Biomedical subjects

Moritz von Scheidt

Publications and source records attributed to Moritz von Scheidt.

3 recordsLinked to original sources

PubMed2026

Targeting super elongation complex-driven RNA polymerase II elongation reduces plaque vulnerability.

Atherosclerotic plaque rupture is a major cause of myocardial infarction and stroke, yet the mechanisms governing plaque stability remain incompletely understood. Endothelial activation can trigger endothelial-to-mesenchymal transition, a program linked to endothelial dysfunction and lesion vulnerability. Here we investigated whether transcriptional pause release and RNA polymerase II elongation constitute an early regulatory layer that promotes endothelial-to-mesenchymal transition and atherosclerosis. Analysis of human plaque single-cell transcriptomics indicated increased expression of super elongation complex components in endothelial cells with a transition signature. In primary human endothelial cell models, pharmacological inhibition of the super elongation complex attenuated the induction of mesenchymal markers. AFF4, pCDK9, and pSMAD2/3 showed physical interaction during endothelial transition. Genome-wide profiling of RNA polymerase II occupancy revealed reduced promoter-proximal pausing during early transition, accompanied by a rapid increase in nascent transcriptional elongation rates. Super elongation complex inhibition restored pausing and suppressed fast-responding transition-associated target genes. In a human cardiac organoid model, inhibition of the super elongation complex prevented EndMT-induced fibrillar collagen deposition and prevented the loss of beating rate. In a hyperlipidemic Pcsk9 gain-of-function mouse model, super elongation complex inhibition administered both prophylactically and therapeutically after established atherosclerosis reduced plaque burden and reduced features of plaque vulnerability. Finally, analysis of 1048 human plaque segments from the Athero-Express biobank showed significant associations between the elongation axis and multiple vulnerability-related plaque traits. Together, these findings identify rapid transcriptional elongation as a mechanistic driver of endothelial plasticity and features of plaque vulnerability and support targeting the elongation machinery as a potential strategy to reduce features of plaque vulnerability in atherosclerotic disease.

Humans↗

PubMed2026

Genetic screening of children for familial hypercholesterolaemia: the VRONI study.

BACKGROUND AND AIMS: The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS: In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS: Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS: The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.

Humans↗

PubMed2025

Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.

IMPORTANCE: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD. OBJECTIVE: To identify genetic risk loci and cardiovascular risk factors with AS-specific associations. DESIGN, SETTING, AND PARTICIPANTS: This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023. EXPOSURES: Genetic variants. MAIN OUTCOMES AND MEASURES: Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts. RESULTS: A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development. CONCLUSIONS AND RELEVANCE: This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.

Humans↗