Association of serum interleukin-6 concentration with a functional IL6 -6331T>C polymorphism

TY - JOUR

T1 - Association of serum interleukin-6 concentration with a functional IL6 -6331T>C polymorphism

AU - Smith, Andrew J.P.

AU - D'Aiuto, Francesco

AU - Palmen, Jutta

AU - Cooper, Jackie A.

AU - Samuel, Jane

AU - Thompson, Simon

AU - Sanders, Julie

AU - Donos, Nikos

AU - Nibali, Luigi

AU - Brull, David

AU - Woo, Pat

AU - Humphries, Steve E.

PY - 2008/5/1

Y1 - 2008/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=43449128097&partnerID=8YFLogxK

U2 - 10.1373/clinchem.2007.098608

DO - 10.1373/clinchem.2007.098608

M3 - Article

C2 - 18356242

AN - SCOPUS:43449128097

SN - 0009-9147

VL - 54

SP - 841

EP - 850

JO - Clinical chemistry

JF - Clinical chemistry

IS - 5

ER -