基于基因-环境因素构建青少年恒牙龋风险预测模型及相关SNPs功能研究

Caries are one of the three critical human diseases, another two are tumor and cardiovascular disease, and the construction of caries risk model is the key to the accurate prevention and control of patients. Caries are the result of the combination of genetic and environmental factors, and the existing caries risk prediction models are based on environmental factors, the predictive sensitivity is only 41%, and the addition of genetic factors in the prediction model is expected to improve the accuracy of their predictions. There are no reports of caries risk predict models based on gene and environment factors. In the early stage, we found the SNPs loci associated with the susceptibility of permanent teeth from Chinese Han teenagers, and this suggested that genetic polymorphism is closely related to the risk of caries in individuals. Therefore, the project will rely on the South China Region caries biological Sample Bank and the built queue population and use high-throughput SNPs location sequencing technology by combining with environmental factors to explore the impact of gene and environment interaction on the pathogenesis of caries. At mean time, we will build the juvenile permanent dental caries risk prediction model and through the ROC curve to evaluate this model. Additionally, we will research the functional verification of SNPs sites related to caries susceptibility by using bioinformatics, report gene experiment and chip. The results not only provide a basis for the development of accurate prevention and control measures for juvenile permanent dental caries, but also reveal clues to the molecular genetic mechanism of caries.

龋病是与肿瘤、心血管疾病并列的人类三大重点防治疾病之一，构建龋风险模型是对其进行精准防控的关键。遗传和环境因素共同影响龋病的发生发展，而现有龋风险预测模型均是基于环境因素构建，预测敏感性仅为41%，在预测模型中增加遗传因素可望提高其预测的准确性。目前尚未见基于基因-环境因素的龋风险预测模型报道。我们前期发现了与中国汉族青少年恒牙龋易感性相关的SNPs位点，提示宿主遗传基因多态性与个体患龋风险密切相关。因此，本项目将拟依托华南区域龋病生物样本库及已构建的队列人群为基础，采用高通量技术对SNPs位点测序，结合环境因素，探究基因-环境交互作用对龋病发病的影响；构建青少年恒牙龋发病风险预测模型，通过ROC曲线对模型进行评估；并采用生物信息学、报告基因实验、CHIP等方法对龋易感相关SNPs位点进行功能分析。研究结果不仅为制定青少年恒牙龋精准防控措施提供依据，也为从宿主遗传学角度阐明龋病病因提供线索

龋病是人类最广泛流行的疾病，对公共卫生造成沉重负担，需要重点防控。构建龋病风险模型，筛选高危人群，根据风险等级进行梯度预防具有良好的卫生经济效益。龋病存在个体遗传易感性，现有的龋风险模型是基于环境因素构建，不考虑影响龋病发生的遗传背景，仅基于环境因素构建龋病风险预测模型必然会导致信息的损失。以往有学者研究发现：综合遗传易感标志和环境因素构建风险预测模型，其预测能力明显高于单纯采用环境因素建立的模型。本人前期发现了与中国汉族青少年恒牙龋易感性相关的SNPs。在此基础上，本项目对前期构建的队列进行随访，探究基因-环境交互作用对龋病发病的影响；构建青少年龋发病风险预测模型并进行验证。研究结果如下：（1）环境因素中的性别、看牙医行为、Cariostat 评分（牙菌斑产酸能力）和既往患龋经历与龋病发病相关（p ＜0.05）。AQP5基因rs1996315位点和TUFT1基因rs3790506位点突变与龋病发病相关（p＜0.05）。其中rs1996315位点突变是龋病发病的保护因素，而rs3790506位点突变是龋病发病的危险因素。（2）根据上述研究结果，我们构建了基于基因-环境因素的龋病风险预测模型，并对模型的准确性进行了验证，训练集人群中预测模型的AUC达0.78，测试集人群中预测模型的AUC达0.73，高于现有模型在中国青少年人群中的预测准确性（AUC为0.71）。风险分层图结果表明：基于基因-环境因素构建的龋病风险预测模型的区分度较好，可以准确的筛选高风险患龋人群，但低估了低风险和极低风险人群的患龋风险。综合本课题发现：与传统的龋病风险预测模型相比，加入遗传因素可以提高风险模型的预测准确性，该模型可用于中国青少年的龋病风险预测，为开展个性化的干预措施提供依据，具有一定的临床应用前景。

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