title: Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.
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.
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina, United States of America.|Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.|Division of Endocrinology, Department of Medicine, Duke University, Durham, North Carolina, United States of America.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Stevens
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Damian
authors.initials: D
authors.lastname: Craig
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Grass
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kwee
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Qin
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Dorothy H
authors.initials: DH
authors.lastname: Slentz
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Deidre
authors.initials: D
authors.lastname: Krupp
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Muehlbauer
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.|Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States of America.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina, United States of America.|Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics* / Q000473:pathology; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D006801:Humans; D055432:Metabolomics; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D040641:Quantitative Trait Loci; D012307:Risk Factors; D025801:Ubiquitin / Q000235:genetics*
chemical_list: D025801:Ubiquitin; C116917:acylcarnitine; D046988:Proteasome Endopeptidase Complex; D002331:Carnitine