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 geneticepidemiological 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 ¼ 0.01) and an increased risk of all-cause mortality (HR 2.52; 95% CI 1.46-4.35; p ¼ 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 allcause mortality in females.

Upstream Transcription Factor 1 (USF1) Polymorphisms Associate with Alzheimer's Disease‐related Neuropathological Lesions: Tampere Autopsy Study

“…This SNP has not been previously linked to disturbances in lipid metabolism. The rs2774276 has previously been linked to higher total serum cholesterol and LDL‐levels (GG genotype), and the G‐allele with higher waist‐to‐hip ratios (21). In our study, the G‐allele of rs2774276 associated with increased risk for both early‐stage (men and younger individuals) and late‐stage SP (women).…”

“…The salt precipitation method was used on frozen blood samples for DNA isolation. Six reported USF1 haplotype‐tagging single‐nucleotide polymorphisms (SNPs) were genotyped (rs10908821, rs2073658, rs2774276, rs2516839, rs1556259 and rs2774279) to capture common allelic variants of the gene using the commercially available TaqMan ® assays with the ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA) (21). APOE genotyping was performed as described elsewhere (16).…”

“…The upstream transcription factor 1 (USF1) gene located on chromosome 1q22‐q23 (39) encodes a ubiquitously expressed important and general transcription factor with multiple roles in transcriptional regulation of several genes involved in glucose and lipid metabolism (27), including APOE (36). Polymorphisms of the USF1 gene associate with familial combined hyperlipidemia (FCHL) (33), increased risk for cardiovascular disease in women (21), high plasma triglyceride and low‐density lipoprotein (LDL) levels (3), early markers of atherosclerosis (2), and coronary artery calcifications and atherosclerotic lesions (23), and lowered APOE gene expression in fat tissue (31). USF1 also represses the gene encoding ATP‐binding cassette A1 (ABCA1) transporter protein, which has a key role in the cellular efflux of cholesterol and phospholipids (48).…”

Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population

“…In particular, carriers of the rare allele of both SNPs in APOA5 and homozygotes of the common allele of 9996G > A (rs2073658) in USF1 had a worse lipid profile compared to carriers of other genotypes. The association of both 9996G > A (rs2073658) and 11235C > T (rs3737787) in USF1 with triglyceride levels was previously reported in FCH patients [14,17,18] as well as in patients with cardiovascular disease [19], carotid artery intima-media thickness [20], type 2 diabetes [21] or obesity [22].…”

Gene Trapping Uncovers Sex-Specific Mechanisms for Upstream Stimulatory Factors 1 and 2 in Angiotensinogen Expression

“…13 They are recruited to the transcriptional complex to modulate the state of chromatin. 14,15 USF1-null mice were viable and fertile with elevated levels of USF2, which may compensate for the absence of USF1 16,17 .…”