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

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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.

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References

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Chen Y (1999) Genetics and pulmonary medicine. 10: genetic epidemiology of pulmonary function. Thorax 54:818–824

    Article  PubMed  CAS  Google Scholar 

  • 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 45:7–17

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Dupont WD, Plummer WD (1990) Power and sample size calculations: a review and computer program. Control Clin Trials 11:116–128

    Article  PubMed  CAS  Google Scholar 

  • Escarcega RO (2010) The transcription factor NF-kappaB in human diseases. Rev Med Inst Mex Seguro Soc 48:55–60

    PubMed  Google Scholar 

  • 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 

  • 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 127:1072–1079

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. doi:10.1016/j.cell.2010.01.025

    Article  PubMed  CAS  Google Scholar 

  • Hayden MS, West AP, Ghosh S (2006) SnapShot: NF-kappaB signaling pathways. Cell 127:1286–1287. doi:10.1016/j.cell.2006.12.005

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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 28:683–692

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Petrescu F, Voican SC, Silosi I (2010) Tumor necrosis factor-alpha serum levels in healthy smokers and nonsmokers. Int J Chron Obstruct Pulmon Dis 5:217–222

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhang H, Cai B (2003) The impact of tobacco on lung health in China. Respirology 8:17–21

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

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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.

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The authors have declared no conflicts of interest.

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Authors and Affiliations

  1. School of Public Health, The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou, 510182, China

    Dongsheng Huang, Lei Yang, Yehua Liu, Weidong Ji & Jiachun Lu

  2. Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China

    Yumin Zhou, Wenju Lu, Jian Wang, Pixin Ran & Nanshan Zhong

  3. Department of Respiratory Medicine, Guangzhou Chest Hospital, Guangzhou, Guangdong, China

    Dongsheng Huang, Yunnan Wang & Yigang Tan

  4. The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

    Yuan Guo

  5. Department of Respiratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Mingan Pan

  6. Department of Respiratory Medicine, Guangzhou Red Cross Hospital, Guangzhou, Guangdong, China

    Haibo Zhong

  7. Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, 215123, China

    Min Hu & Yifeng Zhou

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  1. Dongsheng Huang
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  3. Yehua Liu
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Corresponding author

Correspondence to Jiachun Lu.

Additional information

D. Huang, L. Yang and Y. Liu contributed equally to this work.

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439_2013_1264_MOESM1_ESM.tif

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

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

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

Supplementary Figure S4. Association between the 2758G>A genotypes and IκBα expressions in situ by immunohistochemical stain (TIFF 986 kb)

Supplementary material 5 (DOC 248 kb)

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Huang, D., Yang, L., Liu, Y. et al. Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese. Hum Genet 132, 451–460 (2013). https://doi.org/10.1007/s00439-013-1264-9

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