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

Matthias Munz; Christina Willenborg; Gesa M. Richter; Yvonne Jockel-Schneider; Christian Graetz; Ingmar Staufenbiel; Jürgen Wellmann; Klaus Berger; Bastian Krone; Per Hoffmann; Nathalie van der Velde; André G. Uitterlinden; Lisette C.P.G.M. de Groot; Amr H. Sawalha; Haner Direskeneli; Güher Saruhan-Direskeneli; Esra Guzeldemir-Akcakanat; Gencay Keceli; Matthias Laudes; Barbara Noack; Alexander Teumer; Birte Holtfreter; Thomas Kocher; Peter Eickholz; Jörg Meyle; Christof Doerfer; Corinna Bruckmann; Wolfgang Lieb; Andre Franke; Stefan Schreiber; Rahime M. Nohutcu; Jeanette Erdmann; Bruno G. Loos; Soeren Jepsen; Henrik Dommisch; Arne S. Schaefer

doi:10.1093/hmg/ddx151

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

Matthias Munz, Christina Willenborg, Gesa M. Richter, Yvonne Jockel-Schneider, Christian Graetz, Ingmar Staufenbiel, Jürgen Wellmann, Klaus Berger, Bastian Krone, Per Hoffmann, Nathalie van der Velde, André G. Uitterlinden, Lisette C.P.G.M. de Groot, Amr H. Sawalha, Haner Direskeneli, Güher Saruhan-Direskeneli, Esra Guzeldemir-Akcakanat, Gencay Keceli, Matthias Laudes, Barbara NoackAlexander Teumer, Birte Holtfreter, Thomas Kocher, Peter Eickholz, Jörg Meyle, Christof Doerfer, Corinna Bruckmann, Wolfgang Lieb, Andre Franke, Stefan Schreiber, Rahime M. Nohutcu, Jeanette Erdmann, Bruno G. Loos, Soeren Jepsen, Henrik Dommisch, Arne S. Schaefer^*

^*Korrespondierende/r Autor/-in für diese Arbeit

93 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Human Molecular Genetics
Jahrgang	26
Ausgabenummer	13
Seiten (von - bis)	2577-2588
Seitenumfang	12
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddx151
Publikationsstatus	Veröffentlicht - 01.01.2017

Fördermittel

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 Cach? Campus program of the InterSystems GmbH.

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Dokumente

10.1093/hmg/ddx151

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Genomweite Assoziationsstudie zur Identifikation Genetischer Risikofaktoren der Parodontitis
Schäfer, A. (Projektleiter*in (PI)), Erdmann, J. (Beteiligte Person), Franke, A. (Beteiligte Person), Jepsen, S. (Beteiligte Person), Krawczak, M. (Beteiligte Person), Loos, B. G. (Beteiligte Person) & Padyukov, L. (Beteiligte Person)
01.01.14 → 31.12.18
Projekt: DFG Einzelprojekte › DFG Einzelförderungen (Sachbeihilfen)

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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, 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

@article{a92f7afc799a47908c631e8068373f65,

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 = "Matthias Munz and Christina Willenborg and Richter, \{Gesa M.\} and Yvonne Jockel-Schneider and Christian Graetz and Ingmar Staufenbiel and J{\"u}rgen Wellmann and Klaus Berger and Bastian Krone and Per Hoffmann and \{van der Velde\}, Nathalie and Uitterlinden, \{Andr{\'e} G.\} and \{de Groot\}, \{Lisette C.P.G.M.\} and Sawalha, \{Amr H.\} and Haner Direskeneli and G{\"u}her Saruhan-Direskeneli and Esra Guzeldemir-Akcakanat and Gencay Keceli and Matthias Laudes and Barbara Noack and Alexander Teumer and Birte Holtfreter and Thomas Kocher and Peter Eickholz and J{\"o}rg Meyle and Christof Doerfer and Corinna Bruckmann and Wolfgang Lieb and Andre Franke and Stefan Schreiber and Nohutcu, \{Rahime M.\} and Jeanette Erdmann and Loos, \{Bruno G.\} and Soeren Jepsen and Henrik Dommisch and Schaefer, \{Arne S.\}",

year = "2017",

month = jan,

day = "1",

doi = "10.1093/hmg/ddx151",

language = "English",

volume = "26",

pages = "2577--2588",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "13",

}

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, G, 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, Jg. 26, Nr. 13, S. 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, Matthias

AU - Willenborg, Christina

AU - Richter, Gesa M.

AU - Jockel-Schneider, Yvonne

AU - Graetz, Christian

AU - Staufenbiel, Ingmar

AU - Wellmann, Jürgen

AU - Berger, Klaus

AU - Krone, Bastian

AU - Hoffmann, Per

AU - van der Velde, Nathalie

AU - Uitterlinden, André G.

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

AU - Sawalha, Amr H.

AU - Direskeneli, Haner

AU - Saruhan-Direskeneli, Güher

AU - Guzeldemir-Akcakanat, Esra

AU - Keceli, Gencay

AU - Laudes, Matthias

AU - Noack, Barbara

AU - Teumer, Alexander

AU - Holtfreter, Birte

AU - Kocher, Thomas

AU - Eickholz, Peter

AU - Meyle, Jörg

AU - Doerfer, Christof

AU - Bruckmann, Corinna

AU - Lieb, Wolfgang

AU - Franke, Andre

AU - Schreiber, Stefan

AU - Nohutcu, Rahime M.

AU - Erdmann, Jeanette

AU - Loos, Bruno G.

AU - Jepsen, Soeren

AU - Dommisch, Henrik

AU - Schaefer, Arne S.

PY - 2017/1/1

Y1 - 2017/1/1

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.

UR - https://www.scopus.com/pages/publications/85021708938

U2 - 10.1093/hmg/ddx151

DO - 10.1093/hmg/ddx151

M3 - Journal articles

C2 - 28449029

AN - SCOPUS:85021708938

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

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Genomweite Assoziationsstudie zur Identifikation Genetischer Risikofaktoren der Parodontitis

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