IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1β and C-reactive protein

Abstract

Interleukin-1beta (IL-1beta) activates inflammatory mediator cascades and has been implicated in the pathogenesis of several diseases. Single nucleotide polymorphisms (SNPs) of the IL1B promoter have been associated with various inflammatory diseases. We recently reported that IL1B gene transcription was influenced by four promoter SNPs, and that individual SNP function in vitro was governed by haplotype context. In the present study we tested the in vivo relevance of this observation by comparing IL1B promoter haplotype-pairs with IL-1beta protein levels in 900 gingival tissue fluid samples. Three SNPs (-511, -1464, -3737) defined four IL1B promoter haplotypes that occurred in the study population and could be assigned unambiguously to each chromosome. The four haplotypes defined ten haplotype-pairs of which four pairs, representing 57% of the population, were associated with 28-52% higher IL-1beta protein levels in vivo. Two of these pairs, characterized by homozygosity for the common allele at -3737, were also associated with raised serum levels of C-reactive protein (p = 0.02). We validated these findings in stimulated peripheral blood mononuclear cells (PBMCs) from a separate population (N = 70). PBMCs with IL1B haplotype-pairs associated with higher in vivo levels of IL-1beta produced 86-287% more IL-1beta in vitro than the reference group. We believe that this is the first demonstration of a relationship between in vivo levels of an inflammatory mediator and gene promoter haplotypes on both chromosomes. These findings may apply to other inducible genes and could provide a logical framework for exploring disease risk related to genetic variability in pathogenic mediators.

Orthodontically induced external apical root resorption in patients treated with fixed appliances vs removable aligners

“…27,28 Interleukin 1 is one of the first cytokines implicated in inflammation of the vessel wall during tooth movement, affecting leucocyte recruitment and transmigration. [29][30][31][32][33] Closely connected to this, the function of interleukin 1 is antagonized by the IL1ra protein encoded in the IL1RN gene, wherein specific sequence variants have been associated with an increased predisposition to suffer OIEARR.…”

Functional analysis of a lung cancer risk haplotype in the IL1B gene regulatory region

“…5 We found higher frequency of a haplotype containing four SNPs (G-3893A, G-1464C, C-511T and T-31C), where À3893G, À1464G, À511C and À31T were associated with lung cancer risk and higher expression of the IL1B gene in normal lung tissue from lung cancer patients. 5 A few prior studies have investigated the À1464, À511 and À31 SNPs either as a haplotype or single SNPs, [5][6][7][8][9][10][11][12][13] but little is known about the IL1B À3893 SNP. Epidemiological studies show risk association with the IL1B À511 SNP, 7,13 but functional studies show little biological evidence for this polymorphism, and therefore IL1B À1464 and À31 SNPs have received more attention.…”

Allele-specific induction of IL1B −31 T/C promoter polymorphism by lung carcinogens

“…The C-511T and T-31C polymorphisms are in near-complete linkage disequilibrium and T-31C is a TATA-box polymorphism that markedly affects DNA-protein interactions in vitro [139,140]. These polymorphisms may affect IL1B expression by changing affinity for transcription factor binding or creating new binding sites for other transcription factors [82,141]. The SNPs may also interact with each other forming various haplotype structures.…”

“…The SNPs may also interact with each other forming various haplotype structures. Several studies have shown that studying SNPs as haplotypes may better explain the interindividual differences in IL1B expression [82,141].…”