ArticlePLoS genetics2015
Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 94 citations in OpenAlex.
- Use of Mendelian Randomization to Unveil Metabolic Markers inJournal of Korean medical science · 2026Pooled it
- Metabolic markers of kidney function and oxidative stress are associated with heart failure with preserved ejection fraction (HFpEF) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD).Metabolomics : Official journal of the Metabolomic Society · 2026Article
- Unbiased Discovery of Genetic Determinants of Resilience to CAD: Insights From PROMISE and CATHGEN.JACC. Advances · 2026Article
- Association of programmed cell death with atrial fibrillation risk: A multi-omics Mendelian randomization study.Medicine · 2026Article
- Application of Mendelian randomization to explore metabolic pathways in colorectal cancer.Annals of medicine and surgery (2012) · 2025Article
- Trans-omics analyses identify the biochemical network of LPCAT1 associated with coronary artery disease.Biomarker research · 2025Article
- Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes.Molecular psychiatry · 2025Article
- Metabolic origin and significance of 3-methylglutaryl CoA.Clinica chimica acta; international journal of clinical chemistry · 2025Review
- Multiomics of Aging and Aging-Related Diseases.International journal of molecular sciences · 2024Review
- Article
- Leveraging molecular quantitative trait loci to comprehend complex diseases/traits from the omics perspective.Human genetics · 2023Review
- 3-Methylglutarylcarnitine: A biomarker of mitochondrial dysfunction.Clinica chimica acta; international journal of clinical chemistry · 2023Review
- Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma.Cell metabolism · 2023Article
- Role of STIM1 in the Regulation of Cardiac Energy Substrate Preference.International journal of molecular sciences · 2023Review
- Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.Cell metabolism · 2023Article
- An antiplatelet response gene expression signature is associated with bleeding.Cardiovascular research · 2023Article
- Regulation of MAPK Signaling Pathways by the Large HERC Ubiquitin Ligases.International journal of molecular sciences · 2023Review
- Sex-dimorphic gene effects on survival outcomes in people with coronary artery disease.American heart journal plus : cardiology research and practice · 2022Article
- The Potential of Metabolomics in Biomedical Applications.Metabolites · 2022Review
- COMETS Analytics: An Online Tool for Analyzing and Meta-Analyzing Metabolomics Data in Large Research Consortia.American journal of epidemiology · 2022Article
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
Abstract
Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.
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