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

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 - PLoS Genet. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Representation of metabolomics, GWAS, eQTL, and methylation leading to convergence on ER stress as a pathway for CVD event pathogenesis.
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pgen.1005553.g004: Representation of metabolomics, GWAS, eQTL, and methylation leading to convergence on ER stress as a pathway for CVD event pathogenesis.

Mentions: Many SCDAs result from the catabolism of amino acids, ω-oxidation of fatty acids or perhaps represent products of microbial metabolism [19], but the reasons for their accumulation in plasma in at-risk subjects, and how they may be related to CVD pathogenesis remain uncertain. Based on the convergence of GWAS, transcriptomic, metabolomic and functional data presented herein, we hypothesize that genetic and epigenetic variation predisposes to increased susceptibility to ER stress through proteasome dysfunction (reflected by the observation of upregulation of expression of ER stress genes), with ER stress in turn contributing to increased production of SCDA metabolites. This pathway of increased ER stress then leads to increased risk of CVD events, with SCDA metabolites and the genetic variants themselves predicting increased risk by reporting on this pathway (Fig 4). Epigenetic variation could be the influence of environmental or lifestyle factors inducing methylation changes; in this working model, diet and lifestyle-induced dyslipidemia and hyperglycemia could result in methylation changes as a regulatory mechanism to handle nutrient overload, thus predisposing to dysregulated ER stress which then leads to subsequent CVD events.


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

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 - PLoS Genet. (2015)

Representation of metabolomics, GWAS, eQTL, and methylation leading to convergence on ER stress as a pathway for CVD event pathogenesis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4634848&req=5

pgen.1005553.g004: Representation of metabolomics, GWAS, eQTL, and methylation leading to convergence on ER stress as a pathway for CVD event pathogenesis.
Mentions: Many SCDAs result from the catabolism of amino acids, ω-oxidation of fatty acids or perhaps represent products of microbial metabolism [19], but the reasons for their accumulation in plasma in at-risk subjects, and how they may be related to CVD pathogenesis remain uncertain. Based on the convergence of GWAS, transcriptomic, metabolomic and functional data presented herein, we hypothesize that genetic and epigenetic variation predisposes to increased susceptibility to ER stress through proteasome dysfunction (reflected by the observation of upregulation of expression of ER stress genes), with ER stress in turn contributing to increased production of SCDA metabolites. This pathway of increased ER stress then leads to increased risk of CVD events, with SCDA metabolites and the genetic variants themselves predicting increased risk by reporting on this pathway (Fig 4). Epigenetic variation could be the influence of environmental or lifestyle factors inducing methylation changes; in this working model, diet and lifestyle-induced dyslipidemia and hyperglycemia could result in methylation changes as a regulatory mechanism to handle nutrient overload, thus predisposing to dysregulated ER stress which then leads to subsequent CVD events.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus