Human Molecular Genetics Advance Access originally published online on August 2, 2005
Human Molecular Genetics 2005 14(17):2595-2605; doi:10.1093/hmg/ddi294
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USF1 and dyslipidemias: converging evidence for a functional intronic variant
1Department of Molecular Medicine, National Public Health Institute, Finland, 2Department of Medical Genetics, University of Helsinki, Biomedicum, 00290 Helsinki, Finland, 3Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland, 4Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095-7088, USA and 5Biomedicum Bioinformatics Unit, University of Helsinki, Finland
* To whom correspondence should be addressed at: Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. Tel: +358 947448393; Fax: +358 947448480; Email: leena.peltonen{at}ktl.fi
Received May 23, 2005; Accepted July 21, 2005
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. As no disease-associated mutations in the coding region of USF1 have been identified, we addressed the functional role of intronic single nucleotide polymorphisms (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.
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