Published online before print June 12, 2009, doi: 10.1161/CIRCGENETICS.108.840421
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original Articles |
Functional Variant Disrupts Insulin Induction of USF1
Mechanism for USF1-Associated Dyslipidemias
From the Institute for Molecular Medicine Finland (FIMM) (J.N., L.P.); Division of Welfare and Health Promotion (J.N., L.P.), National Institute for Health and Welfare; Department of Medical Genetics and Research Program of Molecular Medicine (J.N.), University of Helsinki, Helsinki, Finland; Steno Diabetes Center (E.N., A.V., P.P.), Gentofte, Denmark; Division of Cardiology (H.A.K., S.S., M.-R.T.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research (H.A.K.), Biomedicum, Helsinki, Finland; Department of Clinical Sciences, Diabetes and Endocrinology (V.L., A.V., L.G.), Clinical Research Center, Malmo University Hospital, Lund University, Malmo, Sweden; The Broad Institute (L.P.), Massachusetts Institute of Technology, Boston, Mass; and Wellcome Trust Sanger Institute (L.P.), Hinxton, Cambridge, United Kingdom.
Correspondence to Leena Peltonen, MD, PhD, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. E-mail leena.peltonen{at}ktl.fi
Received December 8, 2008; accepted June 10, 2009.
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.
Methods and 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.
Key Words: USF1 • genetics • hypercholesterolemia • hyperlipoproteinemia • cardiovascular diseases
CLINICAL PERSPECTIVE
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.840421.