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

TitleGWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation.
Publication TypeJournal Article
Year of Publication2018
AuthorsOffenbacher S, Jiao Y, Kim SJ, Marchesan J, Moss KL, Jing L, Divaris K, Bencharit S, Agler CS, Morelli T, Zhang S, Sun L, Seaman WT, Cowley D, Barros SP, Beck JD, Munz M, Schaefer AS
Secondary AuthorsNorth KE
JournalNat Commun
Volume9
Issue1
Pagination3686
Date Published2018 09 11
ISSN2041-1723
KeywordsAmino Acid Sequence, Animals, Chronic Periodontitis, Disease Models, Animal, Female, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Gingival Crevicular Fluid, Haplotypes, HEK293 Cells, Humans, Inflammation, Interleukin-1, Interleukin-1beta, Leukocytes, Mononuclear, Mice, Transgenic, Periodontium, Polymorphism, Single Nucleotide, RNA, Messenger, Stroke, Tooth Loss
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) 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) associates with attenuated IL37 mRNA expression. Overall, we demonstrate that IL37 variants modulate the inflammatory cascade in periodontal disease.

DOI10.1038/s41467-018-05940-9
Alternate JournalNat Commun
PubMed ID30206230
PubMed Central IDPMC6134146
Grant ListR01DE023836 / / U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR) / International
T90DE02198 / / U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR) / International
F32 DE026688 / / U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR) / International