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.
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.
Centre for Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Royal Free and University College London Medical School, Rayne Building, 5 University Street, London WC1E 6JF, UK.
Daniel
D
Kelberman
Mark
M
Fife
Matthew V
MV
Rockman
David J
DJ
Brull
Patricia
P
Woo
Steve E
SE
Humphries
D000818:Animals; D001483:Base Sequence; D001026:Coronary Artery Bypass; D005786:Gene Expression Regulation; D005838:Genotype; D006071:Gorilla gorilla; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D008969:Molecular Sequence Data; D019974:Pan paniscus; D002679:Pan troglodytes; D010215:Papio; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011148:Pongo pygmaeus; D011323:Primates / Q000235:genetics; D011401:Promoter Regions, Genetic
D015850:Interleukin-6