Human Genetics

, Volume 132, Issue 4, pp 451–460 | Cite as

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

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.

Notes

Acknowledgments

This study was supported by the National Natural Scientific Foundation of China grants 30671813, 30872178, 81072366, 81273149 (Dr. J. Lu), and partly by 81170043 (Dr. P.Ran), 30872142 (Dr. W. Ji) and 81001278, 81171895 (Dr. Y. Zhou); Guangdong Provincial High Level Experts Grants 2010-79 (Dr. J. Lu); Guangdong Provincial Science and Technology Planning Project Grant 2011B031800378 (Dr. D. Huang), Guangdong Provincial Medical Scientific Research Grants A2012520 (Dr. D. Huang); Guangzhou civic Science and Technology grant 2012-Y2-00029 (Dr. B. Liu); Changjiang Scholars and Innovative Research Team in University grant IRT0961 (Dr. J. Wang), Guangdong natural science foundation team grant 10351012003000000 (Dr. W. Lu). We thank Dr. Bohang Zeng, Dr. Yunnan Wang, Dr. Zhanhong Xie and Ms. Wanmin Zeng for their assistance in recruiting the subjects; Hongjun Zhao, Xiaoxuan Ling and Lin Liu for their laboratory assistance.

Conflict of interest

The authors have declared no conflicts of interest.

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)

