GWAS for Interleukin-1\u03b2 levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation

Steven Offenbacher,James D Beck,Matthias Munz,Yizu Jiao,Dale Cowley,Kevin L Moss,Kari E North,Lu Sun,Arne S Schaefer,Kimon Divaris,Cary S Agler,Li Jing,Julie Marchesan,Silvana P Barros,Sompop Bencharit,Shaoping Zhang,Thiago Morelli,Steven J Kim,William T Seaman

doi:10.1038/s41467-018-05940-9

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.

Highlights

There is no agnostic genome-wide association studies (GWAS) evidence for the genetic control of IL-1β expression in periodontal disease
GWAS Discovery of loci related to Gingival crevicular fluid (GCF)-IL-1β response
GWAS findings and investigate whether there was a concordant increase in other mediators of the innate immune response, we explored in a different cohort with 143 subjects to assess the association between IL-37 Variant1 (IL-37V1) and high levels of IL-1β

Summary

Introduction

There is no agnostic GWAS evidence for the genetic control of IL-1β expression in periodontal disease. IL1β has been established as a robust GCF biomarker for a hyperinflammatory phenotype, as well as severe clinical inflammation, bone loss and periodontal disease progression[6,7,8,9,10] It is a key pluripotent activator of the innate immune response that acts on a myriad of cell types as a trigger for the expression of an expanding cascade of cytokine mediators inducing inflammatory cell recruitment and activation[11]. IL-37, located within the IL-1 gene cluster on 2q12, has recently been identified as a regulatory cytokine that dampens the immune response in humans[14] These loci have been reported to be associated with several inflammatory pathogenetic conditions including Alzheimer’s disease[15], End-stage Renal Disease (ESRD)[12], osteoarthritis[16], coronary artery disease[17], type I diabetes mellitus[18], stroke[19], and periodontal disease[16]. Our findings demonstrate two IL37 variants with functional roles in decreased expression of IL-37, leading to up-regulation of IL-1β and IL-6, constituting a hyper-inflammatory trait

Methods

Results

Conclusion