title: A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.
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.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Plaisier
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vazquez
authors.forename: Ivette
authors.initials: I
authors.lastname: Cruz-Bautista
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Herrera
authors.forename: Teresa
authors.initials: T
authors.lastname: Tusie-Luna
authors.forename: Carlos
authors.initials: C
authors.lastname: Aguilar-Salinas
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002460:Cell Line; D044943:Fatty Acid Desaturases / Q000235:genetics*; D005260:Female; D005821:Genetic Techniques; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics* / Q000378:metabolism; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000235:genetics*
chemical_list: D014280:Triglycerides; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D044943:Fatty Acid Desaturases; C545859:FADS3 protein, human