Effects of genetic variation on chromatin structure and the transcriptional machinery: analysis of the IL6 gene locus

Abstract

The presence of functional regulatory polymorphism at the interleukin 6 (IL6) locus is uncertain, with many conflicting in vitro findings. To examine the in vivo effect of the three putative functional IL6 promoter variants, À 174G4C, À 572G4C and À 6331T4C, two complementary techniques, allele-specific chromatin immunoprecipitation and allele-specific formaldehydeassisted isolation of regulatory elements, were carried out using unrelated lymphoblast cell lines of known genotype. There were no allele-specific effects for all three single-nucleotide polymorphisms (SNPs) under basal conditions. Upon IL-1b stimulation, however, allele-specific effects were seen for the À 6331 allele, which showed both increased RNA polymerase II loading (56%, P ¼ 0.001) and increased open chromatin (59%, P ¼ 0.004) for the T allele, which is in line with previous reports of this SNP and the effects from acute inflammation. These studies highlight the importance of examining chromatin under different environmental conditions when studying the functionality of regulatory polymorphisms.

Genetic and environmental determinants of population variation in interleukin-6, its soluble receptor and C-reactive protein: Insights from identical and fraternal twins

“…Although these polymorphisms do affect inflammatory responses in patients (Bruunsgaard et al, 2004; Sen et al, 2011; Walston et al, 2007), they do not appear to have a strong influence on basal IL-6 in the blood of a healthy individual. In addition, these SNPs do not have a strong effect on IL-6 transcription at baseline or even a large influence when the cells are activated by proinflammatory stimulants (Smith et al, 2012). That may help to explain why studies of the association between the -176C/G SNP and cardiovascular disease have been inconsistent (Brull et al, 2001; Burzotta et al, 2001; Lieb et al, 2004; Nauck et al, 2002).…”

The varying faces of IL-6: From cardiac protection to cardiac failure

“…The many polymorphisms in the IL6 promoter region as well as polymorphisms in the IL6R gene locus which exist in the population are associated with inflammation and increased disease risk [11–14]. A particular polymorphism in the promoter region of IL6 was shown to lead to higher systemic levels of IL6 [11–13].…”

“…A particular polymorphism in the promoter region of IL6 was shown to lead to higher systemic levels of IL6 [11–13]. This variant is uniquely associated with susceptibility to systemic juvenile idiopathic arthritis and importantly, led to the use of anti-IL6R antibody for its treatment [14–17].…”

IL-6 polymorphisms: a useful genetic tool for inflammation research?

“…Subsequent analysis of the 5′-flanking region of IL6 by our groups at UCL identified further genetic variants up to 6 kb from the start of transcription that influence expression and are associated with serum levels (3) and constitutive expression (4). Most recently, we reported on a chromatin loop structure involving this -6-kb region that interacts directly with the proximal promoter region through OCT1 binding (5). We are still working to identify the additional nuclear proteins involved in the exquisite control of this intriguing cytokine.…”