References

  1. Abe H, Hayes CN, Ochi H, Tsuge M, Miki D, Hiraga N, Imamura M, Takahashi S, Kubo M, Nakamura Y, Kamatani N, Chayama K (2011) Inverse association of IL28B genotype and liver mRNA expression of genes promoting or suppressing antiviral state. J Med Virol 83:1597–1607. doi: 10.1002/jmv.22158 PubMedCrossRefGoogle Scholar
  2. Brown V, Elborn JS, Bradley J, Ennis M (2009) Dysregulated apoptosis and NFkappaB expression in COPD subjects. Respir Res 10:24. doi: 10.1186/1465-9921-10-24 PubMedCrossRefGoogle Scholar
  3. Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, Menezes AM, Sullivan SD, Lee TA, Weiss KB, Jensen RL, Marks GB, Gulsvik A, Nizankowska-Mogilnicka E (2007) International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 370:741–750. doi: 10.1016/S0140-6736(07)61377-4 PubMedCrossRefGoogle Scholar
  4. Castaldi PJ, Cho MH, Litonjua AA, Bakke P, Gulsvik A, Lomas DA, Anderson W, Beaty TH, Hokanson JE, Crapo JD, Laird N, Silverman EK (2011) The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility. Am J Respir Cell Mol Biol 45:1147–1153. doi: 10.1165/rcmb.2011-0055OC PubMedCrossRefGoogle Scholar
  5. Chaturvedi MM, Sung B, Yadav VR, Kannappan R, Aggarwal BB (2011) NF-kappaB addiction and its role in cancer: ‘one size does not fit all’. Oncogene 30:1615–1630. doi: 10.1038/onc.2010.566 PubMedCrossRefGoogle Scholar
  6. Chen Y (1999) Genetics and pulmonary medicine. 10: genetic epidemiology of pulmonary function. Thorax 54:818–824PubMedCrossRefGoogle Scholar
  7. Chen F, Castranova V, Shi X, Demers LM (1999) New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45:7–17PubMedGoogle Scholar
  8. de Torres JP, Marin JM, Casanova C, Cote C, Carrizo S, Cordoba-Lanus E, Baz-Davila R, Zulueta JJ, Aguirre-Jaime A, Saetta M, Cosio MG, Celli BR (2011) Lung cancer in patients with chronic obstructive pulmonary disease–incidence and predicting factors. Am J Respir Crit Care Med 184:913–919. doi: 10.1164/rccm.201103-0430OC PubMedCrossRefGoogle Scholar
  9. Dupont WD, Plummer WD (1990) Power and sample size calculations: a review and computer program. Control Clin Trials 11:116–128PubMedCrossRefGoogle Scholar
  10. Escarcega RO (2010) The transcription factor NF-kappaB in human diseases. Rev Med Inst Mex Seguro Soc 48:55–60PubMedGoogle Scholar
  11. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: gLOBOCAN 2008. Int J Cancer. doi: 10.1002/ijc.25516 Google Scholar
  12. Ferrer M, Alonso J, Morera J, Marrades RM, Khalaf A, Aguar MC, Plaza V, Prieto L, Anto JM (1997) Chronic obstructive pulmonary disease stage and health-related quality of life. The Quality of Life of Chronic Obstructive Pulmonary Disease Study Group. Ann Intern Med 127:1072–1079PubMedGoogle Scholar
  13. Garcia-Rio F, Miravitlles M, Soriano JB, Munoz L, Duran-Tauleria E, Sanchez G, Sobradillo V, Ancochea J (2010) Systemic inflammation in chronic obstructive pulmonary disease: a population-based study. Respir Res 11:63. doi: 10.1186/1465-9921-11-63 PubMedCrossRefGoogle Scholar
  14. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. doi: 10.1016/j.cell.2010.01.025 PubMedCrossRefGoogle Scholar
  15. Hayden MS, West AP, Ghosh S (2006) SnapShot: NF-kappaB signaling pathways. Cell 127:1286–1287. doi: 10.1016/j.cell.2006.12.005 PubMedCrossRefGoogle Scholar
  16. He Y, Zhang H, Yin J, Xie J, Tan X, Liu S, Zhang Q, Li C, Zhao J, Wang H, Cao G (2009) IkappaBalpha gene promoter polymorphisms are associated with hepatocarcinogenesis in patients infected with hepatitis B virus genotype C. Carcinogenesis 30:1916–1922. doi: 10.1093/carcin/bgp226 PubMedCrossRefGoogle Scholar
  17. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD (2004) The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350:2645–2653. doi: 10.1056/NEJMoa032158 PubMedCrossRefGoogle Scholar
  18. Hu Z, Wu C, Shi Y, Guo H, Zhao X, Yin Z, Yang L, Dai J, Hu L, Tan W, Li Z, Deng Q, Wang J, Wu W, Jin G, Jiang Y, Yu D, Zhou G, Chen H, Guan P, Chen Y, Shu Y, Xu L, Liu X, Liu L, Xu P, Han B, Bai C, Zhao Y, Zhang H, Yan Y, Ma H, Chen J, Chu M, Lu F, Zhang Z, Chen F, Wang X, Jin L, Lu J, Zhou B, Lu D, Wu T, Lin D, Shen H (2011) A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat Genet 43:792–796. doi: 10.1038/ng.875 PubMedCrossRefGoogle Scholar
  19. Hung YH, Wu CC, Ou TT, Lin CH, Li RN, Lin YC, Tsai WC, Liu HW, Yen JH (2010) IkappaBalpha promoter polymorphisms in patients with Behcet’s disease. Dis Markers 28:55–62. doi: 10.3233/DMA-2010-0684 PubMedGoogle Scholar
  20. Karban AS, Okazaki T, Panhuysen CI, Gallegos T, Potter JJ, Bailey-Wilson JE, Silverberg MS, Duerr RH, Cho JH, Gregersen PK, Wu Y, Achkar JP, Dassopoulos T, Mezey E, Bayless TM, Nouvet FJ, Brant SR (2004) Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet 13:35–45. doi: 10.1093/hmg/ddh008 PubMedCrossRefGoogle Scholar
  21. Karin M (2009) NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 1:a000141. doi: 10.1101/cshperspect.a000141 PubMedCrossRefGoogle Scholar
  22. Kim HJ, Kim KW, Yu BP, Chung HY (2000) The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation. Free Radic Biol Med 28:683–692PubMedCrossRefGoogle Scholar
  23. Lee J, Taneja V, Vassallo R (2012) Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res 91(2):142–149. doi: 10.1177/0022034511421200 Google Scholar
  24. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85. doi: 10.1056/NEJM200007133430201 PubMedCrossRefGoogle Scholar
  25. Liu B, Yang L, Huang B, Cheng M, Wang H, Li Y, Huang D, Zheng J, Li Q, Zhang X, Ji W, Zhou Y, Lu J (2012) A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer. Am J Hum Genet 91:384–390. doi: 10.1016/j.ajhg.2012.07.003 PubMedCrossRefGoogle Scholar
  26. Lize M, Pilarski S, Dobbelstein M (2010) E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis. Cell Death Differ 17:452–458. doi: 10.1038/cdd.2009.188 PubMedCrossRefGoogle Scholar
  27. Lu J, Yang L, Zhao H, Liu B, Li Y, Wu H, Li Q, Zeng B, Wang Y, Ji W, Zhou Y (2011) The polymorphism and haplotypes of PIN1 gene are associated with the risk of lung cancer in Southern and Eastern Chinese populations. Hum Mutat 32:1299–1308. doi: 10.1002/humu.21574 PubMedCrossRefGoogle Scholar
  28. Marcos M, Pastor I, Gonzalez-Sarmiento R, Laso FJ (2009) A functional polymorphism of the NFKB1 gene increases the risk for alcoholic liver cirrhosis in patients with alcohol dependence. Alcohol Clin Exp Res 33:1857–1862. doi: 10.1111/j.1530-0277.2009.01023.x PubMedCrossRefGoogle Scholar
  29. Petrescu F, Voican SC, Silosi I (2010) Tumor necrosis factor-alpha serum levels in healthy smokers and nonsmokers. Int J Chron Obstruct Pulmon Dis 5:217–222PubMedGoogle Scholar
  30. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J (2007) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176:532–555. doi: 10.1164/rccm.200703-456SO PubMedCrossRefGoogle Scholar
  31. Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V, Huffman JE, Igl W, Albrecht E, Deloukas P, Henderson J, Granell R, McArdle WL, Rudnicka AR, Barroso I, Loos RJ, Wareham NJ, Mustelin L, Rantanen T, Surakka I, Imboden M, Wichmann HE, Grkovic I, Jankovic S, Zgaga L, Hartikainen AL, Peltonen L, Gyllensten U, Johansson A, Zaboli G, Campbell H, Wild SH, Wilson JF, Glaser S, Homuth G, Volzke H, Mangino M, Soranzo N, Spector TD, Polasek O, Rudan I, Wright AF, Heliovaara M, Ripatti S, Pouta A, Naluai AT, Olin AC, Toren K, Cooper MN, James AL, Palmer LJ, Hingorani AD, Wannamethee SG, Whincup PH, Smith GD, Ebrahim S, McKeever TM, Pavord ID, MacLeod AK, Morris AD, Porteous DJ, Cooper C, Dennison E, Shaheen S, Karrasch S, Schnabel E, Schulz H, Grallert H, Bouatia-Naji N, Delplanque J, Froguel P, Blakey JD, Britton JR, Morris RW, Holloway JW, Lawlor DA, Hui J, Nyberg F, Jarvelin MR, Jackson C, Kahonen M, Kaprio J, Probst-Hensch NM, Koch B, Hayward C, Evans DM, Elliott P, Strachan DP, Hall IP, Tobin MD (2010) Genome-wide association study identifies five loci associated with lung function. Nat Genet 42:36–44. doi: 10.1038/ng.501 PubMedCrossRefGoogle Scholar
  32. Sampath V, Le M, Lane L, Patel AL, Cohen JD, Simpson PM, Garland JS, Hines RN (2011) The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants. J Surg Res 169:e51–e57. doi: 10.1016/j.jss.2011.03.017 PubMedCrossRefGoogle Scholar
  33. Song S, Chen D, Lu J, Liao J, Luo Y, Yang Z, Fu X, Fan X, Wei Y, Yang L, Wang L, Wang J (2011) NFkappaB1 and NFkappaBIA polymorphisms are associated with increased risk for sporadic colorectal cancer in a southern Chinese population. PLoS ONE 6:e21726. doi: 10.1371/journal.pone.0021726 PubMedCrossRefGoogle Scholar
  34. Tang X, Liu D, Shishodia S, Ozburn N, Behrens C, Lee JJ, Hong WK, Aggarwal BB, Wistuba II (2006) Nuclear factor-kappaB (NF-kappaB) is frequently expressed in lung cancer and preneoplastic lesions. Cancer 107:2637–2646. doi: 10.1002/cncr.22315 PubMedCrossRefGoogle Scholar
  35. Tanni SE, Pelegrino NR, Angeleli AY, Correa C, Godoy I (2010) Smoking status and tumor necrosis factor-alpha mediated systemic inflammation in COPD patients. J Inflamm (Lond) 7:29. doi: 10.1186/1476-9255-7-29 CrossRefGoogle Scholar
  36. Yang L, Li Y, Cheng M, Huang D, Zheng J, Liu B, Ling X, Li Q, Zhang X, Ji W, Zhou Y, Lu J (2012a) A functional polymorphism at microRNA-629-binding site in the 3′-untranslated region of NBS1 gene confers an increased risk of lung cancer in Southern and Eastern Chinese population. Carcinogenesis 33:338–347. doi: 10.1093/carcin/bgr272 PubMedCrossRefGoogle Scholar
  37. Yang L, Qiu F, Lu X, Huang D, Ma G, Guo Y, Hu M, Zhou Y, Pan M, Tan Y, Zhong H, Ji W, Wei Q, Ran P, Zhong N, Lu J (2012b) Functional polymorphisms of CHRNA3 predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese. PLoS ONE 7:e46071. doi: 10.1371/journal.pone.0046071 PubMedCrossRefGoogle Scholar
  38. Zhang H, Cai B (2003) The impact of tobacco on lung health in China. Respirology 8:17–21PubMedCrossRefGoogle Scholar
  39. Zhang P, Wei Q, Li X, Wang K, Zeng H, Bu H, Li H (2009) A functional insertion/deletion polymorphism in the promoter region of the NFKB1 gene increases susceptibility for prostate cancer. Cancer Genet Cytogenet 191:73–77. doi: 10.1016/j.cancergencyto.2009.01.017 PubMedCrossRefGoogle Scholar
  40. Zhong N, Wang C, Yao W, Chen P, Kang J, Huang S, Chen B, Ni D, Zhou Y, Liu S, Wang X, Wang D, Lu J, Zheng J, Ran P (2007) Prevalence of chronic obstructive pulmonary disease in China: a large, population-based survey. Am J Respir Crit Care Med 176:753–760. doi: 10.1164/rccm.200612-1749OC PubMedCrossRefGoogle Scholar
  41. Zhou Y, Hu G, Wang D, Wang S, Wang Y, Liu Z, Hu J, Shi Z, Peng G, Liu S, Lu J, Zheng J, Wang J, Zhong N, Ran P (2010) Community based integrated intervention for prevention and management of chronic obstructive pulmonary disease (COPD) in Guangdong, China: cluster randomised controlled trial. BMJ 341:c6387. doi: 10.1136/bmj.c6387 PubMedCrossRefGoogle Scholar
  42. Zou YF, Wang F, Feng XL, Tao JH, Zhu JM, Pan FM, Su H (2011) Association of NFKB1 -94ins/delATTG promoter polymorphism with susceptibility to autoimmune and inflammatory diseases: a meta-analysis. Tissue Antigens 77:9–17. doi: 10.1111/j.1399-0039.2010.01559.x PubMedCrossRefGoogle Scholar

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

Personalised recommendations