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Analysis of common IL-6 promoter SNP variants and the AnTn tract in humans and primates and effects on plasma IL-6 levels following coronary artery bypass graft surgery

Kelberman, D; Fife, M; Rockman, MV; Brull, DJ; Woo, P; Humphries, SE; (2004) Analysis of common IL-6 promoter SNP variants and the AnTn tract in humans and primates and effects on plasma IL-6 levels following coronary artery bypass graft surgery. BBA-MOL BASIS DIS , 1688 (2) 160 - 167. 10.1016/j.bbadis.2003.11.010.

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Abstract

Interleukin-6 (IL-6) is a pro-inflammatory cytokine and major mediator of the acute phase response. Single nucleotide polymorphisms within the 5' flanking region (-597G>A, -572G>C and -174G>C) have previously been associated with increased risk of coronary heart disease and influencing transcription of IL-6 both in vitro and in vivo. In addition to these, a polymorphic AnTn tract is also present in the promoter of IL-6. Analysis in five different primate species demonstrated a G allele at -597, -572 and -174 in all species. By contrast, the AnTn tract was polymorphic in at least three species, and was roughly conserved in overall length despite an increase in the relative proportion of A versus T in the evolution of the human sequence from that in the ancestor of the great apes. The effect of the AnTn polymorphism on IL-6 levels was examined following coronary artery bypass graft surgery (CABG), a known inflammatory stimulus for IL-6 production. One hundred and thirty-two patients undergoing CABG were genotyped for the AnTn tract by automated sequencing. Four alleles were identified: A8T12 (allele frequency 0.35, 95% CI 0.29-0.40); A9T11 (0.26, 0.21-0.31); A10T11 (0.21, 0.16-0.26); and A10T10 (0.18, 0.14-0.23). Isolation of the effect of different alleles of the AnTn tract on an identical haplotypic background for the other polymorphisms in the promoter showed that individuals homozygous for A9T11 had significantly higher post-operative IL-6 levels than A10T11 homozygotes (275 +/- 46 pg/ml versus 152 +/- 29; P = 0.04). The effect of the A8T12 allele could not be determined separately due to strong allelic association with -174C. The conserved length of the AnTn tract and the association in vivo with IL-6 levels strongly suggest the functionality of the tract on IL-6 expression, independent of contributions from other polymorphic sites within the promoter. (C) 2004 Elsevier B.V. All rights reserved.

Type:Article
Title:Analysis of common IL-6 promoter SNP variants and the AnTn tract in humans and primates and effects on plasma IL-6 levels following coronary artery bypass graft surgery
DOI:10.1016/j.bbadis.2003.11.010
Keywords:Interleukin-6, promoter polymorphism, haplotype analysis, coronary artery bypass graft surgery, coronary heart disease, INTERLEUKIN-6 GENE, MYOCARDIAL-INFARCTION, INCREASED RISK, HEART-DISEASE, HEALTHY-MEN, POLYMORPHISMS, -174G-GREATER-THAN-C, SUSCEPTIBILITY, TRANSCRIPTION, EXPRESSION
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Infection and Immunity (Division of)
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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