Human Genetics

, Volume 132, Issue 4, pp 451–460

Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese

  • Dongsheng Huang
  • Lei Yang
  • Yehua Liu
  • Yumin Zhou
  • Yuan Guo
  • Mingan Pan
  • Yunnan Wang
  • Yigang Tan
  • Haibo Zhong
  • Min Hu
  • Wenju Lu
  • Weidong Ji
  • Jian Wang
  • Pixin Ran
  • Nanshan Zhong
  • Yifeng Zhou
  • Jiachun Lu
Original Investigation

DOI: 10.1007/s00439-013-1264-9

Cite this article as:
Huang, D., Yang, L., Liu, Y. et al. Hum Genet (2013) 132: 451. doi:10.1007/s00439-013-1264-9

Abstract

Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: −94del>insATTG; NFκB2: −2966G>A; IκBα: −826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the −94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95 % CI 1.06–1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95 % CI 1.30–1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the −94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for −2966G>A and −826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (−94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.

Supplementary material

439_2013_1264_MOESM1_ESM.tif (779 kb)
Supplementary Figure S1.NFκB1 -94del>ins ATTG, NFκB2 -2966G>A, IκBα g-826C>T and 2758G>A genotyping. A, by Taqman assays. B, by direct sequencing (TIFF 778 kb)
439_2013_1264_MOESM2_ESM.tif (144 kb)
Supplementary Figure S2. Stratification analysis of the -94del>ins ATTG polymorphism for COPD. P value for the homogeneity test in each stratum was tested by Breslow-Day Test. A multiplicative interaction was suggested to detect the possible gene-environment interaction (TIFF 144 kb)
439_2013_1264_MOESM3_ESM.tif (189 kb)
Supplementary Figure S3. Stratification analysis of the 2758G>A polymorphism for lung cancer risk. P value for the homogeneity test in each stratum was tested by Breslow-Day Test. A multiplicative interaction was suggested to detect the possible gene-environment interaction (TIFF 188 kb)
439_2013_1264_MOESM4_ESM.tif (987 kb)
Supplementary Figure S4. Association between the 2758G>A genotypes and IκBα expressions in situ by immunohistochemical stain (TIFF 986 kb)
439_2013_1264_MOESM5_ESM.doc (248 kb)
Supplementary material 5 (DOC 248 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Dongsheng Huang
    • 1
    • 3
  • Lei Yang
    • 1
  • Yehua Liu
    • 1
  • Yumin Zhou
    • 2
  • Yuan Guo
    • 4
  • Mingan Pan
    • 5
  • Yunnan Wang
    • 3
  • Yigang Tan
    • 3
  • Haibo Zhong
    • 6
  • Min Hu
    • 7
  • Wenju Lu
    • 2
  • Weidong Ji
    • 1
  • Jian Wang
    • 2
  • Pixin Ran
    • 2
  • Nanshan Zhong
    • 2
  • Yifeng Zhou
    • 7
  • Jiachun Lu
    • 1
  1. 1.School of Public Health, The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory DiseaseGuangzhou Medical UniversityGuangzhouChina
  2. 2.Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, The State Key Lab of Respiratory DiseaseGuangzhou Medical UniversityGuangzhouChina
  3. 3.Department of Respiratory MedicineGuangzhou Chest HospitalGuangzhouChina
  4. 4.The Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
  5. 5.Department of Respiratory MedicineThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  6. 6.Department of Respiratory MedicineGuangzhou Red Cross HospitalGuangzhouChina
  7. 7.Soochow University Laboratory of Cancer Molecular GeneticsMedical College of Soochow UniversitySuzhouChina