Tong Xiaoqian, Zhu Xiaoli, Wang Xila, Xu Yanlin, Huang Pei, Zhou Leiqing, Ji Yanxiang, Wu Lifang
Department of Obstetrics and Gynecology, 184 Hospital of Yingtan City, 4 Hudong Road, Yingtan, 335002, China.
Department of Obstetrics and Gynecology, Yingtan City People's Hospital, Yingtan, China.
Biochem Genet. 2025 Feb 13. doi: 10.1007/s10528-025-11044-z.
The NRF2/KEAP1 signaling pathway, crucial for cellular defense against oxidative stress, may influence epithelial ovarian cancer (EOC) risk. This study investigates the association between KEAP1 gene polymorphisms and EOC risk in Han Chinese individuals, while exploring correlations between these genetic variants and serum levels of KEAP1 and NRF2 proteins. We conducted a case-control study involving 1962 EOC patients and 2057 controls, genotyping ten tag single-nucleotide polymorphisms (SNPs) in KEAP1. Serum KEAP1 and NRF2 levels were measured using ELISA. Genetic association analyses and ANOVA were employed to assess relationships between SNPs, EOC risk, and serum protein levels. Notably, only SNP rs3177696 in KEAP1 showed a significant association with EOC risk. The G allele of rs3177696 conferred a protective effect against EOC (OR [95% CI] = 0.58 [0.47-0.72], P = 2.91 × 10). Furthermore, rs3177696 genotypes were significantly associated with serum levels of both KEAP1 and NRF2, as well as their ratio. EOC patients carrying GG, AG, and AA genotypes exhibited mean serum KEAP1 levels of 2.46, 2.16, and 2.04 (P = 2.43 × 10), respectively. Conversely, serum NRF2 levels decreased with increasing G allele copies (GG: 4.58, AG: 4.95, AA: 5.02; P = 0.0002). This study provides compelling evidence linking EOC risk to the oxidative stress-related gene KEAP1, with the G allele of rs3177696 demonstrating a protective effect. These findings suggest a potential role for the NRF2/KEAP1 pathway in EOC pathogenesis and highlight promising avenues for future research in EOC prevention and treatment strategies.
NRF2/KEAP1信号通路对细胞抵御氧化应激至关重要，可能影响上皮性卵巢癌（EOC）风险。本研究调查了汉族人群中KEAP1基因多态性与EOC风险之间的关联，同时探索这些基因变异与KEAP1和NRF2蛋白血清水平之间的相关性。我们进行了一项病例对照研究，纳入1962例EOC患者和2057例对照，对KEAP1中的10个标签单核苷酸多态性（SNP）进行基因分型。使用酶联免疫吸附测定法（ELISA）测量血清KEAP1和NRF2水平。采用遗传关联分析和方差分析来评估SNP、EOC风险和血清蛋白水平之间的关系。值得注意的是，KEAP1中只有SNP rs3177696与EOC风险存在显著关联。rs3177696的G等位基因对EOC具有保护作用（比值比[95%可信区间]=0.58[0.47 - 0.72]，P = 2.91×10）。此外，rs3177696基因型与KEAP1和NRF2的血清水平及其比值均显著相关。携带GG、AG和AA基因型的EOC患者血清KEAP1平均水平分别为2.46、2.16和2.04（P = 2.43×10）。相反，血清NRF2水平随着G等位基因拷贝数的增加而降低（GG：4.58，AG：4.95，AA：5.02；P = 0.0002）。本研究提供了令人信服的证据，将EOC风险与氧化应激相关基因KEAP1联系起来，rs3177696的G等位基因具有保护作用。这些发现表明NRF2/KEAP1通路在EOC发病机制中可能发挥作用，并为EOC预防和治疗策略的未来研究指明了有前景的方向。
