Published Online
on June 12, 2009

A more recent version of this article appeared on October 1, 2009

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Original Article

Functional Variant Disrupts Insulin Induction of USF1: Mechanism for USF1 Associated Dyslipidemias

Jussi Naukkarinen¹; Emma Nilsson²; Heikki Koistinen³; Sanni Söderlund⁴; Valeriya Lyssenko⁵; Allan Vaag⁶; Pernille Poulsen²; Leif Groop⁵; Marja–Riitta Taskinen⁴ and Leena Peltonen^7,8

¹ University of Helsinki & Nat. Instit. for Health and Welfare, Finland;
² Steno Diabetes Center, Denmark;
³ Helsinki University Central Hospital & Biomedicum Helsinki, Finland;
⁴ Helsinki University Central Hospital, Finland;
⁵ Malmo University Hospital, Lund University, Sweden;
⁶ Steno Diabetes Center, Denmark & Malmo University Hospital, Lund University, Sweden;
⁷ Univ. of Helsinki, Finland & MIT, Boston & Wellcome Trust Sang. Inst., Cambridge, MA

⁸ E-mail: leena.peltonen{at}ktl.fi

Background—The upstream transcription factor 1 (USF1) gene is associated with familial combined hyperlipidemia (FCHL), 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 explicit mutations have been described, nor have the functional consequences for risk allele carriers been reported at the cellular or tissue level.

Methods and Results—In the present study we aimed at describing the molecular mechanism through which the strongest associating intronic SNP variant in USF1 is involved in the development of dyslipidemia. The effects of the risk variant on gene expression were studied in two 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 prior to, and following a euglycemic hyperinsulinemic clamp. The risk allele of SNP 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.

Key Words: cardiovascular diseases • genetics • hypercholesterolemia • hyperlipoproteinemia • USF1