Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.,Carcinogenesis

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Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.
Carcinogenesis ( IF 3.3 ) Pub Date : 2021-10-05 , DOI: 10.1093/carcin/bgab064
Yuzhuo Wang _{1,

2} , Mengmeng Ji _{1,

3} , Meng Zhu _{1,

2,

4} , Jingyi Fan ₁ , Junxing Xie ₁ , Yanqian Huang ₁ , Xiaoxia Wei ₁ , Xiangxiang Jiang ₁ , Jing Xu ₅ , Liang Chen ₅ , Rong Yin ₂ , Cheng Wang _{1,

4} , Ruyang Zhang _{6,

7,

8} , Yang Zhao _{4,

6,

9} , Juncheng Dai _{1,

4} , Guangfu Jin _{1,

4} , Zhibin Hu _{1,

4} , David C Christiani _{7,

10} , Hongxia Ma _{1,

4} , Lin Xu ₂ , Hongbing Shen _{1,

4,

11}

Affiliation

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China.
Department of Epidemiology, School of Public Health, Southeast University, Nanjing 210009, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.
Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China.

Gene-smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single-nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene-smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies of NSCLC, which included 13 327 cases and 13 328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5 × 10-8 for identifying significant gene-smoking interactions and 1 × 10-6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene-smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.54-0.74, P = 3.31 × 10-8], and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95% CI: 0.63-0.82, P = 8.10 × 10-7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95% CI: 0.51-0.73, P = 7.55 × 10-8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations.

更新日期：2021-07-23

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