目前的研究旨在调查 circRNA 和相关遗传变异与前列腺癌 (PCa) 风险的关联，并阐明这些关联背后的生物学机制。通过使用 MiOncoCirc 数据库，我们首先比较了 25 对 PCa 和邻近正常组织之间的 circRNA 表达水平，以确定与风险相关的 circRNA。然后，我们使用逻辑回归模型来评估 4662 名前列腺癌患者和 3114 名健康对照者中候选 circRNA 的遗传变异与 PCa 风险之间的关联，并将 circHIBADH rs11973492 确定为显着的风险相关变异（比值比 = 1.20，95% 置信区间： 1.08-1.34, P = 7.06 × 10 -4) 在显性遗传模型中，这改变了相应RNA链的二级结构。在计算机分析中，我们发现 circHIBADH 能够吸收并沉默富含 RNA 剪接途径的 21 个 RNA 结合蛋白 (RPB)，其中 HNRNPA1 被使用外部 RNA 测序数据以及内部（四个组织样本）和公开的单细胞转录组。此外，我们证明 HNRNPA1 可能影响 MYC、DNA 修复和 E2F 靶信号通路等标志，从而促进癌变。总之，circHIBADH 的遗传变异可能充当 RNA 剪接相关 RBP（包括 HNRNPA1）的海绵和抑制剂，在 PCa 中发挥致癌作用。

The current study aimed to investigate associations of circRNAs and related genetic variants with risk of prostate cancer (PCa) as well as to elucidate biological mechanisms underlying the associations. By using the MiOncoCirc database, we first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify risk-associated circRNAs. We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls, and identified circHIBADH rs11973492 as a significant risk-associated variant (odds ratio = 1.20, 95% confidence interval: 1.08-1.34, P = 7.06 × 10 -4) in a dominant genetic model, which altered the secondary structure of the corresponding RNA chain. In the in silico analysis, we found circHIBADH to sponge and silence 21 RNA-binding proteins (RPBs) enriched in the RNA splicing pathway, among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house (four tissue samples) and publicly available single-cell transcriptomes. Additionally, we demonstrated that HNRNPA1 might influence hallmarks including MYC, DNA repair, and E2F target signaling pathways, thereby promoting carcinogenesis. In conclusion, genetic variants in circHIBADH may act as a sponge and inhibitor of RNA splicing-associated RBPs including HNRNPA1, playing an oncogenic role in PCa.