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Cited by 163Genetic Associations and EpidemiologyLipid metabolism and disordersNutrition, Genetics, and Disease

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

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Plaisier, Christopher L., Horvath, Steve, Huertas-Vazquez, Adriana, Cruz-Bautista, Ivette, Herrera, Miguel F., Tusie-Luna, Teresa, Aguilar-Salinas, Carlos, Pajukanta, Päivi·2009·PLoS Genetics
DOI 10.1371/journal.pgen.1000642PMC PMC2730565
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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.

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Cited by

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Authors
Plaisier, C. L., Horvath, S., Huertas-Vazquez, A., Cruz-Bautista, I., Herrera, M. F., Tusie-Luna, T., Aguilar-Salinas, C., & Pajukanta, P.
Affiliations
  • University of California, Los Angeles (US)
  • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX)
Corresponding author
Pajukanta, Päivi
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2009-09-11
Volume
5
Issue
9
Pages
e1000642
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1000642
PMC
PMC2730565
OpenAlex
W2010517054
Cited by
163
References
4
Citations by year
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FWCI
9.16
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • American Heart Association
  • National Institutes of Health (HL‐28481)
  • National Heart, Lung, and Blood Institute (HL28481, HL-082762, R01HL082762, P01HL028481)
  • National Human Genome Research Institute (T32HG02536, T32HG002536)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
Keywords
familial combined hyperlipidemia, USF1, FADS3, 3' untranslated region, triglycerides, gene co-expression modules, lipid metabolism, dyslipidemia, Mexican population, systems genetics
MeSH terms
Adult, Cell Line, Female, Genetic Techniques, Humans, Hyperlipidemia, Familial Combined, Male, Middle Aged, Pedigree, Triglycerides, Case-Control Studies, Mexican Americans, Polymorphism, Single Nucleotide, Fatty Acid Desaturases, Upstream Stimulatory Factors

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