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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:983.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Association Analysis of Allelic Variants of USF1 in Coronary Atherosclerosis

Kati Kristiansson; Erkki Ilveskoski; Terho Lehtimäki; Leena Peltonen; Markus Perola; Pekka J. Karhunen

From the Department of Molecular Medicine (K.K., L.P., M.P.), National Public Health Institute, Helsinki, Finland; School of Medicine (E.I.), University of Tampere and Heart Center, Tampere University Hospital, Tampere, Finland; School of Medicine (E.I., T.L., P.J.K.), University of Tampere and Research Unit of Laboratory Center, Tampere University Hospital, Tampere, Finland; Department of Medical Genetics (L.P., M.P.), University of Helsinki, Finland; The Broad Institute (L.P.), MIT and Harvard University, Cambridge, Mass; Wellcome Trust Sanger Institute (L.P.), Hinxton, United Kingdom.

Correspondence to Leena Peltonen, National Public Health Institute, Department of Molecular Medicine, Biomedicum, Haartmaninkatu 8, Po.Box 104, 00251 Helsinki, Finland. E-mail leena.peltonen{at}ktl.fi

Abstract

Objective— USF1 regulates the transcription of more than 40 cardiovascular related genes and is well established as a gene associated with familial combined hyperlipidemia, a condition increasing the risk for coronary heart disease. No detailed data, however, exists on the impact of this gene to the critical outcome at the tissue level: different types of atherosclerotic lesions.

Methods and Results— We analyzed the USF1 in 2 autopsy series of altogether 700 middle-aged men (the Helsinki Sudden Death Study) with quantitative morphometric measurements of coronary atherosclerosis. SNP rs2516839, tagging common USF1 haplotypes, associated with the presence of several types of atherosclerotic lesions, particularly with the proportion of advanced atherosclerotic plaques (P=0.02) and area of calcified lesions (P<0.001) of the coronary arteries. Importantly, carriers of risk alleles of rs2516839 also showed a 2-fold risk for sudden cardiac death (genotype TT versus CC; OR 2.10, 95% CI 1.17 to 3.75, P=0.04). The risk effect of rs2516839 was present also in aorta samples of the men.

Conclusions— Our findings in this unique study sample suggest that USF1 contributes to atherosclerosis, the pathological arterial wall phenotype resulting in coronary heart disease and in its most dramatic consequence—sudden cardiac death.

USF1 is well established as a gene associated with familial combined hyperlipidemia. Our findings in a unique autopsy series of middle-aged men provide evidence that USF1 contributes to coronary atherosclerosis, the pathological arterial wall phenotype resulting in CHD and in its most dramatic consequence—sudden cardiac death.

Key Words: atherosclerosis • coronary • genes • genetics • death, sudden