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

Steven Offenbacher, Yizu Jiao (), Steven J. Kim, Julie Marchesan, Kevin L. Moss, Li Jing, Kimon Divaris, Sompop Bencharit, Cary S. Agler, Thiago Morelli, Shaoping Zhang, Lu Sun, William T. Seaman, Dale Cowley, Silvana P. Barros, James D. Beck, Matthias Munz, Arne S. Schaefer and Kari E. North
Additional contact information
Steven Offenbacher: University of North Carolina
Yizu Jiao: University of North Carolina
Steven J. Kim: University of North Carolina
Julie Marchesan: University of North Carolina
Kevin L. Moss: University of North Carolina
Li Jing: University of North Carolina
Kimon Divaris: University of North Carolina
Sompop Bencharit: Virginia Commonwealth University
Cary S. Agler: University of North Carolina
Thiago Morelli: University of North Carolina
Shaoping Zhang: University of North Carolina
Lu Sun: University of North Carolina
William T. Seaman: University of North Carolina
Dale Cowley: University of North Carolina
Silvana P. Barros: University of North Carolina
James D. Beck: University of North Carolina
Matthias Munz: Charité - University Medicine Berlin
Arne S. Schaefer: Charité - University Medicine Berlin
Kari E. North: University of North Carolina

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05940-9

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