基因组功能性遗传变异与煤工尘肺易感性关联研究

Pneumoconiosis is the most serious occupational disease in China, and contributing to about 89.66% of the reported occupational diseases in 2014. Occupational exposure of silica dust is the major etiological factor of pneumoconiosis; however, only a few of individuals developed into pneumoconiosis despite with similar exposure at a given time. It suggests that genetic variants are also involved in the susceptibility of pneumoconiosis. We had performed a genome-wide association study (GWAS) on coal workers’ pneumoconiosis and identified several susceptibility loci in our previous study. However, ‘missing heritability’ is still the major challenge, and the potential biological functional variants are still unclear. We therefore plan to impute the missing variants based on 1000 Genome database firstly, and then annotated potentially associated variants with SIFT, PolyPhen-2, DHS and GTEx. Candidate functional variants will be replicated with 1000 cases and 1000 controls, and the significant variants will be further confirmed by molecular biology experiments. We aim to identify new susceptibility loci and explain the mechanisms underlying the associations. The findings of this project could be used to screen high-risk population, provide a new tool for early prevention, diagnosis and treatment of pneumoconiosis.

尘肺病是我国影响最广泛，受侵害人群最多的职业病。在相同的累积粉尘暴露量下，仅有部分接尘者最终发展为尘肺病，提示遗传背景可能与尘肺病发生的易感性相关。本课题组前期成功地开展了全球首项煤工尘肺全基因组关联研究（GWAS），发现多个煤工尘肺易感区域，在揭示尘肺病遗传易感机制中取得了新突破。然而，目前仍面临“遗传性丢失”及真正致病位点尚未确认等关键的科学问题。因此，本课题拟在前期研究成果基础上，基于1000 Genome数据库进行基因型填补，综合应用SIFT、PolyPhen-2，DHS和GTEx等网络资源进行功能注释，进一步降低初筛阶段验证标准，增加验证阶段样本量，并应用分子生物学手段探讨遗传变异及对应靶基因的生物学功能，以期发现新的煤工尘肺遗传易感变异，完善中国人群煤工尘肺遗传易感图谱，揭示尘肺病发生机制。研究结果有望用于尘肺病高危人群筛查，为实施个体化预防及早诊早治提供理论依据和技术支持。

尘肺病是我国影响最广泛，受侵害人群最多的职业病。在相同的累积粉尘暴露量下，仅有部分接尘者最终发展为尘肺病，提示遗传背景可能与尘肺病发生的易感性相关。本课题组前期成功地开展了全球首项煤工尘肺全基因组关联研究（GWAS），发现多个煤工尘肺易感区域，在揭示尘肺病遗传易感机制中取得了新突破。然而，目前仍面临“遗传性丢失”及真正致病位点尚未确认等关键的科学问题。因此，本课题拟在前期研究成果基础上，基于1000 Genome数据库进行基因型填补，综合应用多种网络资源进行功能注释，进一步降低初筛阶段验证标准，增加验证阶段样本量进行验证，并应用分子生物学手段探讨遗传变异及对应靶基因的生物学功能，以期发现新的煤工尘肺遗传易感变异，完善中国人群煤工尘肺遗传易感图谱，揭示尘肺病发生机制。研究结果有望用于尘肺病高危人群筛查，为实施个体化预防及早诊早治提供理论依据和技术支持。