Hyperlipidemias: Naukkarinen J

Naukkarinen J, Ehnholm C, Peltonen L. · Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland. · Curr Opin Lipidol. · Pubmed #16680034 No free full text.

Abstract: PURPOSE OF REVIEW: To provide an overview of recent advances that have defined the first putative genes behind familial combined hyperlipidemia, the most common genetic dyslipidemia and a major risk factor for early coronary heart disease. RECENT FINDINGS: The first locus for familial combined hyperlipidemia on 1q21-23 revealed a gene encoding a transcription factor critical in lipid and glucose metabolism, USF1. All the associated variants represent noncoding single nucleotide polymorphisms, one of which affects the binding site of nuclear proteins with a putative effect on transcript levels of USF1. Transcript analyses of fat biopsies have exposed risk-allele related changes in the downstream genes. Another recent clue to the molecular pathogenesis of familial combined hyperlipidemia is the association of the high triglyceride trait with the APOA5 gene, located on 11q. More familial combined hyperlipidemia genes are expected to be found, since linkage evidence exists for additional loci on 16q24 and 20q12-q13.1. SUMMARY: Genetic research of familial combined hyperlipidemia families has revealed several linked loci guiding to susceptibility genes. The USF1 transcription factor is the major gene underlying the 1q21-23 linkage. Modifying genes, especially influencing the high triglyceride trait, include APOC3 and APOA5, the latter representing a downstream target of USF1 and implying a USF1-dependent pathway in the molecular pathogenesis of dyslipidemias.

Naukkarinen J, Gentile M, Soro-Paavonen A, Saarela J, Koistinen HA, Pajukanta P, Taskinen MR, Peltonen L. · Department of Molecular Medicine, National Public Health Institute, Finland. · Hum Mol Genet. · Pubmed #16076849 links to  free full text

Abstract: 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.

Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M, Duan XJ, Soro-Paavonen A, Naukkarinen J, Saarela J, Laakso M, Ehnholm C, Taskinen MR, Peltonen L. · Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California 90095-7088, USA. · Nat Genet. · Pubmed #14991056 No free full text.

Abstract: Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both, is observed in about 20% of individuals with premature coronary heart disease. We previously identified a locus linked to FCHL on 1q21-q23 in Finnish families with the disease. This region has also been linked to FCHL in families from other populations as well as to type 2 diabetes mellitus. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies combined hyperlipidemia in mice, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism.