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IL18 Haplotypes Are Associated with Serum IL-18 Concentrations in a Population-Based Study and a Cohort of Individuals with Premature Coronary Heart Disease

¹ Department of Cardiovascular Genetics, University College London, London, United Kingdom.
² Laboratory for Genetic Epidemiology, Western Australian Institute for Medical Research, University of Western Australia, Perth, Australia.
³ Clinical Biochemistry, Western Australia Centre for Pathology and Medical Research, University of Western Australia, Perth, Australia.
⁴ Sir Charles Gairdner Hospital Campus, Heart Research Institute of Western Australia, Perth, Australia.
⁵ School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.

^aAddress correspondence to this author at: Department of Cardiovascular Genetics, University College London, 5 University St., London, WC1E 6JF, United Kingdom. Fax 0207-679-6212; e-mail rmhaseh{at}ucl.ac.uk.

Background: Interleukin (IL)-18 is a proinflammatory cytokine that has been implicated in several diseases, including atherosclerosis, and increased circulating IL-18 concentrations increase risk of future coronary heart disease (CHD). We evaluated the effect of common variation within the IL18 gene on concentrations of circulating IL-18.

Methods: We measured IL-18, by ELISA, in the population-based study group [Carotid Ultrasound Disease Assessment Study (CUDAS)] and a predominantly male cohort with premature cardiovascular disease [Carotid Ultrasound in Patients with Ischaemic Heart Disease (CUPID)]. Using a tagging single-nucleotide polymorphism (SNP) approach that captured >90% of genetic variation, we identified 4 common (>10%) haplotypes.

Results: A common SNP was associated with differences in IL-18 concentrations; in CUDAS individuals carrying 2 copies of the rare allele, concentrations were 13% higher than in those with no copies (P = 0.002). Haplotypes were also associated with significant differences in IL-18 concentrations in CUDAS and CUPID. Haplotype GTATA (frequency 23%) was associated with significantly lower IL-18 than others. In CUDAS, those carrying 2 copies had IL-18 concentrations 15% lower than those carrying no copies (P = 0.002); in CUPID, the difference was 22% (P = 0.004). These associations remained significant after adjustment for age, sex, hypertension, HDL cholesterol, waist-to-hip ratio, and alcohol consumption. Despite being associated with differences in IL-18 concentrations, the haplotypes did not occur at different frequencies in those with or without carotid atherosclerotic plaques.

Conclusions: Variation within IL18 affects IL-18 concentrations in healthy and diseased individuals and thus may influence the pathophysiology of plaques at all stages of CHD progression.