Institute of Health Services Research in Dentistry, University of Münster, Münster, Germany.
Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
Front Immunol. 2024 Oct 8;15:1407431. doi: 10.3389/fimmu.2024.1407431. eCollection 2024.
An excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis.
In our primary analysis, we used 26 independent 'cis' single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1β (IL-1β), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1β, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis.
In our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80-0.98, value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers.
The findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease.
过度激活或失调的补体系统已被证明是牙周病发病机制的重要因素。先前有假说认为，通过靶向 C5a 受体抑制补体成分 C5 的活性是治疗牙周病的有力候选药物。在这里，我们应用药物靶点工具变量（IV）方法来研究基因介导的 C5 抑制对牙周病的治疗效果。
在我们的主要分析中，我们使用了 26 个独立的“顺式”单核苷酸多态性作为 IVs，这些多态性位于编码 C5 的基因座附近，与血浆 C5 水平相关。在二次分析中，我们评估了我们主要发现的有效性，探索了替代下游生物标志物白细胞介素 17（IL-17）、白细胞介素 1β（IL-1β）和肿瘤坏死因子（TNF）的参与情况。来自 35559 名欧洲血统个体的全基因组关联研究（GWAS）中获得了血浆水平（C5、IL-17、IL-1β和 TNF）的汇总统计数据。我们从 17353 例临床牙周炎病例和 28210 例欧洲对照的 GWAS 中提取了关联统计数据。使用逆方差加权荟萃分析对 Wald 比值进行了组合。
在我们的主要方法中，抑制 C5 降低了牙周病的风险（C5 每降低 1 个标准差，风险比为 0.89；95%置信区间为 0.80-0.98，P 值=0.022）。我们的二次分析表明，IL-17 可能参与了潜在的因果途径，但对其他生物标志物的结论尚无定论。
我们的研究结果表明，C5 抑制可能降低牙周病的风险，将 C5 抑制剂作为该疾病潜在的辅助治疗干预措施。
