Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

Holzapfel, Christina; Baumert, Jens; Grallert, Harald; Müller, Andreas; Thorand, Barbara; Khuseyinova, Natalie; Herder, Christian; Meisinger, Christa; Hauner, Hans; Wichmann, HE; Köenig, Wolfgang; Illig, Thomas; Klopp, Norman

doi:10.1530/eje-08-0356

Cited by 27 publications

(36 citation statements)

References 46 publications

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“…Main effects of APOA5 [7] and USF1 were already investigated in KORA S4 [13]. Grallert et al [7] found significant effects of APOA5 SNPs on two features of the metabolic syndrome, namely elevated TG levels and lowered HDL levels, but no effects on metabolic syndrome itself.…”

Section: Introductionmentioning

confidence: 99%

Gene-Gene Interaction between APOA5 and USF1: Two Candidate Genes for the Metabolic Syndrome

et al. 2009

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Objective: The metabolic syndrome, a major cluster of risk factors for cardiovascular diseases, shows increasing prevalence worldwide. Several studies have established associations of both apolipoprotein A5 (APOA5) gene variants and upstream stimulatory factor 1 (USF1) gene variants with blood lipid levels and metabolic syndrome. USF1 is a transcription factor for APOA5. Methods: We investigated a possible interaction between these two genes on the risk for the metabolic syndrome, using data from the German population-based KORA survey 4 (1,622 men and women aged 55–74 years). Seven APOA5 single nucleotide polymorphisms (SNPs) were analyzed in combination with six USF1 SNPs, applying logistic regression in an additive model adjusting for age and sex and the definition for metabolic syndrome from the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP (AIII)) including medication. Results: The overall prevalence for metabolic syndrome was 41%. Two SNP combinations showed a nominal gene-gene interaction (p values 0.024 and 0.047). The effect of one SNP was modified by the other SNP, with a lower risk for the metabolic syndrome with odds ratios (ORs) between 0.33 (95% CI = 0.13–0.83) and 0.40 (95% CI = 0.15–1.12) when the other SNP was homozygous for the minor allele. Nevertheless, none of the associations remained significant after correction for multiple testing. Conclusion: Thus, there is an indication of an interaction between APOA5 and USF1 on the risk for metabolic syndrome.

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Section: Introductionmentioning

confidence: 99%

Gene-Gene Interaction between APOA5 and USF1: Two Candidate Genes for the Metabolic Syndrome

et al. 2009

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“…10 -13 Moreover, risk alleles have been found to associate with cardiovascular disease risk and mortality. 14 -17 The association of USF1 variants with type 2 diabetes (T2D) has been more debatable, with both negative 18,19 and positive 20,21 associations reported. The strongest associating single-nucleotide polymorphism (SNP) (usf1s2) of the original study (and most of the subsequent studies) is likely to be functionally relevant, because it is located in a conserved sequence and shown to bind nuclear proteins.…”

mentioning

confidence: 99%

Functional Variant Disrupts Insulin Induction of USF1

Naukkarinen

Nilsson²,

Koistinen³

et al. 2009

Circ Cardiovasc Genet

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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.)Key Words: USF1 Ⅲ genetics Ⅲ hypercholesterolemia Ⅲ hyperlipoproteinemia Ⅲ cardiovascular diseases T he upstream transcription factor (USF1) is a ubiquitously expressed transcription factor shown to regulate numerous genes involved in lipid and glucose metabolisms. As a homodimer or a heterodimer with the related USF2, it binds an E-box element (consensus sequence CACGTG) within the glucose/insulin responsive element in the promoters of the downstream genes, activating their transcription. 1,2 We have previously identified USF1 as the first gene associated with the dyslipidemia observed in familial combined hyperlipidemia (FCHL), 3 the most common genetic dyslipidemia in humans. 4,5 This finding has since been replicated in multiple FCHL 6 -9 as well as other dyslipidemic cohorts. 10 -13 Moreover, risk alleles have been found to associate with cardiovascular disease risk and mortality. 14 -17 The association of USF1 variants with type 2 diabetes (T2D) has been more debatable, with both negative 18,19 and positive 20,21 associations reported. The strongest associating single-nucleotide polymorphism (SNP) (usf1s2) of the original study (and most of the subsequent studies) is likely to be functionally relevant, because it is located in a conserved sequence and shown to bind nuclear proteins. 22 However, no...

