody concentrations against vaccine antigens were measured in duplicate via ELISA. Subjects were followed for one year after immunisation. MS disease activity (EDSS and relapse rates) was evaluated at follow-up visits. Local and systemic adverse events were registered four weeks after vaccination. Results: In total, 72 MS patients received tetanus and diphtheria vaccination. The annualised relapse rates in the year after vaccination were comparable to the year before vaccination (0.39 vs. 0.37). During the study period, the EDSS score did not change significantly. The score was 2.0 and 2.2 in the two years prior to vaccination and 2.5 in the year following vaccination. No subjects experienced severe adverse events. However, 14 (19.4%) had local adverse events, and 10 (13.9%) had systemic reactions. Following vaccination, all subjects had protective antibody titres against tetanus- and diphtheria-toxoid. Geometric mean antibody titres of tetanus toxoid antibodies increased from 0.64 IU/mL to 2.23 IU/mL (p < 0.0001) and of diphtheria toxoid antibodies from 0.1 IU/mL to 0.45 IU/mL (p < 0.0001). Conclusions: Tetanus- and diphtheria vaccination proved to be safe and effective in MS patients in a real-world situation.

The reduction of LDL cholesterol lowers the risk of coronary and cerebrovascular events in individuals without manifest cardiovascular diseases. In Germany, statins at the expense of statutory health insurance had only been permitted for patients with atherosclerosis-related diseases or those at high cardiovascular risk (over 20 percent event probability within the next 10years, calculated using one of the "available risk calculators"). However, international guidelines recommend lower risk thresholds for the use of statins. The health and economic impacts of different risk thresholds for statin use in primary prevention within the German population are estimated for thresholds of 7.5, 10, and 15 percent over 10years, based on the US Pooled Cohort Equation (PCE) which is valid for Germany, using Markov models. Cost-effectiveness increases with a rising risk threshold, while individual benefit decreases with age at the start of treatment. The use of statins at a risk of 7.5 percent or more is cost-effective at any age (cost per QALY between 410 and 2100 Euros). In none of the examined scenarios does the proportion of the population qualifying for statin therapy exceed 25 percent. Lowering the threshold for statin therapy to a risk of 7.5 percent of either non-fatal myocardial infarction, coronary heart disease death, non-fatal or fatal stroke would align statin prescription in Germany with international standards. There is no urgent rationale for applying age-stratified risk thresholds.

ABSTRACTBackgroundPatients with end-stage kidney disease (ESKD) undergoing haemodialysis (HD) have a high risk of cardiovascular (CV) events. This study evaluated troponin I (hs-cTnI) as a predictor of major adverse cardiac events (MACEs), CV death and all-cause death.MethodsThe AURORA trial, a multicentre, randomized, double-blind trial involved 2776 HD patients comparing rosuvastatin with placebo. No significant effect was found on the composite primary endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke. In this post hoc analysis, we analysed the association between baseline hs-cTnI and outcomes using Cox regression analyses. We adjusted for multiple background factors and available biomarkers. Hs-cTnI was log2-transformed and modelled using a four-knot restricted cubic spline. Variables were ordered by their importance in the models using χ2 value minus degrees of freedom.ResultsBaseline median hs-cTnI was 17.3 pg/mL. During follow-up, 734 MACEs, 598 CV deaths, and 1094 total deaths occurred. Patients in the upper quartile of hs-cTnI (>32.6 pg/mL) had significantly higher risk of MACEs [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.57–2.35], CV death (HR 2.12; 95% CI 1.69–2.66), all-cause death (HR 1.84; 95% CI 1.55–2.17) and non-CV death (HR 1.59; 95% CI 1.23–2.05) after full adjustment compared with those in the lowest quartile (<10.1 pg/mL). Hs-cTnI was identified as the strongest predictor for MACEs, CV death, and all-cause death, but not for non-CV death.ConclusionsBaseline hs-cTnI is a strong and independent predictor for MACEs and death in patients with ESKD undergoing haemodialysis.

Existing leadership theories often fail to address the complexity and uncertainty of today’s volatile environments, reducing leadership to fixed traits, prescriptive styles, or simple cause-and-effect models. This study challenges these paradigms by integrating critical realism with quantum principles, creating a framework that reflects the multifaceted demands of modern leadership. The proposed model views leadership as a multi-layered, adaptive process where past experiences, present conditions, and future possibilities interact continuously. By incorporating quantum concepts like superposition, entanglement, and subjective probabilities, this framework redefines leadership as dynamic and relational, enabling leaders to balance conflicting demands and adapt decisions in real time. This probabilistic approach shifts away from rigid, deterministic models, empowering leaders to operate with resilience in complex, ambiguous contexts. For research, this synthesis provides new opportunities to explore hidden social, psychological, and cultural mechanisms that shape leadership. Beyond observable metrics, it emphasizes the deeper forces underlying leadership dynamics, inviting interdisciplinary studies across physics, psychology, and organizational behavior. For practitioners, retroductive inference fosters an approach that integrates theoretical insights with practical tools, enabling leaders to uncover root causes, analyze patterns, and refine strategies through counterfactual thinking. By addressing underlying mechanisms rather than surface symptoms, it empowers leaders to make informed and decisive choices in complex, dynamic contexts.