CD46 (also known as membrane cofactor protein), which is a member of the membrane‐bound complement regulatory protein family, has been reported to cause cancer cells to escape complement‐dependent cytotoxicity. However, the association between CD46 polymorphisms and the risk of hepatocellular carcinoma (HCC) has not been investigated. This two‐stage association study was conducted to assess the relationship between the tagging single nucleotide polymorphisms (tagSNPs) of CD46 and HCC risk and prognosis. A series of functional analyses were performed to study the underlying mechanisms. Among the eight tagSNPs, rs2796267 (P = .003) and rs2796268 (P = .011) were found to modify HCC risk in the discovery set. Only rs2796267 (P < .0001) was confirmed to be associated with HCC susceptibility in the validation set. Compared with the wild‐type AA genotype, the GG genotype significantly increased the HCC risk (adjusted odds ratio [OR] = 2.03; 95% confidence interval [CI], 1.34‐3.08; P = .001). Moreover, subgroups analysis suggested a positive correlation among male and younger patients, especially among drinkers, smokers, and hepatitis B surface antigen‐positive individuals. In functional analyses, we found that the rs2796267 G allele in the promoter region of CD46 could increase the expression of CD46 by affecting the binding affinity of STAT5a. Furthermore, Cox regression analysis revealed that the rs2796267 AG/GG genotype was significantly associated with worse prognosis of resected patients with HCC (hazard ratio = 2.27; 95% CI, 1.27‐4.05; P = .006). These results suggest that the CD46 rs2796267 polymorphism may contribute to susceptibility and prognosis of HCC by altering promoter activity.

中文翻译：

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CD46启动子中的遗传变异与肝细胞癌的风险和预后有关。

据报道，CD46（也称为膜辅因子蛋白）是膜结合补体调节蛋白家族的成员，可导致癌细胞逃脱依赖补体的细胞毒性。但是，尚未研究CD46多态性与肝细胞癌（HCC）风险之间的关联。这项为期两阶段的关联研究旨在评估CD46的标记单核苷酸多态性（tagSNPs）与HCC风险和预后之间的关系。进行了一系列功能分析以研究潜在的机制。在八个tagSNP中，发现rs2796267（P  = .003）和rs2796268（P  = .011）会改变发现集中的HCC风险。只有rs2796267（ 在验证集中确认P <.0001）与HCC敏感性有关。与野生型AA基因型相比，GG基因型显着增加了HCC风险（校正比值比[OR] = 2.03； 95％置信区间[CI]，1.34-3.08；P  = .001）。此外，亚组分析表明，男性和年轻患者之间存在正相关，尤其是饮酒者，吸烟者和乙肝表面抗原阳性个体之间。在功能分析，我们发现，rs2796267 G等位基因在启动子区CD46可能增加的表达CD46通过影响STAT5a的结合亲和力。此外，Cox回归分析显示，rs2796267 AG / GG基因型与切除的HCC患者的预后差显着相关（危险比= 2.27； 95％CI为1.27-4.05；P  = .006 ）。这些结果表明，CD46 rs2796267多态性可能通过改变启动子活性来促进肝癌的易感性和预后。