论文题目：Discovery of susceptibility loci associated with tuberculosis in Han Chinese

第一作者：Hui Qi（綦辉）, Yong-Biao Zhang（张永彪）, Lin Sun（孙琳）, Cheng Chen（陈诚）

通讯作者：A-Dong Shen （申阿东）

发表杂志：Human Molecular Genetics

影响因子：5.340

Abstract：Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10^−11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population.

为了明确我国宿主基因多态性与结核病易感的相关性，本研究团队在国内与多家医院和科研院所合作，共同开展了国内外首项针对我国汉族人群结核病的全基因组关联研究（GWAS）。通过在1008名结核病患者和1538名健康对照中开展的中华芯片筛选以及在3460名结核病患者和4862名健康对照进行的质谱验证，最终发现了rs4240897、rs41553512和rs2269497位点突变与结核病易感的显著相关。在此基础上，与甘比亚人群和印尼人群的结核病GWAS研究团队合作，对以上3个SNP位点进行meta分析，发现以上位点与结核病易感仍然显著相关。除此之外，我们还对3个SNP位点对应的候选基因进行转录水平和通路富集分析，发现MFN2和TNFRSF8等基因转录水平在组间存在明显差异，多个基因富集于与结核病发病密切相关的抗原提呈、T淋巴细胞活化以及信号转导等通路。本研究为进一步探索结核病发病新机制提供了重要线索。