Risk Alleles of USF1 Gene Predict Cardiovascular Disease of Women in Two Prospective Studies

Abstract

Upstream transcription factor 1 (USF1) is a ubiquitously expressed transcription factor controlling several critical genes in lipid and glucose metabolism. Of some 40 genes regulated by USF1, several are involved in the molecular pathogenesis of cardiovascular disease (CVD). Although the USF1 gene has been shown to have a critical role in the etiology of familial combined hyperlipidemia, which predisposes to early CVD, the gene's potential role as a risk factor for CVD events at the population level has not been established. Here we report the results from a prospective genetic–epidemiological study of the association between the USF1 variants, CVD, and mortality in two large Finnish cohorts. Haplotype-tagging single nucleotide polymorphisms exposing all common allelic variants of USF1 were genotyped in a prospective case-cohort design with two distinct cohorts followed up during 1992–2001 and 1997–2003. The total number of follow-up years was 112,435 in 14,140 individuals, of which 2,225 were selected for genotyping based on the case-cohort study strategy. After adjustment for conventional risk factors, we observed an association of USF1 with CVD and mortality among females. In combined analysis of the two cohorts, female carriers of a USF1 risk haplotype had a 2-fold risk of a CVD event (hazard ratio [HR] 2.02; 95% confidence interval [CI] 1.16–3.53; p = 0.01) and an increased risk of all-cause mortality (HR 2.52; 95% CI 1.46–4.35; p = 0.0009). A putative protective haplotype of USF1 was also identified. Our study shows how a gene identified in exceptional families proves to be important also at the population level, implying that allelic variants of USF1 significantly influence the prospective risk of CVD and even all-cause mortality in females.

Retinoic Acid Utilizes CREB and USF1 in a Transcriptional Feed-Forward Loop in Order To Stimulate MKP1 Expression in Human Immunodeficiency Virus-Infected Podocytes

“…USF1 is a ubiquitously expressed transcription factor controlling several critical genes in lipid and glucose metabolism (20). Of some 40 genes regulated by USF1, several are involved in the molecular pathogenesis of cardiovascular disease.…”

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

“…Metabolic syndrome, type 2 diabetes and FCHL have all been linked to the USF1 gene [35][36][37]. A number of risk alleles of USF1 have been identified, which all represent variants of the non-coding sequence [36,38,41]. It is not clear how non-coding polymorphisms in USF1 may contribute to these metabolic disorders.…”

“…It is not clear how non-coding polymorphisms in USF1 may contribute to these metabolic disorders. The polymorphism in intron 7 of USF1 [36] has been shown to affect binding of nuclear proteins to this region [38], suggesting that this polymorphism affects transcriptional or posttranscriptional regulation of USF1 expression. Possibly, these polymorphisms interfere with the glucose-mediated nuclear accumulation of USF1 in the liver.…”

“…In liver as well as in other tissues, USFs play an important role in the regulation of genes by insulin [24][25][26] or glucose [30][31][32][33][34]. Interestingly, the USF1 gene on chromosome 1q21 has been linked with type 2 diabetes [35], FCHL [36,37] and both cardiovascular disease and all-cause mortality among women [38]. Allelic variants of USF1 may confer susceptibility to core features of the metabolic syndrome, such as glucose intolerance and dyslipidaemia [36,39,40].…”

“…It is unclear how they convey glucose or insulin responsiveness to susceptible target genes. In USF1 a number of polymorphisms have been reported [36,38,40], some of which are associated with unfavourable results in oral glucose and fat tolerance tests [41], increased adipocyte lipolysis [42] and decreased expression of USF target genes in fat biopsies [40]. In nonhepatic cells, glucose has been shown to increase nuclear expression of either USF1 or USF2 [31][32][33][34].…”