Genetic Variation within the Interleukin 6 Promoter Determines Interleukin 6 Expression Levels in Atherosclerosis

Abstract number: P0587

Khwaja¹ H, Beeton² L, Green² FR

¹¹Dept Cardiovascular Medicine, University of Oxford, UK ²²School of Biomedical & Molecular Sciences, University of Surrey, UK ²²School of Biomedical & Molecular Sciences, University of Surrey, UK

The proposed role of interleukin 6 (IL6) in athero-thrombotic disease is to stimulate the acute phase reactants, fibrinogen and CRP, both themselves independent vascular risk factors, as well as having a proinflammatory role in the atherosclerotic plaque. Our aim was to analyse the impact of IL6 promoter haplotype on IL6 expression in cell types relevant to atherosclerosis and in the atherosclerotic plaque itself. We transfected haplotype-specific IL6 promoter: luciferase constructs into the human microvascular endothelial cell-line, HMEC-1, in the presence and absence of IL1b. In this model, the highest transcriptional induction by IL1b was associated with the GG9/11G and GC10/10G haplotypes and the lowest induction with the AG8/12C and AG8/12G haplotypes (P < 0.001). Quantitative rtPCR analysis of IL6 mRNA from 60 carotid plaques taken at the time of carotid endarterectomy showed that the GG9/11G haplotype was the only haplotype associated with increased IL-6mRNA in the plaque (P= 0.005). Peripheral blood-derived macrophages also showed haplotype-specific differences in IL6 mRNA expression. In conclusion, the GG9/11G haplotype was associated with increased IL6 transcription and IL6 mRNA production in vivo. Haplotype-specific IL6 expression was not determined by the -174G/C polymorphism alone, strongly suggesting that it would be optimal to genotype for the -597G/A, -572G/C and -373AnTn polymorphisms as well as -174G/C in future genetic epidemiological studies.