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Functional Variant Disrupts Insulin Induction of USF1 Mechanism for USF1-Associated Dyslipidemias

Naukkarinen, Jussi; Nilsson, Emma; Koistinen, Heikki A.; Soderlund, Sanni; Lyssenko, Valeriya LU ; Vaag, Allan LU ; Poulsen, Pernille; Groop, Leif LU ; Taskinen, Marja-Riitta and Peltonen, Leena (2009) In Circulation: Cardiovascular Genetics 2(5). p.245-522
Abstract
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... (More)
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. (Circ Cardiovasc Genet. 2009;2:522-529.) (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cardiovascular diseases, hyperlipoproteinemia, hypercholesterolemia, USF1, genetics
in
Circulation: Cardiovascular Genetics
volume
2
issue
5
pages
245 - 522
publisher
American Heart Association
external identifiers
  • wos:000275979500015
  • scopus:77949894164
ISSN
1942-325X
DOI
10.1161/CIRCGENETICS.108.840421
language
English
LU publication?
yes
id
061cf036-35ff-453b-b415-5508bb5bd290 (old id 1586383)
date added to LUP
2010-04-28 07:59:14
date last changed
2017-01-01 04:31:15
@article{061cf036-35ff-453b-b415-5508bb5bd290,
  abstract     = {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. (Circ Cardiovasc Genet. 2009;2:522-529.)},
  author       = {Naukkarinen, Jussi and Nilsson, Emma and Koistinen, Heikki A. and Soderlund, Sanni and Lyssenko, Valeriya and Vaag, Allan and Poulsen, Pernille and Groop, Leif and Taskinen, Marja-Riitta and Peltonen, Leena},
  issn         = {1942-325X},
  keyword      = {cardiovascular diseases,hyperlipoproteinemia,hypercholesterolemia,USF1,genetics},
  language     = {eng},
  number       = {5},
  pages        = {245--522},
  publisher    = {American Heart Association},
  series       = {Circulation: Cardiovascular Genetics},
  title        = {Functional Variant Disrupts Insulin Induction of USF1 Mechanism for USF1-Associated Dyslipidemias},
  url          = {http://dx.doi.org/10.1161/CIRCGENETICS.108.840421},
  volume       = {2},
  year         = {2009},
}