Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Kraus, William E

Muoio, Deborah M

Stevens, Robert

Craig, Damian

Bain, James R

Grass, Elizabeth

Haynes, Carol

Kwee, Lydia

Qin, Xuejun

Slentz, Dorothy H

Krupp, Deidre

Muehlbauer, Michael

Hauser, Elizabeth R

Gregory, Simon G

Newgard, Christopher B

Shah, Svati H

Lusis, Aldons J

United States

2015-12-03T14:24:33Z

2015-11

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.

http://www.ncbi.nlm.nih.gov/pubmed/26540294

PGENETICS-D-15-00625

1553-7404

https://hdl.handle.net/10161/10957

eng

Public Library of Science (PLoS)

PLoS Genet

10.1371/journal.pgen.1005553

Cardiovascular Diseases

Carnitine

DNA Methylation

Endoplasmic Reticulum Stress

Humans

Metabolomics

Polymorphism, Single Nucleotide

Proteasome Endopeptidase Complex

Quantitative Trait Loci

Risk Factors

Ubiquitin

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Journal article

Kraus, William E|0000-0003-1930-9684

Muoio, Deborah M|0000-0003-3760-9277

Bain, James R|0000-0002-8917-9187

Kwee, Lydia|0000-0002-6997-8571

Hauser, Elizabeth R|0000-0003-0367-9189

Gregory, Simon G|0000-0002-7805-1743

Shah, Svati H|0000-0002-3495-2830

http://www.ncbi.nlm.nih.gov/pubmed/26540294

e1005553

11

Basic Science Departments

Biochemistry

Biomedical Engineering

Biostatistics & Bioinformatics

Center for the Study of Aging and Human Development

Clinical Science Departments

Duke

Duke Cancer Institute

Duke Clinical Research Institute

Duke Molecular Physiology Institute

Global Health Institute

Institutes and Centers

Institutes and Provost's Academic Units

Medicine

Medicine, Cardiology

Medicine, Endocrinology, Metabolism, and Nutrition

Molecular Genetics and Microbiology

Neurology

Neurology, MS & Neuroimmunology

Pharmacology & Cancer Biology

Pratt School of Engineering

Sarah Stedman Nutrition & Metabolism Center

School of Medicine

School of Nursing

School of Nursing - Secondary Group

University Institutes and Centers

Published online

11