Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility
Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility
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DOI：
10.1177/0022034517744189
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发表时间：
2018-05-01
影响因子：
7.6
通讯作者：
Haddad, Y. H.
中科院分区：
文献类型：
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作者：
Nashef, A.;Qabaja, R.;Haddad, Y. H.
牙周炎是人类最常见的炎症性疾病之一，具有很强的遗传成分。由于现有牙周炎队列的样本量有限以及潜在的性状异质性，慢性牙周炎（CP）的全基因组关联研究（GWAS）在识别常见易感因素方面基本上不成功。将小鼠的数量性状基因座（QTL）定位与人类的关联研究相结合，有可能发现新的风险基因座。为此，我们评估了牙槽骨损失的实验牙周感染在25行（286只小鼠）从协作交叉（CC）小鼠群体使用微计算机断层扫描（μ CT）分析。使用来自西北欧和欧洲美洲血统的侵袭性牙周炎（AgP; 896例，7，104例对照）和慢性牙周炎（CP; 2，746例，1，864例对照）的病例对照样本的插补基因型数据（OmniExpress BeadChip阵列），分析显著QTL的正交人类染色体区域的关联。在小鼠基因组中，QTL定位揭示了2个显着的位点（-log P = 5.3;错误发现率= 0.06）上的染色体1（Perio 3）和14（Perio 4）。标测分辨率范围为1.5至3 Mb。Perio 3与先前报道的与F2杂交中的残余骨体积相关的QTL重叠，并且包括鼠基因Ccdc 121。它的人类直系同源物先前显示出与人类CP的名义上的显著关联。利用CC创始菌株基因组的变异数据进一步完善了QTL，并提出了7个候选基因（CAPN 8，DUSP 23，PCDH 17，SNORA 17，PCDH 9，LECT 1和LECT 2）。我们没有发现这些候选人与人类直系同源物相关的证据。总之，CC群体能够定位限定的QTL，该QTL赋予小鼠和更大的人类表型-基因型样品中牙槽骨丢失的易感性，并且可能需要来自牙龈组织的额外表达数据来鉴定真正的阳性信号。
Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (mu CT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 (Perio3) and 14 (Perio4). The mapping resolution ranged from similar to 1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes (CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival tissues are likely required to identify true positive signals.