Dataset Information

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.

SUBMITTER: Kraus WE

PROVIDER: S-EPMC4634848 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Kraus William E WE Muoio Deborah M DM Stevens Robert R Craig Damian D Bain James R JR Grass Elizabeth E Haynes Carol C Kwee Lydia L Qin Xuejun X Slentz Dorothy H DH Krupp Deidre D Muehlbauer Michael M Hauser Elizabeth R ER Gregory Simon G SG Newgard Christopher B CB Shah Svati H SH

PLoS genetics 20151105 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 unde ...[more]

PMID: 26540294

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Project description:A new mixed-model method was developed for mapping quantitative trait loci (QTL) by incorporating multiple polygenic covariance structures. First, we used genome-wide markers to calculate six different kinship matrices. We then partitioned the total genetic variance into six variance components, one corresponding to each kinship matrix, including the additive, dominance, additive × additive, dominance × dominance, additive × dominance, and dominance × additive variances. The six different kinship matrices along with the six estimated polygenic variances were used to control the genetic background of a QTL mapping model. Simulation studies showed that incorporating epistatic polygenic covariance structure can improve QTL mapping resolution. The method was applied to yield component traits of rice. We analyzed four traits (yield, tiller number, grain number, and grain weight) using 278 immortal F2 crosses (crosses between recombinant inbred lines) and 1619 markers. We found that the relative importance of each type of genetic variance varies across different traits. The total genetic variance of yield is contributed by additive × additive (18%), dominance × dominance (14%), additive × dominance (48%), and dominance × additive (15%) variances. Tiller number is contributed by additive (17%), additive × additive (22%), and dominance × additive (43%) variances. Grain number is mainly contributed by additive (42%), additive × additive (19%), and additive × dominance (31%) variances. Grain weight is almost exclusively contributed by the additive (73%) variance plus a small contribution from the additive × additive (10%) variance. Using the estimated genetic variance components to capture the polygenic covariance structure, we detected 39 effects for yield, 39 effects for tiller number, 24 for grain number, and 15 for grain weight. The new method can be directly applied to polygenic-effect-adjusted genome-wide association studies (GWAS) in human and other species.

Dataset Information

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

Publications

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

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