Polymorphisms of the Highly Expressed IL-6 Gene in the Papillary Thyroid Cancer Susceptibility Among Chinese

Author(s): Honghui Li*, Hao Dai*, Huajing Li, Baiya Li, Yuan Shao

Journal Name: Current Molecular Medicine

Volume 19 , Issue 6 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: Papillary thyroid cancer (PTC) is the cardinal histologic type of thyroid cancer, which is the most prevalent kind of endocrine malignancy. The expression of IL-6 is found higher in thyroid carcinoma (THCA) samples than paired normal tissues based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue expression (GTEx) database. In this study, we aimed to investigate the association between interleukin-6 (IL-6) polymorphisms and the PTC risk.

Methods: A case-control study was designed using the following data: 241 PTC patients and 463 healthy controls. Five single nucleotide polymorphisms (SNPs) in IL-6 were selected and genotyped using Agena MassARRAY technology.

Results: Our results revealed that SNP rs1800796 was associated with an increased PTC risk in co-dominant model (p = 0.042) and dominant model (p = 0.027). Rs1524107 was also a risk factor for PTC susceptibility in co-dominant model (p = 0.003), dominant model (p = 0.002) and log-additive model (p = 0.044). Moreover, rs2066992 significantly increased the PTC risk in co-dominant model and dominant model (p = 0.011, p = 0.009, respectively). Additionally, rs2069837 variant elevated the PTC risk based on dominant model (p = 0.041). In silico analysis, GTEx results for rs1800796, rs1524107 and rs2066992 variants are known to be associated with IL-6 gene expression. Using HaploReg, we found rs1800796, rs1524107 and rs2066992 in LD with functional importance.

Conclusion: Our study indicates that IL-6 variants may be a risk factor involved in the pathogenesis and development of PTC.

Keywords: Papillary thyroid cancer (PTC), interleukin-6 (IL-6), Single nucleotide polymorphism (SNP), functional annotation, MassARRAY technology, GTEx.

Lubitz CC, Sosa JA. The changing landscape of papillary thyroid cancer: Epidemiology, management, and the implications for patients. Cancer 2016; 122: 3754-9.
Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. JAMA 2017; 317: 1338-48.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
La Vecchia C, Malvezzi M, Bosetti C, et al. Thyroid cancer mortality and incidence: a global overview. Int J Cancer 2015; 136: 2187-95.
He W, Qi B, Zhou Q, et al. Key genes and pathways in thyroid cancer based on gene set enrichment analysis. Oncol Rep 2013; 30: 1391-7.
Gudmundsson J, Thorleifsson G, Sigurdsson JK, et al. A genome-wide association study yields five novel thyroid cancer risk loci. Nat Commun 2017; 8: 14517-24.
Son HY, Hwangbo Y, Yoo SK, et al. Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer. Nat Commun 2017; 8: 15966-77.
Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest 2015; 125: 3347-55.
Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol 2014; 15: e493-503.
Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6: a016295.
Tindall EA, Severi G, Hoang HN, et al. Interleukin-6 promoter variants, prostate cancer risk, and survival. Prostate 2012; 72: 1701-7.
Yu J, Jia Y, Cheung KF, et al. Polymorphisms in interleukin-6-6331 influences the susceptibility of a Chinese population to gastric cancer. Cancer Invest 2011; 29: 564-72.
Shi TY, Zhu ML, He J, et al. Polymorphisms of the Interleukin 6 gene contribute to cervical cancer susceptibility in Eastern Chinese women. Hum Genet 2013; 132: 301-12.
Sghaier I, Mouelhi L, Rabia NA, et al. Genetic variants in IL-6 and IL-10 genes and susceptibility to hepatocellular carcinoma in HCV infected patients. Cytokine 2017; 89: 62-7.
Zhao XM, Gao YF, Zhou Q, Pan FM, Li X. Relationship between interleukin-6 polymorphism and susceptibility to chronic hepatitis B virus infection. World J Gastroenterol 2013; 19: 6888-93.
Li Z, Zhang Z, He Z, et al. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn). Cell Res 2009; 19: 519-23.
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263-5.
Consortium. G. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science 2015; 348: 648-60.
Ward LD, Kellis M. HaploReg v4: Systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res 2016; 44: D877-81.
Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 1990; 63: 1149-57.
Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 2014; 26: 54-74.
Tawara K, Oxford JT, Jorcyk CL. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res 2011; 3: 177-89.
Holmer R, Goumas FA, Waetzig GH, Rose-John S, Kalthoff H. Interleukin-6: A villain in the drama of pancreatic cancer development and progression. Hepatobiliary Pancreat Dis Int 2014; 13: 371-80.
Ataie-Kachoie P, Pourgholami MH, Morris DL. Inhibition of the IL-6 signaling pathway: a strategy to combat chronic inflammatory diseases and cancer. Cytokine Growth Factor Rev 2013; 24: 163-73.
Ho LJ, Luo SF, Lai JH. Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers. Biochem Pharmacol 2015; 97: 16-26.
Provatopoulou X, Georgiadou D, Sergentanis TN, et al. Interleukins as markers of inflammation in malignant and benign thyroid disease. Inflamm Res 2014; 63: 667-74.
Ruggeri RM, Villari D, Simone A, et al. Co-expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) in thyroid nodules is associated with co-expression of CD30 ligand/CD30 receptor. J Endocrinol Invest 2002; 25: 959-66.
Kobawala TP, Trivedi TI, Gajjar KK, Patel DH, Patel GH, Ghosh NR. Significance of Interleukin-6 in Papillary Thyroid Carcinoma. J Thyroid Res 2016; 2016: 6178921.
Tang S, Yuan Y, He Y, et al. Genetic polymorphism of interleukin-6 influences susceptibility to HBV-related hepatocellular carcinoma in a male Chinese Han population. Hum Immunol 2014; 75: 297-301.
Huang WJ, Wu LJ, Min ZC, et al. Interleukin-6 -572G/C polymorphism and prostate cancer susceptibility. Genet Mol Res 2016; 15: 1-9.
Wang W, Chen J, Zhao F, Zhang B, Yu H. Lack of association between a functional polymorphism (rs1800796) in the interleukin-6 gene promoter and lung cancer. Diagn Pathol 2014; 9: 134.
Yin YW, Sun QQ, Hu AM, et al. Associations between interleukin-6 gene -174 C/G and -572 C/G polymorphisms and the risk of gastric cancer: a meta-analysis. J Surg Oncol 2012; 106: 987-93.
Ma Y, Tang RK, Yang X, et al. Lack of an association between interleukin-6 gene promoter polymorphisms
(-174G/C, -572G/C) and ischemic heart disease and/or ischemic stroke: A meta-analysis. Hum Immunol 2011; 72: 641-51.
Cenit MC, Simeon CP, Vonk MC, et al. Influence of the IL6 gene in susceptibility to systemic sclerosis. J Rheumatol 2012; 39: 2294-302.
Farhat SB, de Souza CM, Braosi AP, et al. Complete physical mapping of IL6 reveals a new marker associated with chronic periodontitis. J Periodontal Res 2017; 52: 255-61.
Inoue N, Watanabe M, Morita M, et al. Association of functional polymorphisms in promoter regions of IL5, IL6 and IL13 genes with development and prognosis of autoimmune thyroid diseases. Clin Exp Immunol 2011; 163: 318-23.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [443 - 451]
Pages: 9
DOI: 10.2174/1566524019666190426142432
Price: $65

Article Metrics

PDF: 37
PRC: 1