USF1 and dyslipidemias: converging evidence for a functional intronic variant

Jussi Naukkarinen, Massimiliano Gentile, Aino Soro-Paavonen, Janna Saarela, Päivi Pajukanta, Marja-Riitta Taskinen, Leena Peltonen, Heikki Koistinen

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    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.
    Original languageEnglish
    JournalHuman Molecular Genetics
    Issue number17
    Pages (from-to)2595-2605
    Number of pages11
    Publication statusPublished - 2005
    MoE publication typeA1 Journal article-refereed

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