GWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation

Abstract

There is no agnostic GWAS evidence for the genetic control of IL-1β expression in periodontal disease. Here we report a GWAS for “high” gingival crevicular fluid IL-1β expression among 4910 European-American adults and identify association signals in the IL37 locus. rs3811046 at this locus (p = 3.3 × 10−22) is associated with severe chronic periodontitis (OR = 1.50; 95% CI = 1.12–2.00), 10-year incident tooth loss (≥3 teeth: RR = 1.33; 95% CI = 1.09–1.62) and aggressive periodontitis (OR = 1.12; 95% CI = 1.01–1.26) in an independent sample of 4927 German/Dutch adults. The minor allele at rs3811046 is associated with increased expression of IL-1β in periodontal tissue. In RAW macrophages, PBMCs and transgenic mice, the IL37 variant increases expression of IL-1β and IL-6, inducing more severe periodontal disease, while IL-37 protein production is impaired and shows reduced cleavage by caspase-1. A second variant in the IL37 locus (rs2708943, p = 4.2 × 10−7) associates with attenuated IL37 mRNA expression. Overall, we demonstrate that IL37 variants modulate the inflammatory cascade in periodontal disease.

Periodontal inflammation: Integrating genes and dysbiosis

“…In addition to replication in human participants, interleukin‐37 transgenic mice carrying both rs3811046 and rs3811047 variants exhibited significantly more alveolar bone loss in a ligature‐induced murine periodontitis model than wild‐type interleukin‐37 transgenic mice. The bone marrow‐derived macrophages from variant‐carrying mice also secreted more interleukin‐6 and interleukin‐1beta cytokines upon challenge by lipopolysaccharide . Those biologic data proved that both variant loci within the interleukin‐37 gene promote a hyperinflammatory phenotype by upregulating local production of the cytokine, interleukin‐1beta, in gingival tissue that contributes to alveolar bone loss.…”

“…It is critically important for the genetic variant markers identified through an essentially statistical approach to be verified biologically in vivo. The biologic validation of a genome‐wide association study candidate genetic locus is exemplified by a follow‐up investigation employing interleukin‐37 gene variant‐carrying mice in a ligature‐induced murine periodontitis model . The absence of a homolog of the human interleukin‐37 gene makes mice an appealing tool with which to assess the single nucleotide polymorphism variant effects identified in humans because one can directly observe the expression and function of variant‐carrying human interleukin‐37 knock‐in genes in disease models rather than mutating the counterpart nucleic acids in an innate murine homologue gene .…”

“…Genome‐wide association analysis represents an unbiased discovery tool to identify disease trait‐associating genetic variants. Several genome‐wide association studies have uncovered a number of candidate genetic loci or haplotypes that are significantly associated with different clinical and biologic periodontal inflammatory phenotypes at the genomic scale . Many of these disease‐associated genomic signals exist in or approximate to genes that have an unknown function or have not been previously implicated in periodontitis.…”

Genomics of periodontal disease and tooth morbidity

“…The gingival crevicular fluid is a serum transudate that is modified by the local host response to the subgingival microbiome and it can serve as a biomarker of the microbial activation of the host's immune response. To date, gingival crevicular fluid interleukin‐1beta expression is the only periodontitis‐specific inflammatory endophenotype for which evidence of a genome‐wide association exists . Importantly, interleukin‐1beta has been established as a robust marker for severe inflammation, bone loss, and periodontal disease progression, and is known to be strongly genetically controlled.…”

Epigenetic reprogramming in periodontal disease: Dynamic crosstalk with potential impact in oncogenesis

“…Ever since the correlation between the interleukin‐1 genotype and severity of periodontitis was illustrated by Kornman et al in 1997, the role of other inflammatory mediators such as immune‐regulating cytokines (interleukin‐4, interleukin‐6, interleukin‐10, interleukin‐17, interleukin‐37), growth factors, and related receptors on their pathways of activation have been a focus of investigation . The role of a recently characterized member of the interleukin‐1 family, the interleukin‐37 gene, has been investigated with special focus on its anti‐inflammatory activity, which is exerted by dampening production of pro‐inflammatory cytokines …”