Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease

Steven Offenbacher; Kimon Divaris; Silvana P Barros; Kevin L Moss; Julie T Marchesan; Thiago Morelli; Shaoping Zhang; Steven Kim; Lu Sun; James D Beck; Matthias Laudes; Matthias Munz; Arne S Schaefer; Kari E North

doi:10.1093/hmg/ddw069

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Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease

Journal article

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Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease

Steven Offenbacher, Kimon Divaris, Silvana P Barros, Kevin L Moss, Julie T Marchesan, Thiago Morelli, Shaoping Zhang, Steven Kim, Lu Sun, James D Beck, …

Human molecular genetics, Vol.25(10), pp.2113-2129

05/15/2016

DOI: 10.1093/hmg/ddw069

PMCID: PMC5062586

PMID: 26962152

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Abstract

Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031-moderate CP, 1914-healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.

Germany

Phenotype

Inflammation - pathology

Genome-Wide Association Study

Inflammation - microbiology

Porphyromonas gingivalis - pathogenicity

Humans

Periodontal Diseases - microbiology

SAP90-PSD95 Associated Proteins

Male

Interleukin-1beta - genetics

Nerve Tissue Proteins - genetics

Chronic Periodontitis - pathology

Gingival Crevicular Fluid - microbiology

Periodontal Diseases - pathology

Chronic Periodontitis - microbiology

Chronic Periodontitis - genetics

Inflammation - genetics

Female

Periodontal Diseases - genetics

Ubiquitin-Protein Ligases - genetics

Principal Component Analysis

Details

Title: Subtitle: Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease
Creators: Steven Offenbacher - Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA steven_offenbacher@unc.edu
Kimon Divaris - Department of Pediatric Dentistry, UNC School of Dentistry, Chapel Hill, NC, USA Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA
Silvana P Barros - Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
Kevin L Moss - Department of Dental Ecology, UNC School of Dentistry, Chapel Hill, NC, USA
Julie T Marchesan - Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
Thiago Morelli - Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
Shaoping Zhang - Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
Steven Kim - Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
Lu Sun - Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
James D Beck - Department of Dental Ecology, UNC School of Dentistry, Chapel Hill, NC, USA
Matthias Laudes - Clinic of Internal Medicine I, University Clinic Schleswig-Holstein, Kiel, Germany
Matthias Munz - Department of Periodontology, Institute of Dental, Oral and Maxillary Medicine, Charité-University Medicine Berlin, Berlin, Germany Institute of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
Arne S Schaefer - Department of Periodontology, Institute of Dental, Oral and Maxillary Medicine, Charité-University Medicine Berlin, Berlin, Germany
Kari E North - Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.25(10), pp.2113-2129
DOI: 10.1093/hmg/ddw069
PMID: 26962152
PMCID: PMC5062586
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: T90 DE021986 / NIDCR NIH HHS\r\nR90 DE022527 / NIDCR NIH HHS\r\nK23 DE025093 / NIDCR NIH HHS
Language: English
Date published: 05/15/2016
Academic Unit: Periodontics
Record Identifier: 9984066099502771

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