Laboratory Medicine Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.
Scand J Immunol. 2019 Dec;90(6):e12819. doi: 10.1111/sji.12819. Epub 2019 Oct 3.
Our aim was to evaluate the association of genetic polymorphisms of immunoregulatory molecules with susceptibility to hepatocellular carcinoma (HCC). The polymorphisms in CTLA-4 (-318 T/C, CT60 G/A), TNF (-238 G/A, -308 G/A) and IL10 (-592 C/A, -819 C/T) were genotyped by PCR and DNA sequencing. The functional relevance of the polymorphisms was examined by ELISAs, in vitro lymphocyte proliferation assay and cytotoxic assay. The CTLA-4 -318 TC/TT, CTLA-4 CT60 GG, IL10 -592 CA and -819 CT/TT variants, CTLA-4 -318 T and IL 10 -819 T alleles were positively associated with HCC risk (P < .05). While TNF -238 AA variant, TNF -238 A allele were associated with decreased risk of HCC (P < .05). Furthermore, combinations of CTLA-4 -318 TC/TT and TNF -238 GG/GA; CTLA-4 -318 TC/TT and IL 10 -819 CC; CTLA-4 -318 CC and IL 10 -819 CT/TT in patients with HCC were statistically significant (P < .05). Peripheral blood mononuclear cells (PBMCs) carrying -318 TC/TT genotypes exhibited significantly lower proliferation rates, decreased IL-2, IL-4 levels, fewer cytolytic activities and elevated TGF-β levels. For IL 10 -819 C/T, the CC genotype was significantly associated with higher proliferation rate, decreased TGF-β, IL-10 levels and higher cytolytic activities (P < .05). For TNF -238 G/A, the AA genotype only had association with serum IL-2, IL-4 (P < .05). In addition, we also found that CTLA-4 -318 T/C, IL-10 -819 T/C variants, combinations of CTLA-4 -318 CC with IL 10 -819 CT or TT, CTLA-4 -318 TC or TT with IL 10 -819 CT or TT were associated with the severity of HCC. These findings suggest that CTLA-4 -318 TC/TT and IL 10 -819 CT/TT could promote the pathogenesis of HCC, which might be related with down-regulation of Th1/Th2-type cytokines and/or up-regulation of Th3-type cytokines.
我们的目的是评估免疫调节分子的遗传多态性与肝细胞癌（HCC）易感性之间的关联。通过聚合酶链反应和 DNA 测序对 CTLA-4（-318 T/C、CT60 G/A）、TNF（-238 G/A、-308 G/A）和 IL10（-592 C/A、-819 C/T）的多态性进行了基因分型。通过 ELISA、体外淋巴细胞增殖试验和细胞毒性试验检测了多态性的功能相关性。CTLA-4-318TC/TT、CTLA-4 CT60 GG、IL10-592CA 和-819CT/TT 变体、CTLA-4-318T 和 IL10-819T 等位基因与 HCC 风险呈正相关（P<.05）。而 TNF-238AA 变体、TNF-238A 等位基因与 HCC 风险降低相关（P<.05）。此外，在 HCC 患者中，CTLA-4-318TC/TT 和 TNF-238GG/GA；CTLA-4-318TC/TT 和 IL10-819CC；CTLA-4-318CC 和 IL10-819CT/TT 的组合具有统计学意义（P<.05）。携带-318TC/TT 基因型的外周血单核细胞（PBMCs）表现出明显较低的增殖率、降低的 IL-2、IL-4 水平、较少的细胞毒性活性和升高的 TGF-β水平。对于 IL10-819C/T，CC 基因型与较高的增殖率、降低的 TGF-β、IL-10 水平和较高的细胞毒性活性显著相关（P<.05）。对于 TNF-238G/A，AA 基因型仅与血清 IL-2、IL-4 相关（P<.05）。此外，我们还发现 CTLA-4-318T/C、IL-10-819T/C 变体、CTLA-4-318CC 与 IL10-819CT 或 TT、CTLA-4-318TC 或 TT 与 IL10-819CT 或 TT 的组合与 HCC 的严重程度相关。这些发现表明 CTLA-4-318TC/TT 和 IL10-819CT/TT 可能促进 HCC 的发病机制，这可能与 Th1/Th2 型细胞因子的下调和/或 Th3 型细胞因子的上调有关。
