Translation of mouse model to human gives insights into periodontitis etiology

Aysar Nashef,Arne Schäfer,Munz Matthias,Søren Jepsen,Andre Franke,Henrik Dommisch,Wolfgang Lieb,Bruno G Loos,Fuad A Iraqi,André G Uitterlinden,Jürgen Wellmann,Klaus Berger,Matthias Laudes,Nathalie Van Der Velde,Ervin Weiss,Yael Houri-Haddad,Per Hoffmann

doi:10.1038/s41598-020-61819-0

Abstract

To suggest candidate genes involved in periodontitis, we combined gene expression data of periodontal biopsies from Collaborative Cross (CC) mouse lines, with previous reported quantitative trait loci (QTL) in mouse and with human genome-wide association studies (GWAS) associated with periodontitis. Periodontal samples from two susceptible, two resistant and two lines that showed bone formation after periodontal infection were collected during infection and naïve status. Differential expressed genes (DEGs) were analyzed in a case-control and case-only design. After infection, eleven protein-coding genes were significantly stronger expressed in resistant CC lines compared to susceptible ones. Of these, the most upregulated genes were MMP20 (P = 0.001), RSPO4 (P = 0.032), CALB1 (P = 1.06×10−4), and AMTN (P = 0.05). In addition, human orthologous of candidate genes were tested for their association in a case-controls samples of aggressive (AgP) and chronic (CP) periodontitis (5,095 cases, 9,908 controls). In this analysis, variants at two loci, TTLL11/PTGS1 (rs9695213, P = 5.77×10−5) and RNASE2 (rs2771342, P = 2.84×10−5) suggested association with both AgP and CP. In the association analysis with AgP only, the most significant associations were located at the HLA loci HLA-DQH1 (rs9271850, P = 2.52×10−14) and HLA-DPA1 (rs17214512, P = 5.14×10−5). This study demonstrates the utility of the CC RIL populations as a suitable model to investigate the mechanism of periodontal disease.

Highlights

Www.nature.com/scientificreports rare but severe and early-onset form aggressive periodontitis (AgP), which is believed to have a stronger genetic component, or studies that combined AgP and chronic periodontitis (CP) analysis samples to increase the statistical power, identified five genome-wide significant loci[7,8,9]
Given that expression patterns in mouse models recapitulate those in humans[10], the examination of differences in gene expression as a response to different environmental exposures in genetically identical mice and between genetically different mice living in the same environmental context, can give direct insight into the mechanism that lead to disease susceptibility
We identified Collaborative Cross (CC)-RILs with increased susceptibility and resistance to PD as a result of mixed infection with the oral bacteria Porphyromonas gingivalis (P.g) and Fusobacterium nucleatum (F.n)[21] and mapped two quantitative trait loci (QTL) that were associated with alveolar bone loss in the CC mouse population[22]

Summary

Results

All DEGs except of Bpifa[6] could be mapped to an orthologous autosomal gene in the human genome This chromosome was excluded from the human GWAS data set and the subsequent analyses).Obp2b showed homology with the two human genes OBP2A and OBP2B (Appendix-Table 1). The chromosomal region at TTLL11 was previously suggested to be associated with increased quantities of P.g. colonization of the human oral cavity before[1] In addition to these loci, among the DEGs that mapped to the QTLs Perio[3] and Perio[4] and had been suggested in previous human GWAS on PD as putative risk loci of PD, variants at LBP (chr.20) suggested association in the AgP-CP Meta-analysis (rs1780616, P = 1.67 ×10−3 [AgP; rs1780616, P = 7,78 ×10−3])

Discussion

A G AgP-Ger

Materials and Methods