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; Kari E. North

doi:10.1038/s41467-018-05940-9

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, Kari E. North

^*Corresponding author for this work

Institute of Experimental Dermatology

75 Citations (Scopus)

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.

Original language	English
Article number	3686
Journal	Nature Communications
Volume	9
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-018-05940-9
Publication status	Published - 01.12.2018

Funding

The primary work characterizing the IL-1 locus was carried out under NIDCR R01DE023836 (S.O.). Heartbrokenly, Dr.Offenbacher passed away after the manuscript was accepted. This work definitely could not have been achieved without his hard work and support. Additional support was through T90DE021986 and F32 DE026688 (Y.Z.J.). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HSN268201100012C), R01HL087641,R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; National Institutes of Health contract HHSN268200625226C; National Institute of Environmental Health Sciences grant P30ES010126; and National Institute of Dental and Craniofacial Research grants R01DE11551, R01DE021418. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The GWAS of AgP was supported by a research grant of the Deutsche Forschungsgemeinschaft DFG (GZ: SCHA 1582/3-1). The collection of sociodemographic and clinical data in the Dortmund Health Study was supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from Almirall, Astra Zeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp & Dohme and Pfizer to the University of Muenster. The authors acknowledge George Altshuller of the UNC Animal Models Core for targeting vector construction and ES cell targeting to produce IL-37 transgenic mice.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1038/s41467-018-05940-9

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Offenbacher, S., Jiao, Y., Kim, S. J., Marchesan, J., Moss, K. L., Jing, L., Divaris, K., Bencharit, S., Agler, C. S., Morelli, T., Zhang, S., Sun, L., Seaman, W. T., Cowley, D., Barros, S. P., Beck, J. D., Munz, M., Schaefer, A. S., & North, K. E. (2018). GWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation. Nature Communications, 9(1), Article 3686. https://doi.org/10.1038/s41467-018-05940-9

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title = "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.",

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

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Offenbacher, 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 & North, KE 2018, 'GWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation', Nature Communications, vol. 9, no. 1, 3686. https://doi.org/10.1038/s41467-018-05940-9

TY - JOUR

T1 - GWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation

AU - Offenbacher, Steven

AU - Jiao, Yizu

AU - Kim, Steven J.

AU - Marchesan, Julie

AU - Moss, Kevin L.

AU - Jing, Li

AU - Divaris, Kimon

AU - Bencharit, Sompop

AU - Agler, Cary S.

AU - Morelli, Thiago

AU - Zhang, Shaoping

AU - Sun, Lu

AU - Seaman, William T.

AU - Cowley, Dale

AU - Barros, Silvana P.

AU - Beck, James D.

AU - Munz, Matthias

AU - Schaefer, Arne S.

AU - North, Kari E.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85053241877

U2 - 10.1038/s41467-018-05940-9

DO - 10.1038/s41467-018-05940-9

M3 - Journal articles

C2 - 30206230

AN - SCOPUS:85053241877

SN - 1751-8628

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3686

ER -

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

Abstract

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Genome-wide Association Study for the Identification of Genetic Risk Factors of Periodontitis

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

Abstract

Funding

Research Areas and Centers

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Genome-wide Association Study for the Identification of Genetic Risk Factors of Periodontitis

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