title: 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.
authors.affiliation: Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Komulainen
authors.forename: Mervi
authors.initials: M
authors.lastname: Alanne
authors.forename: Kirsi
authors.initials: K
authors.lastname: Auro
authors.forename: Riika
authors.initials: R
authors.lastname: Kilpikari
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Kaisa
authors.initials: K
authors.lastname: Salminen
authors.forename: Sangita
authors.initials: S
authors.lastname: Kulathinal
authors.forename: Kari
authors.initials: K
authors.lastname: Kuulasmaa
authors.forename: Kaisa
authors.initials: K
authors.lastname: Silander
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012306:Risk; D012737:Sex Factors; D051720:Upstream Stimulatory Factors / Q000235:genetics*; D049629:Waist-Hip Ratio
chemical_list: C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors