Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility

A Nashef; R Qabaja; Y Salaymeh; M Botzman; M Munz; H Dommisch; B Krone; P Hoffmann; J Wellmann; M Laudes; K Berger; T Kocher; B Loos; N van der Velde; A G Uitterlinden; L C P G M de Groot; A Franke; S Offenbacher; W Lieb; K Divaris; R Mott; I Gat-Viks; E Wiess; A Schaefer; F A Iraqi; Y H Haddad

doi:10.1177/0022034517744189

Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility

J Dent Res. 2018 May;97(5):537-546. doi: 10.1177/0022034517744189. Epub 2018 Jan 2.

Authors

A Nashef¹, R Qabaja¹, Y Salaymeh², M Botzman³, M Munz^{4

5}, H Dommisch⁴, B Krone⁶, P Hoffmann^{7

8}, J Wellmann⁹, M Laudes¹⁰, K Berger⁹, T Kocher¹¹, B Loos¹², N van der Velde^{13

14}, A G Uitterlinden¹³, L C P G M de Groot¹⁵, A Franke¹⁶, S Offenbacher¹⁷, W Lieb¹⁸, K Divaris^{19

20}, R Mott²¹, I Gat-Viks³, E Wiess²², A Schaefer⁴, F A Iraqi², Y H Haddad¹

Affiliations

¹ 1 Department of Prosthodontics, Hadassah Faculty of Dental Medicine, Hebrew University, Jerusalem, Israel.
² 2 Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³ 3 Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
⁴ 4 Department of Periodontology and Synoptic Medicine, Institute for Dental and Craniofacial Sciences, Charité-University Medicine Berlin, Berlin, Germany.
⁵ 5 Institute for Integrative and Experimental Genomics, University Medical Center Schleswig-Holstein-Campus, Lübeck, Germany.
⁶ 6 Institute of Medical Informatics, Biometry and Epidemiology, University Clinic Essen, Essen, Germany.
⁷ 7 Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁸ 8 Germany und Human Genomics Research Group, Department of Biomedicine, University Hospital of Basel, Basel, Switzerland.
⁹ 9 Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁰ 10 Clinic of Internal Medicine, University Clinic Schleswig-Holstein, Kiel, Germany.
¹¹ 11 Unit of Periodontology, Department of Restorative Dentistry, Periodontology, Endodontology, Preventive Dentistry and Pedodontics, Dental School, University Medicine Greifswald, Greifswald, Germany.
¹² 12 Department of Periodontology and Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, the Netherlands.
¹³ 13 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
¹⁴ 14 Department of Internal Medicine Section of Geriatrics, Amsterdam Medical Center, Amsterdam, the Netherlands.
¹⁵ 15 Department of Epidemiology and the EMGO Institute of Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
¹⁶ 16 Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
¹⁷ 17 School of Dentistry, Department of Periodontology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
¹⁸ 18 Institute of Epidemiology, Biobank popgen, Christian-Albrechts-University, Kiel, Germany.
¹⁹ 19 Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
²⁰ 20 School of Dentistry, Department of Pediatric Dentistry, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
²¹ 21 Genetics Institute, University Collage of London, London, UK.
²² 22 Maurice and Gabriella Goldschleger School of Dental Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Abstract

Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 ( Perio3) and 14 ( Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes ( CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.

Keywords: Collaborative Cross; GWAS; QTL mapping; alveolar bone loss; animal model; genetic.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alveolar Bone Loss / diagnostic imaging
Alveolar Bone Loss / genetics
Animals
Chromosome Mapping
Disease Models, Animal
Female
Genetic Association Studies
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Humans
Male
Mice
Middle Aged
Periodontitis / diagnostic imaging
Periodontitis / genetics*
Quantitative Trait Loci / genetics
X-Ray Microtomography

Abstract

Publication types

MeSH terms

Grants and funding