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Association of Serum Interleukin-6 Concentration with a Functional IL6 –6331T>C Polymorphism

¹ Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK; ² Periodontology Unit, UCL Eastman Dental Institute, London, UK; ³ Centre for Paediatric and Adolescent Rheumatology, Windeyer Institute, London, UK; ⁴ Department of Surgery, University College London, The Heart Hospital, London, UK; ⁵ Department of Cardiology, The Whittington Hospital NHS Trust, London, UK.

^aAddress correspondence to this author at: Centre for Cardiovascular Genetics, Department of Medicine, University College London, 5 University St., London WC1E 6JF, UK. Fax 44-(0)20-7679-6212; e-mail Andrew.J.P.Smith{at}ucl.ac.uk.

Background: Interleukin-6 (IL-6) concentrations vary substantially among individuals. This study aimed to identify novel genetic markers to explain these differences.

Methods: We sequenced a region 6-kb upstream of the IL6 [interleukin 6 (interferon, beta 2)] transcription start site in a search for functional variants and detected 3 common variants: –6331T>C, –6101A>T, and –5617/–5616C/A>T/G. IL6 –6331T>C (C allele frequency, 0.20; 95% confidence interval, 0.16–0.24) showed strong negative linkage disequilibrium with –174G>C (D' = –0.97) and was studied further in 309 individuals who underwent coronary artery bypass grafting.

Results: Patients with the TT genotype had higher IL-6 concentrations 6 h after surgery than those with the CC genotype (mean, 199.4 ng/L vs 114.9 ng/L; P = 0.02). A similar association was seen in a cohort of 173 patients who underwent intensive periodontal therapy: Individuals with the CC genotype had significantly lower IL-6 concentrations 24 h after therapy than TT patients (mean, 0.78 ng/L vs 5.00 ng/L; P < 0.0001). A similar trend was observed in 203 healthy individuals from northern Europe (1.29 ng/L for the TT genotype vs 0.89 ng/L for the CC genotype; P = 0.07). Reporter assays that used a sequence flanking the –6331 single-nucleotide polymorphism spliced upstream to the IL-6 minimal promoter driving luciferase gene expression demonstrated a 1.3-fold increase in promoter activity (P < 0.01) for constructs containing –6331T. Electrophoretic mobility shift assays revealed enhanced binding of transcription factor Oct-1 to the T allele.

Conclusions: IL6 –6331T is associated with increased IL-6 concentrations in an acute inflammatory state via a mechanism involving binding of the Oct-1 transcription factor. This finding may help resolve conflicting studies based on the IL6 –174G>C variant.