Richter Gesa M, Schaefer Arne S
Department of Periodontology, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany.
J Periodontal Res. 2025 Jul 11. doi: 10.1111/jre.70002.
Periodontitis is a widespread inflammatory disease of the oral cavity that is influenced by genetic and environmental factors. Periodontitis has a high heritability, and particularly severe periodontitis often manifests before the age of 40, suggesting a strong genetic component. Genetic research has identified genetic variants associated with susceptibility to periodontitis that provide insights into the underlying mechanisms, which may improve future diagnostic and treatment strategies. We screened potential risk single-nucleotide variants (SNVs) identified in genetic association studies on periodontitis using the following selection criteria: genome-wide significance (p ≤ 5 × 10) or suggestive significance (p ≤ 5 × 10) with replication in ≥ 1 independent study. Additionally, we included SNVs with p < 5 × 10 and ≥ 2 independent replications and functional validation. Due to the polygenic nature of periodontitis, we prioritized common variants with a minor allele frequency ≥ 1% and included rare variants (MAF ≤ 0.001) identified in whole-exome sequencing studies of severe cases with early onset. These criteria increased the reliability of identifying true genetic risk factors. The identified genetic risk loci for periodontitis can be primarily attributed to two biological functions: immune response and tissue integrity including regeneration. Genes such as SIGLEC5, DEFA1, FCERG1, PPBP/CXCL5/PF4, CDKN2B-AS1, and CTSC have a known function in neutrophil activity, antimicrobial defense, and mediation of the immune response. In particular, SIGLEC5, PLG, RSPO4, ROBO2, HMCN2, and CTSC appear to contribute to wound healing, extracellular matrix remodeling, and hemostasis. In particular, SIGLEC5, PLG, and PPBP/PF4 interact at the interface of immune function and tissue repair. In conclusion, risk genes for periodontitis point to the importance of the interplay between immune response and tissue homeostasis in the etiology of periodontitis. Future large-scale genome-wide association studies, whole-exome sequencing, and functional studies will likely uncover additional risk genes and refine our understanding of genetic contributions to periodontitis and help to develop potential therapeutic targets.
牙周炎是一种广泛存在的口腔炎症性疾病，受遗传和环境因素影响。牙周炎具有较高的遗传度，尤其是重度牙周炎常出现在40岁之前，这表明其有很强的遗传成分。基因研究已确定了与牙周炎易感性相关的基因变异，这有助于深入了解其潜在机制，可能会改善未来的诊断和治疗策略。我们使用以下选择标准筛选了在牙周炎基因关联研究中确定的潜在风险单核苷酸变异（SNV）：全基因组显著性（p≤5×10）或提示性显著性（p≤5×10），且在≥1项独立研究中得到重复验证。此外，我们纳入了p<5×10且有≥2项独立重复验证和功能验证的SNV。由于牙周炎的多基因性质，我们优先考虑次要等位基因频率≥1%的常见变异，并纳入在早发性严重病例的全外显子测序研究中确定的罕见变异（MAF≤0.001）。这些标准提高了识别真正遗传风险因素的可靠性。确定的牙周炎遗传风险位点主要可归因于两种生物学功能：免疫反应和包括再生在内的组织完整性。诸如唾液酸结合免疫球蛋白样凝集素5（SIGLEC5）、防御素1（DEFA1）、Fc受体γ链（FCERG1）、血小板碱性蛋白/趋化因子CXC5/血小板因子4（PPBP/CXCL5/PF4）、细胞周期蛋白依赖性激酶2B反义RNA1（CDKN2B-AS1）和组织蛋白酶C（CTSC）等基因在中性粒细胞活性、抗菌防御和免疫反应介导方面具有已知功能。特别是，SIGLEC5、纤溶酶原（PLG）、富含亮氨酸重复序列的G蛋白偶联受体4（RSPO4）、轴突导向分子2（ROBO2）、透明质酸结合蛋白2（HMCN2）和CTSC似乎有助于伤口愈合、细胞外基质重塑和止血。特别是，SIGLEC5、PLG和PPBP/血小板因子4在免疫功能和组织修复的界面相互作用。总之，牙周炎的风险基因表明免疫反应与组织稳态之间的相互作用在牙周炎病因学中的重要性。未来大规模的全基因组关联研究、全外显子测序和功能研究可能会发现更多风险基因，并深化我们对牙周炎遗传贡献的理解，有助于开发潜在的治疗靶点。
