European Heart Journal Advance Access published online on August 17, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp316
Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study
1 Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere University Hospital, Centre for Laboratory Medicine, University of Tampere, Medical School, Finn Medi 2, 3rd floor, PO Box 2000, FI-33521 Tampere, Finland
2 Department of Forensic Medicine, Tampere University Hospital, University of Tampere, Tampere, Finland
3 Division of Vascular Surgery, Department of Surgery, Tampere University Hospital, Tampere University, Tampere, Finland
4 Department of Clinical Physiology, Tampere University Hospital, University of Tampere, Tampere, Finland
5 Medical School, University of Tampere, and Heart Centre, Pirkanmaa Hospital District, Tampere, Finland
6 Department of Microbiology and Immunology, Tampere University Hospital, University of Tampere, Medical School, Tampere, Finland
Received 4 November 2008; revised 20 April 2009; accepted 16 June 2009 * Corresponding author. Tel: +358 3 311 74049, Fax: +358 3 311 74168, Email: jussi.hernesniemi{at}uta.fi
Aims: The interleukin 18 (IL-18) gene has a single nucleotide promoter region (–137) G-to-C polymorphism (rs187238) which leads to attenuated transcriptional activity of the gene and to lower production of pro-atherogenic IL-18. The C allele of this polymorphism is associated with a lower risk of sudden cardiac death (SCD). We examined the process by which this polymorphism alters the risk of SCD and coronary artery disease (CAD) by analysing the interactions between this polymorphism and environmental factors.
Methods and results: TaqMan 5' nuclease assay was used to genotype the study population of the Helsinki Sudden Death Study, comprising medicolegal autopsies of 700 men. According to adjusted logistic regression analysis, there was a significant interaction between IL-18 genotype and hypertension impacting on the risk of SCD due to coronary heart disease (CHD) (P = 0.011) and the severity of autopsy-verified CAD (P = 0.026). Among GG homozygotes, hypertension was a major risk factor for SCD due to CHD [adjusted odds ratio (OR) 3.75 with 95% CI 1.78–7.91, P < 0.001] and hypertension also associated with larger coronary atherosclerotic plaque areas (P = 0.002) and the occurrence of complicated plaques (adjusted OR 8.38 with 95% CI 2.39–29.33, P < 0.001). Among C allele carriers, hypertension was not a significant risk factor for CHD-related SCD or CAD and did not associate with the development of coronary atherosclerotic plaques. According to gene expression analysis of atherosclerotic tissue samples obtained from live patients, hypertension also interacted significantly with IL-18 genotype affecting the expression of IL-18 (P = 0.030) mRNA and interferon-
mRNA (P = 0.004).
Conclusion: Hypertension interacts with IL-18 gene promoter –137 G/C polymorphism, affecting the risk of SCD and the development of coronary atherosclerosis.
Key Words: Genetics • Sudden cardiac death • Hypertension • Inflammation • Polymorphism • Coronary heart disease