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

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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.

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Author and article information

Journal

Journal ID (iso-abbrev): Hum. Mol. Genet.

Title: Human molecular genetics

Publisher: Oxford University Press (OUP)

ISSN (Electronic): 1460-2083

ISSN (Print): 0964-6906

Publication date (Electronic): July 01 2017

Volume: 26

Issue: 13

Affiliations

[1 ] Department of Periodontology and Synoptic Dentistry, Institute of Dental, Oral and Maxillary Medicine, Charité - University Medicine Berlin, Germany.

[2 ] Institute for Integrative and Experimental Genomics, University Medical Center Schleswig-Holstein - Campus Lübeck, Germany.

[3 ] Department of Periodontology, Clinic of Preventive Dentistry and Periodontology, University Medical Center of the Julius-Maximilians-University, Würzburg, Germany.

[4 ] Department of Operative Dentistry and Periodontology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany.

[5 ] Department of Conservative Dentistry, Periodontology and Preventive Dentistry, Hannover Medical School, Hannover, Germany.

[6 ] Institute of Epidemiology and Social Medicine, University Münster, Germany.

[7 ] Institute of Medical Informatics, Biometry and Epidemiology, University Clinic Essen, Germany.

[8 ] Institute of Human Genetics, University of Bonn, Germany.

[9 ] Human Genomics Research Group, Department of Biomedicine, University Hospital of Basel, Switzerland.

[10 ] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

[11 ] Department of Internal Medicine Section of Geriatrics, Amsterdam Medical Center, Amsterdam, The Netherlands.

[12 ] Department of Epidemiology and the EMGO Institute of Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.

[13 ] Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

[14 ] Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, USA.

[15 ] Division of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey.

[16 ] Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.

[17 ] Department of Periodontology, Faculty of Dentistry, Kocaeli University, Turkey.

[18 ] Department of Periodontology, Faculty of Dentistry, Hacettepe University, Sihhiye, Ankara, Turkey.

[19 ] Clinic of Internal Medicine, University Clinic Schleswig-Holstein, Kiel, Germany.

[20 ] Clinic of Conservational Dentistry, Center of Dental, Oral and Maxillary Medicine, University Medical Center Carl-Gustav-Carus, Technical University Dresden, Germany.

[21 ] Institute for Community Medicine, University Medicine Greifswald, Germany.

[22 ] Unit of Periodontology, Department of Restorative Dentistry, Periodontology, Endodontology, Preventive Dentistry and Pedodontics, Dental School, University Medicine Greifswald, Germany.

[23 ] Department of Periodontology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

[24 ] Department of Periodontology, University Medical Center Giessen and Marburg, Germany.

[25 ] Department of Conservative Dentistry and Periodontology, Medical University Vienna, School of Dentistry, Vienna, Austria.

[26 ] Institute of Epidemiology, Biobank PopGen, Christian-Albrechts-University, Kiel, Germany.

[27 ] Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.

[28 ] Department of Periodontology and Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, The Netherlands.

[29 ] Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany.

Article

Publisher Item ID: 3755421

DOI: 10.1093/hmg/ddx151

PubMed ID: 28449029

SO-VID: 2d154a06-9a7f-4f8a-a0f9-2436e701c5c5

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