Association of serum interleukin-6 concentration with a functional IL6 -6331T>C polymorphism.
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.
Smith
Andrew J P
AJ
Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK. Andrew.J.P.Smith@ucl.ac.uk
D'Aiuto
Francesco
F
Palmen
Jutta
J
Cooper
Jackie A
JA
Samuel
Jane
J
Thompson
Simon
S
Sanders
Julie
J
Donos
Nikos
N
Nibali
Luigi
L
Brull
David
D
Woo
Pat
P
Humphries
Steve E
SE
D016022:Case-Control Studies; D002460:Cell Line; D015331:Cohort Studies; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics / Q000601:surgery; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D010510:Periodontal Diseases / Q000097:blood / Q000235:genetics / Q000628:therapy; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding
D005819:Genetic Markers; D015850:Interleukin-6; D050811:Octamer Transcription Factor-1; D008156:Luciferases