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A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia

We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dysl...

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Autores principales: Plaisier, Christopher L., Horvath, Steve, Huertas-Vazquez, Adriana, Cruz-Bautista, Ivette, Herrera, Miguel F., Tusie-Luna, Teresa, Aguilar-Salinas, Carlos, Pajukanta, Päivi
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730565/
https://www.ncbi.nlm.nih.gov/pubmed/19750004
http://dx.doi.org/10.1371/journal.pgen.1000642
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author Plaisier, Christopher L.
Horvath, Steve
Huertas-Vazquez, Adriana
Cruz-Bautista, Ivette
Herrera, Miguel F.
Tusie-Luna, Teresa
Aguilar-Salinas, Carlos
Pajukanta, Päivi
author_facet Plaisier, Christopher L.
Horvath, Steve
Huertas-Vazquez, Adriana
Cruz-Bautista, Ivette
Herrera, Miguel F.
Tusie-Luna, Teresa
Aguilar-Salinas, Carlos
Pajukanta, Päivi
author_sort Plaisier, Christopher L.
collection PubMed
description We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dyslipidemia. We first associated rs3737787 genotypes in Mexican Familial Combined Hyperlipidemia (FCHL) case/control fat biopsies, with global expression patterns. To identify sets of co-expressed genes co-regulated by similar factors such as transcription factors, genetic variants, or environmental effects, we utilized weighted gene co-expression network analysis (WGCNA). Through WGCNA in the Mexican FCHL fat biopsies we identified two significant Triglyceride (TG)-associated co-expression modules. One of these modules was also associated with FCHL, the other FCHL component traits, and rs3737787 genotypes. This USF1-regulated FCHL-associated (URFA) module was enriched for genes involved in lipid metabolic processes. Using systems genetics procedures we identified 18 causal candidate genes in the URFA module. The FCHL causal candidate gene fatty acid desaturase 3 (FADS3) was associated with TGs in a recent Caucasian genome-wide significant association study and we replicated this association in Mexican FCHL families. Based on a USF1-regulated FCHL-associated co-expression module and SNP rs3737787, we identify a set of causal candidate genes for FCHL-related traits. We then provide evidence from two independent datasets supporting FADS3 as a causal gene for FCHL and elevated TGs in Mexicans.
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spelling pubmed-27305652009-09-11 A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia Plaisier, Christopher L. Horvath, Steve Huertas-Vazquez, Adriana Cruz-Bautista, Ivette Herrera, Miguel F. Tusie-Luna, Teresa Aguilar-Salinas, Carlos Pajukanta, Päivi PLoS Genet Research Article We hypothesized that a common SNP in the 3' untranslated region of the upstream transcription factor 1 (USF1), rs3737787, may affect lipid traits by influencing gene expression levels, and we investigated this possibility utilizing the Mexican population, which has a high predisposition to dyslipidemia. We first associated rs3737787 genotypes in Mexican Familial Combined Hyperlipidemia (FCHL) case/control fat biopsies, with global expression patterns. To identify sets of co-expressed genes co-regulated by similar factors such as transcription factors, genetic variants, or environmental effects, we utilized weighted gene co-expression network analysis (WGCNA). Through WGCNA in the Mexican FCHL fat biopsies we identified two significant Triglyceride (TG)-associated co-expression modules. One of these modules was also associated with FCHL, the other FCHL component traits, and rs3737787 genotypes. This USF1-regulated FCHL-associated (URFA) module was enriched for genes involved in lipid metabolic processes. Using systems genetics procedures we identified 18 causal candidate genes in the URFA module. The FCHL causal candidate gene fatty acid desaturase 3 (FADS3) was associated with TGs in a recent Caucasian genome-wide significant association study and we replicated this association in Mexican FCHL families. Based on a USF1-regulated FCHL-associated co-expression module and SNP rs3737787, we identify a set of causal candidate genes for FCHL-related traits. We then provide evidence from two independent datasets supporting FADS3 as a causal gene for FCHL and elevated TGs in Mexicans. Public Library of Science 2009-09-11 /pmc/articles/PMC2730565/ /pubmed/19750004 http://dx.doi.org/10.1371/journal.pgen.1000642 Text en Plaisier et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Plaisier, Christopher L.
Horvath, Steve
Huertas-Vazquez, Adriana
Cruz-Bautista, Ivette
Herrera, Miguel F.
Tusie-Luna, Teresa
Aguilar-Salinas, Carlos
Pajukanta, Päivi
A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia
title A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia
title_full A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia
title_fullStr A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia
title_full_unstemmed A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia
title_short A Systems Genetics Approach Implicates USF1, FADS3, and Other Causal Candidate Genes for Familial Combined Hyperlipidemia
title_sort systems genetics approach implicates usf1, fads3, and other causal candidate genes for familial combined hyperlipidemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730565/
https://www.ncbi.nlm.nih.gov/pubmed/19750004
http://dx.doi.org/10.1371/journal.pgen.1000642
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