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Arteriosclerosis, thrombosis, and vascular biology (1)
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Naukkarinen, Jussi (2)
Peltonen, Leena (2)
Barter, Philip J. (1)
Ehnholm, Christian (1)
Karhunen, Pekka J. (1)
Kauttu, Tuuli (1)
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Perola, Markus (1)
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Genetic Association and Interaction Analysis of USF1 and APOA5 on Lipid Levels and Atherosclerosis
Karhunen, Pekka J.
Barter, Philip J.
Arteriosclerosis, thrombosis, and vascular biology
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.
Methods and 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.
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.
genes; USF1; APOA5; lipids; atherosclerosis; epistasis
Isolated populations and complex disease gene identification
Isolated populations can be useful for the identification of genes underlying common complex diseases.
The utility of genetically isolated populations (population isolates) in the mapping and identification of genes is not only limited to the study of rare diseases; isolated populations also provide a useful resource for studies aimed at improved understanding of the biology underlying common diseases and their component traits. Well characterized human populations provide excellent study samples for many different genetic investigations, ranging from genome-wide association studies to the characterization of interactions between genes and the environment.
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