A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia

Christopher Plaisier, Steve Horvath, Adriana Huertas-Vazquez, Ivette Cruz-Bautista, Miguel F. Herrera, Teresa Tusie-Luna, Carlos Aguilar-Salinas, Päivi Pajukanta

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1000642
JournalPLoS Genetics
Volume5
Issue number9
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

Fingerprint

Familial Combined Hyperlipidemia
Fatty Acid Desaturases
stearoyl-CoA desaturase
hyperlipidemia
Transcription Factors
fatty acid
transcription factors
gene
Genes
genes
network analysis
Gene Expression
fat
Single Nucleotide Polymorphism
genotype
lipid
lipids
Fats
Genotype
Lipids

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Plaisier, C., Horvath, S., Huertas-Vazquez, A., Cruz-Bautista, I., Herrera, M. F., Tusie-Luna, T., ... Pajukanta, P. (2009). A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. PLoS Genetics, 5(9), [e1000642]. https://doi.org/10.1371/journal.pgen.1000642

A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia. / Plaisier, Christopher; Horvath, Steve; Huertas-Vazquez, Adriana; Cruz-Bautista, Ivette; Herrera, Miguel F.; Tusie-Luna, Teresa; Aguilar-Salinas, Carlos; Pajukanta, Päivi.

In: PLoS Genetics, Vol. 5, No. 9, e1000642, 01.09.2009.

Research output: Contribution to journalArticle

Plaisier, C, Horvath, S, Huertas-Vazquez, A, Cruz-Bautista, I, Herrera, MF, Tusie-Luna, T, Aguilar-Salinas, C & Pajukanta, P 2009, 'A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia', PLoS Genetics, vol. 5, no. 9, e1000642. https://doi.org/10.1371/journal.pgen.1000642
Plaisier, Christopher ; 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. In: PLoS Genetics. 2009 ; Vol. 5, No. 9.
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