TY - JOUR
T1 - Functional variant disrupts insulin induction of USF1
T2 - Mechanism for USF1-associated dyslipidemias
AU - Naukkarinen, Jussi
AU - Nilsson, Emma
AU - Koistinen, Heikki A.
AU - Söderlund, Sanni
AU - Lyssenko, Valeriya
AU - Vaag, Allan
AU - Poulsen, Pernille
AU - Groop, Leif
AU - Taskinen, Marja Riitta
AU - Peltonen, Leena
PY - 2009/10/1
Y1 - 2009/10/1
N2 - 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.
AB - 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.
KW - Cardiovascular diseases
KW - Genetics
KW - Hypercholesterolemia
KW - Hyperlipoproteinemia
UR - http://www.scopus.com/inward/record.url?scp=77949894164&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.108.840421
DO - 10.1161/CIRCGENETICS.108.840421
M3 - Journal article
C2 - 20031629
AN - SCOPUS:77949894164
VL - 2
SP - 522
EP - 529
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
SN - 2574-8300
IS - 5
ER -