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

通过小鼠 QTL 联合定位以及随后的侵袭性牙周炎患者的全基因组关联分析、测序和高通量基因分型来鉴定牙周炎的遗传危险因素

• 批准号: 262320096
• 负责人: Professor Dr. Arne Schäfer
• 金额: --
• 依托单位: Sackler Faculty of Medicine
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/262320096?language=en
• 关键词: Identification; genetic; risk; factors; periodontitis

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.

牙周炎是一种慢性口腔炎症性疾病，会导致牙周支持组织的破坏，也可能对全身造成进一步的影响。牙周炎的群体变异有很大一部分可以归因于遗传因素，但只有一部分的遗传性得到了解释。为了识别广泛的遗传风险基因座谱，我们提出了一种无偏见的策略，用于重新生成人类候选基因区域的假设，该策略考虑了全基因组和候选基因关联研究的局限性。在系统遗传学方法中，我们将使用重组近交系小鼠(RIL)，即合作杂交(CC)，将牙周炎的危险基因定位为数量性状基因座(QTL)。与老鼠QTL相关的人类同源染色体区域将被用作在大量人类病例对照样本中进行详细分析的候选基因座。这些区域将使用来自624名德国侵袭性牙周炎患者和2,600名德国人口代表对照的现有全基因组数据(Illumina HumanOmniExpress-24 v1.0)，在电子计算机中验证与人类牙周炎的潜在关联。最强的相关变异将在一个独立的病例对照分析人群中复制，该病例对照分析人群包括600例起源于西北欧和土耳其的AGP病例、2200例德国慢性牙周炎病例和3000名种族匹配的对照病例。致病变异体将通过随后的有针对性的重新测序来鉴定。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有很大差异。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用药。

项目成果

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

PF4/PPBP/CXCL5基因簇与牙周炎相关

• DOI: 10.1177/0022034517706311
• 发表时间: 2017
• 期刊: Journal of Dental Research
• 影响因子: 7.6
• 作者: Shusterman A;Munz M;Richter G;Jepsen S;Lieb W;Krone B;Hoffman P;Laudes M;Wellmann J;Berger K;Kocher T;Offenbacher S;Divaris K;Franke A;Schreiber S;Dommisch H;Weiss E;Schaefer AS;Houri- Haddad Y;Iraqi FA
• 通讯作者: Iraqi FA

Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility

• DOI: 10.1177/0022034517744189
• 发表时间: 2018-05-01
• 期刊: JOURNAL OF DENTAL RESEARCH
• 影响因子: 7.6
• 作者: Nashef, A.;Qabaja, R.;Haddad, Y. H.
• 通讯作者: Haddad, Y. H.