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 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 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^*

^*Corresponding author for this work

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

81 Citations (Scopus)

Abstract

Periodontitis is one of themost 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 P¼1.09E-08
(rs4284742,-G; OR¼1.34, 95% CI¼1.21–1.48) and P¼5.48E-10 (rs2738058,-T; OR¼1.28, 95% CI¼1.18–1.38), respectively. SIGLEC5 is
expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential tomediate tyrosine phosphatases
SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils andmucosal
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 - 2017

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10.1093/hmg/ddx151

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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., 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{acfe05ca0cea4e52a2b47a0c2ece075e,

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

abstract = "Periodontitis is one of themost common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and anestimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant hostinflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported severalsuggestive 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 aGerman sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positivefindings 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 phenotypesand were associated with periodontitis at a genome-wide significance level in the pooled samples, with P¼1.09E-08(rs4284742,-G; OR¼1.34, 95% CI¼1.21–1.48) and P¼5.48E-10 (rs2738058,-T; OR¼1.28, 95% CI¼1.18–1.38), respectively. SIGLEC5 isexpressed in various myeloid immune cells and classified as an inhibitory receptor with the potential tomediate tyrosine phosphatasesSHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils andmucosalsurfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CPwith 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 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",

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, L, 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, 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, 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

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

Y1 - 2017

N2 - Periodontitis is one of themost common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and anestimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant hostinflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported severalsuggestive 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 aGerman sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positivefindings 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 phenotypesand were associated with periodontitis at a genome-wide significance level in the pooled samples, with P¼1.09E-08(rs4284742,-G; OR¼1.34, 95% CI¼1.21–1.48) and P¼5.48E-10 (rs2738058,-T; OR¼1.28, 95% CI¼1.18–1.38), respectively. SIGLEC5 isexpressed in various myeloid immune cells and classified as an inhibitory receptor with the potential tomediate tyrosine phosphatasesSHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils andmucosalsurfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CPwith genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.

AB - Periodontitis is one of themost common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and anestimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant hostinflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported severalsuggestive 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 aGerman sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positivefindings 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 phenotypesand were associated with periodontitis at a genome-wide significance level in the pooled samples, with P¼1.09E-08(rs4284742,-G; OR¼1.34, 95% CI¼1.21–1.48) and P¼5.48E-10 (rs2738058,-T; OR¼1.28, 95% CI¼1.18–1.38), respectively. SIGLEC5 isexpressed in various myeloid immune cells and classified as an inhibitory receptor with the potential tomediate tyrosine phosphatasesSHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils andmucosalsurfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CPwith 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

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

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