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A two-SNP IL-6 promoter haplotype is associated with increased lung cancer risk

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Abstract

Background

Aberrant expression of interleukin-6 (IL-6) may play an important role in lung carcinogenesis. Whether IL-6 promoter haplotypes are associated with lung cancer risk and their functions have not yet been studied. We tested the hypothesis that single-nucleotide polymorphism (SNP) and/or haplotypes of IL-6 promoter are associated with risk of lung cancer.

Methods

Two functional IL-6 promoter SNPs (-6331T>C and -572C>G) were genotyped in the discovery group including 622 patients and 614 controls, and the results were replicated in an independent validation group including 615 patients and 638 controls. Luciferase reporter gene assays were conducted to examine the function of IL-6 promoter haplotypes.

Results

None of the functional IL-6 promoter SNPs were associated with lung cancer risk in either study. However, a two-SNP CC (-6331C and -572C) IL-6 promoter haplotype was significantly more common among cases than among controls in both groups (P = 0.031 and P = 0.035, respectively), indicating that this haplotype is associated with increased lung cancer risk {adjusted odds ratio [OR], 1.56 [95 % confidence interval (95 % CI), 1.04–2.34] and 1.51 [95 % CI, 1.03–2.22], respectively}. Combined analysis of both studies showed a strong association of this two-SNP haplotype with increased lung cancer risk (adjusted OR, 1.53; 95 % CI, 1.16–2.03; P = 0.003). Comparably, luciferase reporter assays of A549 lung cancer cell lines transfected with the CC haplotype revealed that the two-SNP haplotype had significantly higher IL-6 transcriptional activity compared with cells transfected with the common haplotype.

Conclusions

This is the first evidence of identifying an IL-6 promoter haplotype (CC) associated with increased risk of lung cancer.

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Acknowledgments

This work was supported in part by the grants from National Natural Science Foundation of China (81171894 and 30973425 to H.-T. Zhang), Program for New Century Excellent Talents in University (NCET-09-0165 to H.-T. Zhang), SRF for ROCS, State Education Ministry (2008890 to H.-T. Zhang), Shanghai Science and Technology Research Program (09JC1402200 to D. Lu), Jiangsu Province’s Key Provincial Talents Program (RC2011106 to J. Zhao), Jiangsu Province’s Outstanding Medical Academic Leader Program (LJ201138 to J. He), Qing-Lan Project of Education Bureau of Jiangsu Province (to H.-T. Zhang), “333” Project of Jiangsu Province Government (to H.-T. Zhang), Soochow Scholar Project of Soochow University (to H.-T. Zhang), and Suzhou Key Laboratory for Molecular Cancer Genetics (SZS201209 to H.-T. Zhang).

Conflict of interest

The authors declared no conflicts of interest.

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Authors and Affiliations

  1. Department of Surgery, The First Affiliated Hospital, Soochow University, 188 Shizi Street, Suzhou, 215006, People’s Republic of China

    Jun Chen, Jun Zhao, Jun He & Xiangdong Li

  2. Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, 199 Ren’ai Road, Sino-Singapore Industrial Park, Suzhou, 215123, People’s Republic of China

    Reng-Yun Liu, Zhe Lei, Yifeng Zhou & Hong-Tao Zhang

  3. Department of Cardiothoracic Surgery and Pneumology, Changhai Hospital of Shanghai, The Second Military Medical University, Shanghai, People’s Republic of China

    Lixin Yang

  4. State Key Laboratory of Genetic Engineering and Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China

    Xueying Zhao & Daru Lu

  5. Section on Statistical Genetics, Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    Nengjun Yi & Kui Zhang

  6. Department of Respiratory Disease, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China

    Baohui Han

  7. Department of Surgery, Shanghai Pulmonary Hospital, Shanghai, People’s Republic of China

    Xiao-Feng Chen

  8. Division of Hematology/Oncology, Department of Medicine and Comprehensive Cancer Center, University of Alabama at Birmingham, 1802 6th Ave South, NP 2566, Birmingham, AL, 35294-3300, USA

    Boris Pasche

  9. Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, People’s Republic of China

    Hong-Tao Zhang

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  1. Jun Chen
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Corresponding authors

Correspondence to Boris Pasche, Xiangdong Li or Hong-Tao Zhang.

Additional information

Jun Chen, Reng-Yun Liu, Lixin Yang and Jun Zhao contributed equally to this work.

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Chen, J., Liu, RY., Yang, L. et al. A two-SNP IL-6 promoter haplotype is associated with increased lung cancer risk. J Cancer Res Clin Oncol 139, 231–242 (2013). https://doi.org/10.1007/s00432-012-1314-z

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  • DOI: https://doi.org/10.1007/s00432-012-1314-z

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