A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis

M. Munz; C. Willenborg; G.M. Richter; Y. Jockel-Schneider; C. Graetz; I. Staufenbiel; J. Wellmann; K. Berger; B. Krone; P. Hoffmann; N. van der Velde; A.G. Uitterlinden; L.C.P.G.M. de Groot; A.H. Sawalha; H. Direskeneli; G. Saruhan-Direskeneli; E. Guzeldemir-Akcakanat; H.G. Keceli; M. Laudes; B. Noack; A. Teumer; B. Holtfreter; T. Kocher; P. Eickholz; J. Meyle; C. Doerfer; C. Bruckmann; W. Lieb; A. Franke; S. Schreiber; R.M. Nohutcu; J. Erdmann; B.G. Loos; S. Jepsen; H. Dommisch; A.S. Schaefer

doi:10.1093/hmg/ddx151

A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis

M. Munz, C. Willenborg, G.M. Richter, Y. Jockel-Schneider, C. Graetz, I. Staufenbiel, J. Wellmann, K. Berger, B. Krone, P. Hoffmann, N. van der Velde, A.G. Uitterlinden, L.C.P.G.M. de Groot, A.H. Sawalha, H. Direskeneli, G. Saruhan-Direskeneli, E. Guzeldemir-Akcakanat, H.G. Keceli, M. Laudes, B. NoackA. Teumer, B. Holtfreter, T. Kocher, P. Eickholz, J. Meyle, C. Doerfer, C. Bruckmann, W. Lieb, A. Franke, S. Schreiber, R.M. Nohutcu, J. Erdmann, B.G. Loos, S. Jepsen, H. Dommisch, A.S. Schaefer

Periodontology

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.

Original language	English
Pages (from-to)	2577-2588
Journal	Human molecular genetics
Volume	26
Issue number	13
DOIs	https://doi.org/10.1093/hmg/ddx151
Publication status	Published - Jul 2017

Bibliographical note

Correction published in: Human Molecular Genetics, Volume 27, Issue 5, 1 March 2018, Pages 941–942,.

Funding

The German Research Foundation DFG (Deutsche Forschungsgemeinschaft; GZ: SCHA 1582/3-1) supported this study. Collection of the AgP cases was additionally supported by the German Ministry of Education and Research through the POPGEN biobank project (01GR0468). The Dortmund Health Study (DHS) is 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(collection of sociodemographic and clinical data). Blood collection in the Dortmund Health Study was done through funds from the Institute of Epidemiology and Social Medicine University of Muenster and genotyping supported by the German Ministry of Research and Education (BMBF, grant no. 01ER0816). FOCUS was supported by the Federal Ministry of Education and Research BMBF (FKZ 0315540A). The HNR study is supported by the Heinz Nixdorf Foundation (Germany). Additionally, the HNR study was funded by the German Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI236/9-1, ER 155/6-1). The genotyping of the Illumina HumanOmni-1 Quad BeadChips of the HNR subjects was financed by the German Centre for Neurodegenerative Diseases (DZNE), Bonn. SHIP is part of the Community Medicine Research net (CMR, http://www.community-medicine.de) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). This project was granted by BMBF-01-ZZ-9603/0 and BH was supported by GABA, Switzerland. Generation of genome-wide SNP data has been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg, West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH.

Funders	Funder number
Federal Ministry of Education and Research BMBF	FKZ 0315540A
Federal State of Mecklenburg
Federal State of Mecklenburg-West Pomerania	03IS2061A, BMBF-01-ZZ-9603/0
GABA	03ZIK012
German Migraine & Headache Society
Institute of Epidemiology and Social Medicine University of Muenster
Ministry of Cultural Affairs
University of Muenster
Pfizer
Merck Sharp and Dohme
Deutsche Forschungsgemeinschaft	SCHA 1582/3-1, ER 155/6-1, SI 236/8-1, SI236/9-1
Bundesministerium für Bildung und Forschung	01ZZ0403, 01ER0816, 01GR0468, 01ZZ0103, 01ZZ9603
Deutsches Zentrum für Neurodegenerative Erkrankungen
Deutsche Migräne- und Kopfschmerzgesellschaft e.V.
Heinz Nixdorf Stiftung
Universität Greifswald

