The PF4/PPBP/CXCL5 Gene Cluster Is Associated with Periodontitis

Area of Science:

• Genetics
• Oral Biology
• Inflammatory Diseases

Background:

• Periodontitis is a common inflammatory disease with high heritability, but previous genome-wide association studies (GWAS) have been limited by sample size and trait heterogeneity.
• Identifying genetic susceptibility factors for periodontitis is crucial for understanding disease mechanisms and developing targeted interventions.

Purpose of the Study:

• To discover novel genetic loci associated with periodontitis by integrating quantitative trait loci (QTL) mapping in mice with human GWAS data.
• To identify specific genes and variants conferring risk for aggressive periodontitis (AgP) and chronic periodontitis (CP).

Main Methods:

• Combined RNA-sequencing of gingival tissues with QTL analysis in a mouse model of oral pathogen infection.
• Interrogated human orthologous chromosomal regions using GWAS data from German AgP and European American CP cohorts.
• Validated associated variants in independent CP cohorts.

Main Results:

• Four genes within mapped QTLs exhibited differential expression in the mouse model.
• Two significant haplotype blocks associated with AgP were identified: one near UGT2A1 and another near PF4/PPBP/CXCL5.
• The association near PF4/PPBP/CXCL5 (rs1595009) was successfully validated in two independent chronic periodontitis cohorts.

Conclusions:

• The study successfully identified genetic risk variants for periodontitis by combining mouse genetic data with human association studies.
• The findings demonstrate the utility of integrating multi-omics and cross-species data for discovering disease-associated loci.
• Specific genetic variants near UGT2A1 and PF4/PPBP/CXCL5 are associated with periodontitis risk.