Emerging evidence has shown that aberrant alternative splicing (AS) events are involved in the carcinogenesis. The association between genetic variants in AS and bladder cancer susceptibility remains to be fully elucidated. We searched for single nucleotide polymorphisms (SNPs) which are located in splicing quantitative trait loci (sQTLs) in bladder cancer through CancerSplicingQTL database and the 1000 Genomes Project. A case‐control study including 580 cases and 1,101 controls was conducted to assess the association between the functional genetic variants and bladder cancer risk. Next, we used GTEx, TCGA, and GEO databases conducting sQTL analysis and gene expression differences analysis to evaluate the potential biological function of the candidate SNPs and related genes. We found that SNP rs4383 C>G was remarkably related with the reduced risk of bladder cancer (odds ratio = 0.68, 95% confidence interval = 0.59‐0.79, P  = 3.91 × 10⁻⁷). Similar results were obtained in codominant, dominant and recessive model. Stratified analyses revealed that the effect of SNP rs4383 C>G on bladder cancer was more significant in the older subjects (age > 65), female and nonsmokers. sQTL analysis showed that SNP rs4383 was associated with the AS events of its downstream gene MAFF with a splicing event of alternative 5′ splice site. The messenger RNA expression of MAFF in bladder tumor tissues was lowered compared with normal tissues. Patients with high expression of MAFF had higher survival rates. These findings indicated that SNP rs4383 related with the AS events of MAFF was associated with bladder cancer risk and could represent a possible biomarker for bladder cancer susceptibility.

中文翻译：

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剪接相关的遗传变异也可能导致膀胱癌。

新兴证据表明，异常的可变剪接（AS）事件与致癌作用有关。AS的遗传变异与膀胱癌易感性之间的关联仍有待充分阐明。我们通过CancerSplicingQTL数据库和1000基因组计划搜索了位于膀胱癌的剪接数量性状基因座（sQTL）中的单核苷酸多态性（SNP）。进行了一项包括580例病例和1,101例对照的病例对照研究，以评估功能性遗传变异与膀胱癌风险之间的关联。接下来，我们使用GTEx，TCGA和GEO数据库进行sQTL分析和基因表达差异分析，以评估候选SNP和相关基因的潜在生物学功能。我们发现SNP rs4383 C>P  ＝ 3.91×10 ^-7）。在显性，显性和隐性模型中也获得了相似的结果。分层分析显示，SNP rs4383 C> G对膀胱癌的影响在年龄较大的受试者（> 65岁），女性和非吸烟者中更为明显。sQTL分析显示，SNP rs4383与其下游基因MAFF的AS事件相关，其具有剪接5'剪接位点的剪接事件。与正常组织相比，MAFF在膀胱肿瘤组织中的信使RNA表达降低。MAFF高表达患者的生存率更高。这些发现表明SNP rs4383与MAFF的AS事件相关 与膀胱癌的风险有关，可能代表了膀胱癌易感性的生物标志。