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Munz, M., Willenborg, C., Richter, G. M., Jockel-Schneider, Y., Graetz, C., Staufenbiel, I., Wellmann, J., Berger, K., Krone, B., Hoffmann, P., van der Velde, N., Uitterlinden, A. G., de Groot, L. C. P. G. M., Sawalha, A. H., Direskeneli, H., Saruhan-Direskeneli, G., Guzeldemir-Akcakanat, E., Keceli, H. G., Laudes, M., ... Schaefer, A. S. (2017). A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis. Human molecular genetics, 26(13), 2577-2588. https://doi.org/10.1093/hmg/ddx151

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title = "A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis",

abstract = "Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.",

author = "M. Munz and C. Willenborg and G.M. Richter and Y. Jockel-Schneider and C. Graetz and I. Staufenbiel and J. Wellmann and K. Berger and B. Krone and P. Hoffmann and {van der Velde}, N. and A.G. Uitterlinden and {de Groot}, L.C.P.G.M. and A.H. Sawalha and H. Direskeneli and G. Saruhan-Direskeneli and E. Guzeldemir-Akcakanat and H.G. Keceli and M. Laudes and B. Noack and A. Teumer and B. Holtfreter and T. Kocher and P. Eickholz and J. Meyle and C. Doerfer and C. Bruckmann and W. Lieb and A. Franke and S. Schreiber and R.M. Nohutcu and J. Erdmann and B.G. Loos and S. Jepsen and H. Dommisch and A.S. Schaefer",

note = "Correction published in: Human Molecular Genetics, Volume 27, Issue 5, 1 March 2018, Pages 941–942,.",

year = "2017",

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doi = "10.1093/hmg/ddx151",

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volume = "26",

pages = "2577--2588",

journal = "Human molecular genetics",

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Munz, M, Willenborg, C, Richter, GM, Jockel-Schneider, Y, Graetz, C, Staufenbiel, I, Wellmann, J, Berger, K, Krone, B, Hoffmann, P, van der Velde, N, Uitterlinden, AG, de Groot, LCPGM, Sawalha, AH, Direskeneli, H, Saruhan-Direskeneli, G, Guzeldemir-Akcakanat, E, Keceli, HG, Laudes, M, Noack, B, Teumer, A, Holtfreter, B, Kocher, T, Eickholz, P, Meyle, J, Doerfer, C, Bruckmann, C, Lieb, W, Franke, A, Schreiber, S, Nohutcu, RM, Erdmann, J, Loos, BG, Jepsen, S, Dommisch, H & Schaefer, AS 2017, 'A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis', Human molecular genetics, vol. 26, no. 13, pp. 2577-2588. https://doi.org/10.1093/hmg/ddx151

TY - JOUR

T1 - A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis

AU - Munz, M.

AU - Willenborg, C.

AU - Richter, G.M.

AU - Jockel-Schneider, Y.

AU - Graetz, C.

AU - Staufenbiel, I.

AU - Wellmann, J.

AU - Berger, K.

AU - Krone, B.

AU - Hoffmann, P.

AU - van der Velde, N.

AU - Uitterlinden, A.G.

AU - de Groot, L.C.P.G.M.

AU - Sawalha, A.H.

AU - Direskeneli, H.

AU - Saruhan-Direskeneli, G.

AU - Guzeldemir-Akcakanat, E.

AU - Keceli, H.G.

AU - Laudes, M.

AU - Noack, B.

AU - Teumer, A.

AU - Holtfreter, B.

AU - Kocher, T.

AU - Eickholz, P.

AU - Meyle, J.

AU - Doerfer, C.

AU - Bruckmann, C.

AU - Lieb, W.

AU - Franke, A.

AU - Schreiber, S.

AU - Nohutcu, R.M.

AU - Erdmann, J.

AU - Loos, B.G.

AU - Jepsen, S.

AU - Dommisch, H.

AU - Schaefer, A.S.

N1 - Correction published in: Human Molecular Genetics, Volume 27, Issue 5, 1 March 2018, Pages 941–942,.

PY - 2017/7

Y1 - 2017/7

N2 - Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.

AB - Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.

U2 - 10.1093/hmg/ddx151

DO - 10.1093/hmg/ddx151

M3 - Article

C2 - 28449029

SN - 0964-6906

VL - 26

SP - 2577

EP - 2588

JO - Human molecular genetics

JF - Human molecular genetics

IS - 13

ER -

A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis

Abstract

Bibliographical note

Funding

UN SDGs

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