Identification of genetic risk factors of periodontitis by combined QTL mapping in mice and subsequent genome-wide association analysis, sequencing, and high-throughput genotyping of patients of aggressive periodontitis

牙周炎是口腔的慢性炎症性疾病，导致牙周支持组织的破坏，并且可能还导致进一步的全身性影响。一个主要的比例与牙周炎的人口方差可归因于遗传因素，但只有一部分的遗传力已得到解释。为了识别一个全面的遗传风险位点，我们提出了一个无偏的策略，从头生成的假设，考虑到全基因组和候选基因关联研究的局限性，在人类的候选基因区域。在系统遗传学的方法中，我们将使用重组近交系小鼠（RIL），即协作杂交（CC），用于牙周炎的风险基因定位的数量性状位点（QTL）。与小鼠QTL相关的人类正向染色体区域将被用作候选基因座，用于在大型人类病例对照样品中进行详细分析。这些区域将使用来自624名德国侵袭性牙周炎患者和> 2，600名德国人口代表性对照的可用全基因组数据（Illumina HumanOmniExpress-24 v1.0）通过计算机验证与人类牙周炎的潜在关联。最强相关的变异将在一个独立的病例对照分析人群中复制，该人群包括600例西北欧和土耳其血统的AgP病例，2，200例德国慢性牙周炎病例和3，000例种族匹配的对照。将通过随后的靶向重测序鉴定致病变体。这些发现将有助于理解影响疾病易感性或对口腔细菌感染的抵抗力的分子机制，并有助于理解为什么这种反应在个体之间往往存在很大差异。通过这一点，该项目有可能指导慢性口腔炎症的早期诊断和个性化治疗。

Periodontitis is a chronic inflammatory disease of the oral cavity, resulting in destruction of the periodontal supporting tissues and likely, also in further systemic implications. A major proportion of the population variance with periodontitis can be attributed to genetic factors but only a proportion of the heritability has been explained. For identification of a comprehensive spectrum of genetic risk loci, we propose an unbiased strategy for the de novo generation of hypotheses of candidate gene regions in humans that takes into account the limitations of both genome-wide and candidate-gene association studies. In a systems genetics approach, we will use recombinant inbred mouse lines (RIL), namely the Collaborative Cross (CC), for mapping risk genes of periodontitis as quantitative trait loci (QTLs). The human orthologous chromosomal regions that correlate to the mouse-QTLs will be used as candidate loci for detailed analysis in large human case-control samples. These regions will be validated in silico for potential association with human periodontitis, using available genome-wide data (Illumina HumanOmniExpress-24 v1.0) from 624 German aggressive periodontitis patients and > 2,600 German population representative controls. The strongest associated variants will be replicated in an independent case-control analysis population of 600 AgP cases of North-West European and Turkish origin, 2,200 German chronic periodontitis cases and 3,000 ethnically matched controls. The causative variants will be identified by subsequent targeted resequencing. The findings will help to understand the molecular mechanisms, which influence disease susceptibility or resistance to oral bacterial infection and help to understand why this response often greatly differs between individuals. Through this, the project has the potential to guide early diagnosis and personalized medicine for chronic oral inflammation.