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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: clinchem.2007.098608v1 54/5/841    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Smith, A. J. P. Articles by Humphries, S. E. Search for Related Content PubMed PubMed Citation Articles by Smith, A. J. P. Articles by Humphries, S. E. Related Collections Molecular Diagnostics and Genetics

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.