Human Molecular Genetics Advance Access published online on August 2, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi294
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1 Department of Molecular Medicine, National Public Health Institute, Finland and Department of Medical Genetics, University of Helsinki, Biomedicum, 00290 Helsinki, Finland
* To whom correspondence should be addressed. Upstream transcription factor 1 (USF1), the first gene associated with familial combined hyperlipidemia (FCHL), regulates numerous genes of glucose and lipid metabolism. Phenotypic overlap between FCHL, type 2 diabetes and the metabolic syndrome makes this gene an intriguing candidate in the disease process of these traits as well. Since no disease-associated mutations in the coding region of USF1 have been identified, we addressed the functional role of intronic SNPs which define the FCHL-risk alleles of USF1, and identified that a 20 bp DNA sequence, containing the critical intronic SNP, binds nuclear protein(s), representing a likely transcriptional regulatory element. This functional role is further supported by the differential expression of USF1 regulated genes in fat biopsy between individuals carrying different allelic variants of USF1. Importantly, apolipoprotein E (APOE) is the most downregulated gene in the risk individuals, linking the potential risk alleles of USF1 with the impaired APOE-dependent catabolism of atherogenic lipoprotein particles.
Received May 23, 2005
Revised July 21, 2005
Accepted July 21, 2005
Article
USF1 and Dyslipidemias: converging evidence for a functional intronic variant
2 Department of Molecular Medicine, National Public Health Institute, Finland and Department of Medical Genetics, University of Helsinki, Biomedicum, 00290 Helsinki, Finland; Biomedicum Bioinformatics Unit, University of Helsinki, Finland
3 Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
4 Departmenf of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California 90095-7088, USA
5 Department of Molecular Medicine, National Public Health Institute, Finland and Department of Medical Genetics, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; Departmenf of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California 90095-7088, USA
Leena Peltonen, E-mail: leena.peltonen{at}ktl.fi
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