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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

Genomic region plots for significant mQTL associated with SCDA levels.Displayed are LocusZoom plots with -log10(p-value) (left Y-axis) and LD (right Y-axis), additive model, discovery cohort: (A)USP3/HERC1, whites only; (B)STON2/SEL1L, race meta-analysis; (C)RRM1/STIM1, race meta-analysis; (D)OLFM4/SUGT1, whites only.
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pgen.1005553.g002: Genomic region plots for significant mQTL associated with SCDA levels.Displayed are LocusZoom plots with -log10(p-value) (left Y-axis) and LD (right Y-axis), additive model, discovery cohort: (A)USP3/HERC1, whites only; (B)STON2/SEL1L, race meta-analysis; (C)RRM1/STIM1, race meta-analysis; (D)OLFM4/SUGT1, whites only.

Mentions: We have previously shown that all three metabolite factors predict risk of incident CVD events, however the results from those studies were most robust for the SCDA metabolites [5]. Given these prior results, and the strength and consistency of findings for the SCDA metabolite factor in these GWAS analyses, we chose to focus the remainder of our analyses on this factor. Fig 2 and S5 Fig display Locus Zoom plots for these eight mQTL most strongly associated with SCDA metabolite factor levels. Interestingly, the majority of these (i.e. HERC1, USP3, STIM1, SUGT1, FBXO25 and SEL1L) encode proteins reporting on endoplasmic reticulum (ER) stress.


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)

Genomic region plots for significant mQTL associated with SCDA levels.Displayed are LocusZoom plots with -log10(p-value) (left Y-axis) and LD (right Y-axis), additive model, discovery cohort: (A)USP3/HERC1, whites only; (B)STON2/SEL1L, race meta-analysis; (C)RRM1/STIM1, race meta-analysis; (D)OLFM4/SUGT1, whites only.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005553.g002: Genomic region plots for significant mQTL associated with SCDA levels.Displayed are LocusZoom plots with -log10(p-value) (left Y-axis) and LD (right Y-axis), additive model, discovery cohort: (A)USP3/HERC1, whites only; (B)STON2/SEL1L, race meta-analysis; (C)RRM1/STIM1, race meta-analysis; (D)OLFM4/SUGT1, whites only.
Mentions: We have previously shown that all three metabolite factors predict risk of incident CVD events, however the results from those studies were most robust for the SCDA metabolites [5]. Given these prior results, and the strength and consistency of findings for the SCDA metabolite factor in these GWAS analyses, we chose to focus the remainder of our analyses on this factor. Fig 2 and S5 Fig display Locus Zoom plots for these eight mQTL most strongly associated with SCDA metabolite factor levels. Interestingly, the majority of these (i.e. HERC1, USP3, STIM1, SUGT1, FBXO25 and SEL1L) encode proteins reporting on endoplasmic reticulum (ER) stress.

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