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 & 6 others R. Mott, I. Gat-Viks, E. Wiess, A. Schaefer, F.A. Iraqi, Y.H. Haddad

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

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.

LanguageEnglish
Pages537-546
Number of pages10
JournalJournal of Dental Research
Volume97
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Fingerprint

Periodontitis
Quantitative Trait Loci
Chronic Periodontitis
Alveolar Bone Loss
Genotype
Genome
Aggressive Periodontitis
Chromosomes, Human, Pair 14
Residual Volume
Chromosomes, Human, Pair 1
Genome-Wide Association Study
Sample Size
Population
Genes
Tomography
Phenotype
Bone and Bones
Infection

Keywords

  • alveolar bone loss
  • animal model
  • Collaborative Cross
  • genetic
  • GWAS
  • QTL mapping

Cite this

Nashef, A., Qabaja, R., Salaymeh, Y., Botzman, M., Munz, M., Dommisch, H., ... Haddad, Y. H. (2018). Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility. Journal of Dental Research, 97(5), 537-546. https://doi.org/10.1177/0022034517744189
Nashef, A. ; Qabaja, R. ; Salaymeh, Y. ; Botzman, M. ; Munz, M. ; Dommisch, H. ; Krone, B. ; Hoffmann, P. ; Wellmann, J. ; Laudes, M. ; Berger, K. ; Kocher, T. ; Loos, B. ; van der Velde, N. ; Uitterlinden, A.G. ; de Groot, L.C.P.G.M. ; Franke, A. ; Offenbacher, S. ; Lieb, W. ; Divaris, K. ; Mott, R. ; Gat-Viks, I. ; Wiess, E. ; Schaefer, A. ; Iraqi, F.A. ; Haddad, Y.H. / Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility. In: Journal of Dental Research. 2018 ; Vol. 97, No. 5. pp. 537-546.
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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.",
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Nashef, A, Qabaja, R, Salaymeh, Y, Botzman, M, Munz, M, Dommisch, H, Krone, B, Hoffmann, P, Wellmann, J, Laudes, M, Berger, K, Kocher, T, Loos, B, van der Velde, N, Uitterlinden, AG, de Groot, LCPGM, Franke, A, Offenbacher, S, Lieb, W, Divaris, K, Mott, R, Gat-Viks, I, Wiess, E, Schaefer, A, Iraqi, FA & Haddad, YH 2018, 'Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility', Journal of Dental Research, vol. 97, no. 5, pp. 537-546. https://doi.org/10.1177/0022034517744189

Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility. / Nashef, A.; Qabaja, R.; Salaymeh, Y.; Botzman, M.; Munz, M.; Dommisch, H.; Krone, B.; Hoffmann, P.; Wellmann, J.; Laudes, M.; Berger, K.; Kocher, T.; Loos, B.; van der Velde, N.; Uitterlinden, A.G.; de Groot, L.C.P.G.M.; Franke, A.; Offenbacher, S.; Lieb, W.; Divaris, K.; Mott, R.; Gat-Viks, I.; Wiess, E.; Schaefer, A.; Iraqi, F.A.; Haddad, Y.H.

In: Journal of Dental Research, Vol. 97, No. 5, 01.05.2018, p. 537-546.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility

AU - Nashef, A.

AU - Qabaja, R.

AU - Salaymeh, Y.

AU - Botzman, M.

AU - Munz, M.

AU - Dommisch, H.

AU - Krone, B.

AU - Hoffmann, P.

AU - Wellmann, J.

AU - Laudes, M.

AU - Berger, K.

AU - Kocher, T.

AU - Loos, B.

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AU - Uitterlinden, A.G.

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

AU - Franke, A.

AU - Offenbacher, S.

AU - Lieb, W.

AU - Divaris, K.

AU - Mott, R.

AU - Gat-Viks, I.

AU - Wiess, E.

AU - Schaefer, A.

AU - Iraqi, F.A.

AU - Haddad, Y.H.

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N2 - 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.

AB - 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.

KW - alveolar bone loss

KW - animal model

KW - Collaborative Cross

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SP - 537

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JO - Journal of Dental Research

T2 - Journal of Dental Research

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SN - 0022-0345

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Nashef A, Qabaja R, Salaymeh Y, Botzman M, Munz M, Dommisch H et al. Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility. Journal of Dental Research. 2018 May 1;97(5):537-546. https://doi.org/10.1177/0022034517744189