title: Genetic association and interaction analysis of USF1 and APOA5 on lipid levels and atherosclerosis.
abstract: OBJECTIVE
  USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined.
  
  
  RESULTS
  We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta (P=0.0028), with TGs in dyslipidemic coronary artery disease subjects (P=0.03), and with high-density lipoprotein cholesterol (P=0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated.
  
  
  CONCLUSIONS
  Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects.
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare and Institute for Molecular Medicine, Helsinki, Finland.
authors.forename: Pirkka-Pekka
authors.initials: PP
authors.lastname: Laurila
authors.forename: Jussi
authors.initials: J
authors.lastname: Naukkarinen
authors.forename: Kati
authors.initials: K
authors.lastname: Kristiansson
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Tuuli
authors.initials: T
authors.lastname: Kauttu
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: Pekka J
authors.initials: PJ
authors.lastname: Karhunen
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.forename: Christian
authors.initials: C
authors.lastname: Ehnholm
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000328:Adult; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D001315:Australia; D001344:Autopsy; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics* / Q000473:pathology; D004843:Epistasis, Genetic; D005260:Female; D005355:Fibrosis; D005387:Finland; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D014280:Triglycerides / Q000097:blood; D051720:Upstream Stimulatory Factors / Q000235:genetics*
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D014280:Triglycerides; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors