Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

中文翻译：

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胰腺表达数量性状与胰腺导管腺癌风险之间的关联。

胰腺导管腺癌 (PDAC) 是最致命的癌症之一。其不良预后主要是由于大多数患者在疾病达到晚期之前保持无症状，同时缺乏早期标志物和筛查策略。更好地了解 PDAC 风险因素对于识别人群中的高危人群至关重要。全基因组关联研究 (GWAS) 已成为检测与复杂特征（包括胰腺癌）相关的遗传变异的有力工具。通过利用功能和 GWAS 数据，我们研究了影响胰腺基因功能的多态性（表达数量性状位点，eQTL）与 PDAC 风险之间的关联。在两阶段的方法中，我们分析了 13 713 个 PDAC 病例和 43 784 个对照，并确定了 rs2035875 多态性的 A 等位基因与 PDAC 风险增加之间的全基因组显着关联（P = 7.14 × 10-10）。已知该等位基因与角蛋白基因 KRT8 和 KRT18 在胰腺中的表达增加有关，据报道，KRT8 和 KRT18 的水平增加与各种肿瘤细胞特征相关。此外，rs789744 变体的 A 等位基因与患 PDAC 的风险降低相关（P = 3.56 × 10-6）。这种单核苷酸多态性位于 SRGAP1 基因中，A 等位基因与该基因的更高表达相关，这反过来又使细胞周期蛋白依赖性蛋白 42 (CDC42) 基因表达失活，从而降低了 PDAC 的风险。综上所述，