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“…1) [3] o całkowitej długości 9549 par zasad zlokalizowany jest na ramieniu długim chromosomu 1 (1q22-23). W swej strukturze zawiera 11 egzonów.…”

Section: Budowa Białka Usf1 I Genu Usf1unclassified

“…Ponadto USF1 prawdopodobnie wpływa także na ekspresję genów odpowiedzialnych za procesy starzenia komórkowego, które bezpośrednio przyczyniają RYCINA 1. Struktura genu USF1 z najczęściej omawianymi w literaturze miejscami polimorficznymi [3] Białko USF1 charakteryzują wysoce konserwatywne domeny helisa-pętla-helisa oraz motyw zamka leucynowego [5]. Domeny HLH i LZ, będące amfipatycznymi α-helisami, współuczestniczą w procesie parowania dimerów USF1-USF2 [6,7].…”

Section: Związek Wariantów Polimorfizmów Usf1 Z Chorobą Wieńcowąunclassified

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USF1 w patologii wybranych jednostek chorobowych

Iwanicka

Zak

2017

Pomeranian J Life Sci

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USF1 belongs to a family of transcription factors characterized by highly conserved helix-loop-helix and leucine zipper domains. The USF1 polypeptide is encoded by the USF1 gene located in the long arm of chromosome 1. The USF1 protein can form homodimers or heterodimers with the USF2 polypeptide. Being a subunit of the dimeric upstream transcription factor, USF1 plays multiple roles in the transcription regulation of many genes, which includes the E-box motif in the promoter region. The activation of gene transcription depends on the integrity of the b-HLH-LZ dimerized domains of USF with the region of DNA. The expression of the USF1 gene and the binding abilities of the protein transcription factor to the promoter region of a target gene is regulated by phosphorylation and methylation processes. The transcription factor USF1 regulates the expression of numerous genes involved, e.g. in the cell cycle, cellular proliferation, cellular ageing, stress and immune response, carcinogenesis, and lipid and carbohydrate metabolism. Moreover, the genetic variants of USF1 can be associated, e.g. with changed levels of serum lipids, glucose and specific markers of carcinogenesis. Among the studied polymorphisms of USF1 a group of genetic variants can be identified, which are associated with risk factors for cardiovascular events. USF1 is also one of the main factors for coronary artery disease, metabolic syndrome, diabetes type II, and familial combined hyperlipidemia. Keywords: USF1; polymorphism; coronary artery disease; diabetes mellitus type II; cancers. ABSTRAKT USF1 należy do rodziny czynników transkrypcyjnych charakteryzujących się obecnością wysoce konserwatywnych domen: helisa-pętla-helisa oraz zamka leucynowego. USF1 kodowany jest przez gen USF1, którego locus znajduje się na ramieniu dłu-gim chromosomu 1. Białko USF1 może tworzyć homodimery lub heterodimery z polipeptydem USF2. Będąc podjednostką dimerycznego czynnika transkrypcyjnego, USF1 reguluje ekspresję wielu genów cechujących się obecnością motywu E-box w obrę-bie regionu promotorowego. Aktywacja transkrypcji danego genu jest zależna od integralności zdimeryzowanych domen b-HLH-LZ USF z regionem DNA. Procesy fosforylacji i metylacji mogą regulować zarówno ekspresję samego genu USF1, jak i zdolność wiązania się białkowego czynnika transkrypcyjnego z regionem promotora genu docelowego. Czynnik transkrypcyjny USF1 reguluje ekspresję istotnych genów zaangażowanych m.in. w cykl komórkowy, proliferację komórkową, procesy starzenia komórkowego, reakcję na stres, odpowiedź immunologiczną organizmu, procesy nowotworzenia oraz w metabolizm węglo-wodanów i lipidów. Ponadto warianty polimorficzne genu USF1 mogą być związane m.in. z ponadnormatywnymi stężeniami wskaźników gospodarki lipidowej, glukozy, a także markerów specyficznych dla procesów kancerogenezy. Spośród zbadanych polimorfizmów genu USF1 można wyróżnić grupę wariantów genetycznych, którym przypisuje się również związek z czynnikami ryzyka predysponującymi do wystąpienia zdarzeń sercowo-naczyniow...

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Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

Cited by 27 publications

References 46 publications

Gene-Gene Interaction between <i>APOA5</i> and <i>USF1</i>: Two Candidate Genes for the Metabolic Syndrome

Gene-Gene Interaction between <i>APOA5</i> and <i>USF1</i>: Two Candidate Genes for the Metabolic Syndrome

Functional Variant Disrupts Insulin Induction of USF1

USF1 w patologii wybranych jednostek chorobowych

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