Dong Jing, Cheng Yang, Zhu Meng, Wen Yang, Wang Cheng, Wang Yuzhuo, Geng Liguo, Shen Wei, Liu Jia, Li Zhihua, Zhang Jiahui, Ma Hongxia, Dai Juncheng, Jin Guangfu, Hu Zhibin, Shen Hongbing
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
Int J Cancer. 2017 Aug 1;141(3):447-456. doi: 10.1002/ijc.30702. Epub 2017 May 9.
Genome-wide association studies in European and Asian populations have consistently identified chromosome 5p15.33 as a lung cancer susceptibility region. To investigate further the genetic architecture of common variants in this region, we conducted a two-stage fine-mapping analysis discovered by targeted resequencing of 200 cases and 300 controls individually, and validated in multiethnic lung cancer Genome wide association studies (GWASs) with 12,843 cases and 12,639 controls. Two independent variants were identified in approximate conditional analysis with GCTA and consistently validated in lung cancer GWASs in both Asian and European populations. These were rs10054203 in TERT (resequencing: OR = 1.69, p = 2.70 × 10 ; validation: OR = 1.34, p = 2.10 × 10 for Asian, and OR = 1.09, p = 6.00 × 10 for European), and rs397640 in CLPTM1L (resequencing: OR = 0.37, p = 1.19 × 10 ; validation: OR = 0.75, p = 5.89 × 10 for Asian, and OR = 0.90, p = 2.40 × 10 for European). Expression quantitative trait loci analysis showed the risk allele (C) of rs10054203 was significantly associated with lower mRNA expression of CTD-2245Ef15.3 (p = 0.019) and Tubulin Polymerization-Promoting Protein (TPPP, p = 0.031) in 167 lung tissues. In conclusion, in this largest and first resequencing-based fine-mapping analysis of 5p15.33 region in Han Chinese, we identified two novel variants associated with lung cancer susceptibility. Further validation studies and functional work is required to confirm the roles of the newly discovered variants.
在欧洲和亚洲人群中开展的全基因组关联研究一致将5号染色体p15.33区域确定为肺癌易感区域。为了进一步研究该区域常见变异的遗传结构，我们进行了两阶段精细定位分析，首先对200例病例和300例对照进行靶向重测序，然后在包含12843例病例和12639例对照的多民族肺癌全基因组关联研究（GWAS）中进行验证。在使用GCTA进行的近似条件分析中确定了两个独立变异，并在亚洲和欧洲人群的肺癌GWAS中得到一致验证。这两个变异分别是TERT基因中的rs10054203（重测序：比值比[OR]=1.69，p=2.70×10 ；验证：亚洲人群中OR=1.34，p=2.10×10 ，欧洲人群中OR=1.09，p=6.00×10 ），以及CLPTM1L基因中的rs397640（重测序：OR=0.37，p=1.19×10 ；验证：亚洲人群中OR=0.75，p=5.89×10 ，欧洲人群中OR=0.90，p=2.40×10 ）。表达数量性状位点分析显示，rs10054203的风险等位基因（C）与167个肺组织中CTD-2245Ef15.3（p=0.019）和微管聚合促进蛋白（TPPP，p=0.031）的mRNA表达降低显著相关。总之，在本次针对汉族人群5p15.33区域开展的规模最大且首次基于重测序的精细定位分析中，我们鉴定出两个与肺癌易感性相关的新变异。需要进一步的验证研究和功能研究来证实新发现变异的作用。
