International Journal of COPD (2018-03-01)

A functional SNP upstream of the ADRB2 gene is associated with COPD

  • Li JX,
  • Fu WP,
  • Zhang J,
  • Zhang XH,
  • Sun C,
  • Dai LM,
  • Zhong L,
  • Yu L,
  • Zhang YP

Journal volume & issue
Vol. Volume 13
pp. 917 – 925


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Jin-Xiu Li,1,2,* Wei-Ping Fu,3,* Jing Zhang,4 Xiao-Hua Zhang,1,2 Chang Sun,1,5 Lu-Ming Dai,3 Li Zhong,1,5,6 Li Yu,1,2 Ya-Ping Zhang1,7 1State Key Laboratory for Conservation and Utilization of Bio-Resource in Yunnan, 2Key Laboratory for Animal Genetic Diversity and Evolution of High Education in Yunnan Province, School of Life Sciences, Yunnan University, 3Department of Respiratory Critical Care Medicine, 4Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 5College of Life Sciences, 6Provincial Demonstration Center for Experimental Biology Education, Shaanxi Normal University, Xi’an, 7State Key Laboratory of Genetic Resources and Evolution, and Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China *These authors contributed equally to this work Background: Previous studies have suggested that β2-adrenergic receptor (ADRB2) is associated with COPD. However, the role of genetic polymorphisms in ADRB2 on COPD has not been evaluated yet. Methods: In this study, SNaPshot genotyping, luciferase assay, chromatin immunoprecipitation and real-time polymerase chain reaction were adopted to investigate the association between ADRB2 genetic polymorphisms and COPD, comprehensively. Results: One single nucleotide polymorphism (rs12654778), located upstream of ADRB2, showed a significant association with COPD by the logistic regression analysis after adjusting for age, sex and smoking history (p=0.04) in 200 COPD patients and 222 controls from southwest Chinese population. Furthermore, the luciferase assay indicated that rs12654778-A allele reduced the relative promoter activity by ~26% compared with rs12654778-G allele (p=0.0034). The chromatin immunoprecipitation analysis demonstrated that rs12654778 modulated the binding affinity of transcription factor neurofibromin 1. In addition, a significantly reduced expression of ADRB2 in COPD patients was observed, compared with normal controls (p=0.017). Conclusion: Our findings suggest a previously unknown mechanism linking allele-specific effects of rs12654778 on ADRB2 expression to COPD onset, for the first time. Keywords: β2-adrenergic receptor, ADRB2, FEV1, lung, polymorphism