title: Functional variant disrupts insulin induction of USF1: mechanism for USF1-associated dyslipidemias.
abstract: BACKGROUND
  The upstream transcription factor 1 (USF1) gene is associated with familial combined hyperlipidemia, the most common genetic dyslipidemia in humans, as well as with various dyslipidemic changes in numerous other studies. Typical of complex disease-associated genes, neither the explicit mutations have been described nor the functional consequences for risk allele carriers been reported at the cellular or tissue level.
  
  
  RESULTS
  In this study, we aimed at describing the molecular mechanism through which the strongest associating intronic single-nucleotide polymorphism variant in USF1 is involved in the development of dyslipidemia. The effects of the risk variant on gene expression were studied in 2 relevant human tissues, fat and muscle. Global transcript profiles of 47 fat biopsies ascertained for carriership of the risk allele were tested for differential expression of known USF1 target genes as well as for broader effects on the transcript profile. Allelic imbalance of USF1 in fat was assessed using a quantitative sequencing approach. The possible allele-specific effect of insulin on the expression of USF1 was studied in 118 muscle biopsies before and after a euglycemic hyperinsulinemic clamp. The risk allele of single-nucleotide polymorphism rs2073658 seems to eradicate the inductive effect of insulin on the expression of USF1 in muscle and fat. The expression of numerous target genes is in turn perturbed in adipose tissue.
  
  
  CONCLUSIONS
  In risk allele carriers, a defective response of USF1 to insulin results in the suboptimal response of relevant target genes that contributes to the enhanced risk of developing dyslipidemia and coronary heart disease.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Naukkarinen
authors.forename: Emma
authors.initials: E
authors.lastname: Nilsson
authors.forename: Heikki A
authors.initials: HA
authors.lastname: Koistinen
authors.forename: Sanni
authors.initials: S
authors.lastname: Söderlund
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D050171:Dyslipidemias / Q000235:genetics* / Q000378:metabolism*; D005223:Fats / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014427:Twins / Q000235:genetics; D015854:Up-Regulation; D051720:Upstream Stimulatory Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D005223:Fats; D007328:Insulin; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors