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

Publication ,  Journal Article
Kraus, WE; Muoio, DM; Stevens, R; Craig, D; Bain, JR; Grass, E; Haynes, C; Kwee, L; Qin, X; Slentz, DH; Krupp, D; Muehlbauer, M; Hauser, ER ...
Published in: PLoS Genet
November 2015

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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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

November 2015

Volume

11

Issue

11

Start / End Page

e1005553

Location

United States

Related Subject Headings

  • Ubiquitin
  • Risk Factors
  • Quantitative Trait Loci
  • Proteasome Endopeptidase Complex
  • Polymorphism, Single Nucleotide
  • Metabolomics
  • Humans
  • Endoplasmic Reticulum Stress
  • Developmental Biology
  • DNA Methylation
 

Citation

APA
Chicago
ICMJE
MLA
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Kraus, W. E., Muoio, D. M., Stevens, R., Craig, D., Bain, J. R., Grass, E., … Shah, S. H. (2015). Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis. PLoS Genet, 11(11), e1005553. https://doi.org/10.1371/journal.pgen.1005553
Kraus, William E., Deborah M. Muoio, Robert Stevens, Damian Craig, James R. Bain, Elizabeth Grass, Carol Haynes, et al. “Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.PLoS Genet 11, no. 11 (November 2015): e1005553. https://doi.org/10.1371/journal.pgen.1005553.
Kraus WE, Muoio DM, Stevens R, Craig D, Bain JR, Grass E, et al. Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis. PLoS Genet. 2015 Nov;11(11):e1005553.
Kraus, William E., et al. “Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.PLoS Genet, vol. 11, no. 11, Nov. 2015, p. e1005553. Pubmed, doi:10.1371/journal.pgen.1005553.
Kraus WE, Muoio DM, Stevens R, Craig D, Bain JR, Grass E, Haynes C, Kwee L, Qin X, Slentz DH, Krupp D, Muehlbauer M, Hauser ER, Gregory SG, Newgard CB, Shah SH. Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis. PLoS Genet. 2015 Nov;11(11):e1005553.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

November 2015

Volume

11

Issue

11

Start / End Page

e1005553

Location

United States

Related Subject Headings

  • Ubiquitin
  • Risk Factors
  • Quantitative Trait Loci
  • Proteasome Endopeptidase Complex
  • Polymorphism, Single Nucleotide
  • Metabolomics
  • Humans
  • Endoplasmic Reticulum Stress
  • Developmental Biology
  • DNA Methylation