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.
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.
Authors: Bradley E Aouizerat; Anand Dhruva; Steven M Paul; Bruce A Cooper; Kord M Kober; Christine Miaskowski Journal: J Pain Symptom Manage Date: 2015-05-29 Impact factor: 3.612
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Authors: Christine Miaskowski; Marylin Dodd; Kathryn Lee; Claudia West; Steven M Paul; Bruce A Cooper; William Wara; Patrick S Swift; Laura B Dunn; Bradley E Aouizerat Journal: J Pain Symptom Manage Date: 2010-06-08 Impact factor: 3.612
Authors: J-Q He; M G Foreman; K Shumansky; X Zhang; L Akhabir; D D Sin; S F P Man; D L DeMeo; A A Litonjua; E K Silverman; J E Connett; N R Anthonisen; R A Wise; P D Paré; A J Sandford Journal: Thorax Date: 2009-04-08 Impact factor: 9.139
Authors: Benjamin P Fairfax; Fredrik O Vannberg; Jayachandran Radhakrishnan; Hakon Hakonarson; Brendan J Keating; Adrian V S Hill; Julian C Knight Journal: Hum Mol Genet Date: 2009-11-26 Impact factor: 6.150