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Genetic variants of USF1 are associated with the increased risk for cardiovascular disease

University of Helsinki

Cardiovascular diseases (CVD) are major contributors to morbidity and mortality worldwide. Several interacting environmental, biochemical, and genetic risk factors can increase disease susceptibility. While some of the genes involved in the etiology of CVD are known, many are yet to be discovered. During the last few decades, scientists have searched for these genes with genome-wide linkage and association methods, and with more targeted candidate gene studies.

Master of Science, Kati Kristiansson, from the research group of Professor Leena Peltonen at the National Public Health Institute and the University of Helsinki, Finland, has investigated variation within the upstream transcription factor 1 (USF1) gene locus in relation to CVD risk factors, atherosclerosis, and incidence and prevalence of CVD.

USF1 gene was first identified in Finnish families ascertained for familial combined hyperlipidemia, a common dyslipidemia predisposing to coronary heart disease. The gene encodes a ubiquitously expressed transcription factor regulating expression of several genes from lipid and glucose metabolism, inflammation, and endothelial function.

"We examined association between USF1 variants and several CVD risk factors, such as lipid phenotypes, body composition measures, and metabolic syndrome, in two prospective population cohorts, and our data suggested that USF1 contributes to these CVD risk factors at the population level", Kristiansson says. Notably, the associations with quantitative measurements were mostly detected among study subjects with CVD or metabolic syndrome, suggesting complex interactions between USF1 effects and the pathophysiological state of an individual.

To address the question if carriership of this risk allele has a direct impact on the atherosclerotic lesions of the coronary arteries and abdominal aorta, Kristansson used two study samples of middle-aged men with detailed measurements of atherosclerosis obtained in autopsy. It turned out that USF1 variation significantly associated with the size of the areas of several types of arterial wall lesions, especially with calcification of the arteries.

Finally, when Kristiansson tested what effect the USF1 risk variants have on sudden cardiac death and incidence of CVD at the population level, she found out that the risk variant increased the risk of sudden cardiac death of the same study subjects. Furthermore, USF1 alleles associated with incidence of CVD in Finnish population follow-up cohorts. These associations were especially prominent among women, suggesting a sex specific effect, which has also been detected in subsequent studies.

"In conclusion, USF1 seems to have a role in the etiology of CVD. Additional studies are warranted to identify functional variants and to study interactions between USF1 and other genetic or environmental factors. These studies, which uncover the details of the disease etiology, provide tools for the prevention and treatment cardiovascular disease", Kristiansson states.

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M.Sc. Kristiansson presents her doctoral thesis "Genetics of cardiovascular disease: a candidate gene study of USF1" for public examination on the 11th April, 2008 at the University of Helsinki (http://ethesis.helsinki.fi/en). The thesis is based on the following original articles:

I: Auro K, Kristiansson K, Zethelius B, Berne C, Lannfelt L, Taskinen MR, Jauhiainen M, Perola M, Peltonen L, Syvänen AC. USF1 gene variants contribute to metabolic traits in males in a longitudinal 32-year follow-up study. Diabetologia. 2008 Mar;51(3):464-72.

II: Kristiansson K, Ilveskoski E, Lehtimäki T, Peltonen L, Perola M, Karhunen PJ. Association analysis of Allelic Variants of USF1 in Coronary Atherosclerosis. Arterioscler Thromb Vasc Biol. 2008 Feb 14.

III: Komulainen K, Alanne M, Auro K, Kilpikari R, Pajukanta P, Saarela J, Ellonen P, Salminen K, Kulathinal S, Kuulasmaa K, Silander K, Salomaa V, Perola M, Peltonen L. Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies. PLoS Genet. 2006 May;2(5):e69.

IV: Silander K, Komulainen K, Ellonen P, Jussila M, Alanne M, Levander M, Tainola P, Kuulasmaa K, Salomaa V, Perola M, Peltonen L, Saarela J. Evaluating whole genome amplification via multiply-primed rolling circle amplification for SNP genotyping of samples with low DNA yield. Twin Res Hum Genet. 2005 Aug;8(4):368-75.

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