Community health service office, Department of outpatients, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu 610072, Sichuan Province, China.
Department of Oncological Sciences, The University of Utah, Salt Lake City, UT, USA.
Int Immunopharmacol. 2019 Jan;66:154-161. doi: 10.1016/j.intimp.2018.11.015. Epub 2018 Nov 16.
Most cases of cervical cancer are the result of infection with specific high-risk types of human papillomavirus (HPV). Investigating the genetic basis of the host immune response, particularly cytokine function, could help further characterize the progression of cervical HPV infection into neoplasia. Prior studies have demonstrated a correlation between genetic variants of tumor necrosis factor alpha (TNF-α, TNF gene) and/or interleukin-10 (IL-10, IL10 gene) and cervical cancer susceptibility. However, some of the results have been contradictory. We sought to resolve these discrepancies by carrying out our study in a large cohort of Chinese women. In order to assess the association of TNF and IL10 genotypes with cervical cancer susceptibility, the polymorphisms in TNF (-238 G/A, -308 G/A) and IL10 (-592 C/A, -819 C/T, -1082 A/G) were genotyped and odds ratios for the genotype and allele frequencies between cervical cancer patients and healthy controls were calculated. Also, the functional relevance of these polymorphisms was evaluated using enzyme-linked immunosorbent assays (ELISAs) and in vitro lymphocyte proliferation assays. The TNF-238 AA genotype frequency was lower in patients than in controls (p < 0.05). TNF-308 AA, IL10-592 CA/AA, and IL10-819 CC/CT genotype frequencies were higher in cervical cancer patients than in controls (p < 0.05). The frequency of the TNF-238 A allele was significantly lower in patients, while the frequency of the -308 A allele was significantly higher (p < 0.05). No significant differences between patients and controls were found in the genotype or allele frequencies of IL10-1082 A/G (p > 0.05). Furthermore, the combinations of TNF-238 GA or GG and IL10-592 CC; TNF-238 GA or GG and IL10-592 CA or AA; TNF-308 AA and IL10-592 CC; and TNF-308 AA and IL10-592 CA or AA in cervical cancer patients were statistically significant (p < 0.0167). Upon stimulation with PHA, peripheral blood mononuclear cells (PBMCs) with the TNF-308AA genotype exhibited significantly higher proliferation rates, elevated IL-4, TGF-β levels, and lower IL-2 levels (p < 0.05). For IL10-592C/A, the AA and CA genotypes were significantly associated with higher proliferation rates, elevated IL-4 and IL-10 levels (p < 0.05). We also found that for TNF-308 G/A or IL10-592 C/A variants, the combination of TNF-308 GG or GA with IL10 CA or AA had an association with the severity of cervical cancer. Taken together, these results suggest that TNF-308 AA and IL10-592 CA/AA genotypes may increase susceptibility to cervical cancer by altering the immune response of an individual.
大多数宫颈癌病例是由特定的高危型人乳头瘤病毒（HPV）感染引起的。研究宿主免疫反应的遗传基础，特别是细胞因子功能，有助于进一步描述 HPV 感染向宫颈癌进展的过程。先前的研究表明，肿瘤坏死因子-α（TNF-α，TNF 基因）和/或白细胞介素-10（IL-10，IL10 基因）的遗传变异与宫颈癌易感性之间存在相关性。然而，一些结果存在矛盾。我们试图通过对大量中国女性进行研究来解决这些差异。为了评估 TNF 和 IL10 基因型与宫颈癌易感性的关系，我们对 TNF（-238 G/A、-308 G/A）和 IL10（-592 C/A、-819 C/T、-1082 A/G）的多态性进行了基因分型，并计算了宫颈癌患者与健康对照组之间基因型和等位基因频率的比值比。此外，还通过酶联免疫吸附试验（ELISA）和体外淋巴细胞增殖试验评估了这些多态性的功能相关性。与对照组相比，TNF-238 AA 基因型频率在患者中较低（p<0.05）。TNF-308 AA、IL10-592 CA/AA 和 IL10-819 CC/CT 基因型频率在宫颈癌患者中较高（p<0.05）。TNF-238 A 等位基因的频率在患者中显著降低，而 -308 A 等位基因的频率显著升高（p<0.05）。患者与对照组之间的 IL10-1082 A/G 基因型或等位基因频率无显著差异（p>0.05）。此外，TNF-238 GA 或 GG 和 IL10-592 CC；TNF-238 GA 或 GG 和 IL10-592 CA 或 AA；TNF-308 AA 和 IL10-592 CC；以及 TNF-308 AA 和 IL10-592 CA 或 AA 在宫颈癌患者中的组合具有统计学意义（p<0.0167）。在用 PHA 刺激后，具有 TNF-308AA 基因型的外周血单核细胞（PBMC）表现出更高的增殖率、升高的 IL-4、TGF-β水平和降低的 IL-2 水平（p<0.05）。对于 IL10-592C/A，AA 和 CA 基因型与更高的增殖率、升高的 IL-4 和 IL-10 水平显著相关（p<0.05）。我们还发现，对于 TNF-308 G/A 或 IL10-592 C/A 变体，TNF-308 GG 或 GA 与 IL10 CA 或 AA 的组合与宫颈癌的严重程度有关。综上所述，这些结果表明，TNF-308 AA 和 IL10-592 CA/AA 基因型可能通过改变个体的免疫反应而增加宫颈癌的易感性。
