Biology subjects

Bjorkegren, J.

Publications and source records attributed to Bjorkegren, J..

5 recordsLinked to original sources

bioRxiv2026

Sex-Specific Regulation of Endothelial-to-Mesenchymal Transition (EndMT) During Atherosclerosis

Sex differences in atherosclerotic plaque biology underlie clinically distinct manifestations of acute coronary syndromes, yet the molecular mechanisms driving these differences remain incompletely understood. Endothelial-to-mesenchymal transition (EndMT) is increasingly recognized as a contributor to plaque remodeling, but whether EndMT is regulated in a sex-specific and stage-dependent manner across atherosclerosis has not been systematically examined. Here, we integrated bulk RNA sequencing with single-cell transcriptomic analyses in endothelial cells and human atherosclerotic plaques to define sex-specific EndMT regulation across healthy and advanced-stage disease. Using trajectory analyses in endothelial cells undergoing EndMT, we observed pronounced sex-specific regulation in healthy endothelium, with females exhibiting stronger early EndMT activation, whereas endothelial cells derived from atherosclerotic plaques displayed markedly attenuated sex differences with disease progression. Consistent sex-divergent pseudotime trajectories were observed in human carotid plaque endothelial single-cell RNA-seq data, with females showing greater EndMT activation at earlier stages and males at later stages. Together, these findings support a stage-dependent model of sex-specific EndMT regulation, indicating that the functional consequences of EndMT are highly context dependent and may differ across early and late disease stages. Integration of these datasets prioritized high-confidence sex-specific EndMT regulators, including COL4A1, PECAM1, CD151, JAG1, FN1, NEDD9, PODXL, MAFB, PROCR, and CDH13, providing a mechanistic framework to explain clinically observed sex differences in plaque biology and to guide targeted functional interrogation.

genomics↗

bioRxiv2025

Multi-Tissue Profiling Reveals tissue-specific protein regulation and relationships Between Protein Quantitative Trait Loci (pQTLs) and Cardiometabolic Disease

Integrating genetic data with protein levels, known as protein quantitative trait loci (pQTLs), can enhance our understanding of disease mechanisms and provide actionable insights for drug discovery, by guiding the direction of therapeutic interventions, clarifying mechanisms of action, and predicting potential side effects. However, most pQTL studies have focused on the plasma proteome, overlooking tissue-specific effects. Here, we investigate the plasma and tissue proteome and derive tissue-specific pQTLs in a unique dataset derived from a cohort of 284 STARNET patients, predominantly male, with a mean age of 65 years and a high prevalence of coronary artery disease (CAD). Importantly, our dataset includes paired tissue samples from aortic wall, mammary artery, liver, and skeletal muscle alongside plasma, allowing for a comprehensive comparative analysis across tissues--all from the same individuals. We employed the Olink Explore 3.2k platform to assess relative protein levels in each tissue. We identify 608 cis-pQTLs, the majority of which are found in plasma, reflecting greater protein variability. Notably, we find 13 proteins with exclusive tissue-specific pQTLs, underscoring distinct as well as shared genetic influences across tissues. Colocalization analyses reveal shared genetic regulation between tissue proteins and cardiometabolic traits, including LDL, HDL, and triglycerides levels, implicating proteins such as PNLIPRP2, SORT1, and PRSS53 as potential mediators of lipid regulation. Furthermore, Mendelian randomization analyses suggest a liver-specific role for SORT1 and PSRC1 in modulating CAD risk and lipid profiles. Our findings highlight the importance of profiling tissue-shared, and tissue-specific, protein expression and pQTLs to elucidate disease mechanisms and accelerate precision drug and biomarker discovery.

genetics↗

bioRxiv2023

Shared and distinct pathways and networks genetically linked to coronary artery disease between human and mouse

Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.

systems biology↗

bioRxiv2022

Predicting mechanisms of action at genetic loci associated with discordant effects on type 2 diabetes and abdominal fat accumulation

Metabolic syndrome (MetSyn) is a cluster of dysregulated metabolic conditions that occur together to increase the risk for cardiometabolic disorders such as type 2 diabetes (T2D). One key condition associated with MetSyn, abdominal obesity, is measured by computing the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI). WHRadjBMI and T2D are complex traits with genetic and environmental components, which has enabled genome-wide association studies (GWAS) to identify hundreds of loci associated with both. Statistical genetics analyses of these GWAS have predicted that WHRadjBMI is a strong causal risk factor of T2D and that these traits share genetic architecture at many loci. To date, no variants have been described that are simultaneously associated with protection from T2D but with increased abdominal obesity. Here, we used colocalization analysis to identify genetic variants with a shared association for T2D and abdominal obesity. This analysis revealed the presence of five loci associated with discordant effects on T2D and abdominal obesity. The alleles of the lead genetic variants in these loci that were protective against T2D were also associated with increased abdominal obesity. We further used publicly available expression, epigenomic, and genetic regulatory data to predict the effector genes (eGenes) and functional tissues at the 2p21, 5q21.1, and 19q13.11 loci. We also computed the correlation between the subcutaneous adipose tissue (SAT) expression of predicted effector genes (eGenes) with metabolic phenotypes and adipogenesis. We proposed a model to resolve the discordant effects at the 5q21.1 locus. We find that eGenes gypsy retrotransposon integrase 1 (GIN1), diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2), and peptidylglycine alpha-amidating monooxygenase (PAM) represent the likely causal eGenes at the 5q21.1 locus. Taken together, these results are the first to describe a potential mechanism through which a genetic variant can confer increased abdominal obesity but protection from T2D risk. Understanding precisely how and which genetic variants confer increased risk for MetSyn will develop the basic science needed to design novel therapeutics for metabolic syndrome.

genomics↗

bioRxiv2020

Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 - implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients

Accumulating clinical observations implicate vascular inflammation as an underlying cause of coagulopathy in severely ill COVID-19 patients and it was recently suggested that SARS-CoV-2 virus particles infect endothelial cells. Here, we show that endothelial cells do not express angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 receptor. Instead, pericytes and microvascular smooth muscle cells express ACE2 in an organotypic manner. Pericyte deficiency leads to increased endothelial expression and release of Von Willebrand factor and intravascular platelet and fibrin aggregation, suggesting that pericytes limit endothelial pro-thrombotic responses. That pericytes and not endothelial cells express ACE2 may provide important clues to the pathology of COVID-19, as pericytes are normally shielded behind an endothelial barrier and may get infected only when this barrier is compromised by COVID-19 risk factors.

pathology↗