Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10−8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10−7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10−6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10−5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

中文翻译：

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转录因子结合位点和增强子区域的多态性与胰腺导管腺癌风险

全基因组关联研究 (GWAS) 是检测与复杂特征相关的变异的强大工具，可以帮助制定胰腺导管腺癌 (PDAC) 的风险分层和预防策略。然而，常用的严格显着性阈值可能会遗漏许多真正的风险位点。 GWAS 多态性的功能注释是一种经过验证的识别其他风险位点的策略。我们的目的是研究调控区域 [转录因子结合位点 (TFBS) 和增强子] 中的单核苷酸多态性 (SNP)，这些多态性可能会改变其作用的多个基因的表达谱，从而改变 PDAC 风险。我们分析了来自 PanScan/PanC4 和东亚 GWAS（发现群体）以及 PANDoRA 联盟（复制群体）的总共 12,636 个 PDAC 病例和 43,443 个对照。我们确定了在总体荟萃分析中达到研究范围统计显着性的四个关联：rs2472632(A)（增强子变体，OR 1.10，95%CI 1.06,1.13，p = 5.5 × 10−8），rs17358295（G）（增强子变体，OR 1.16，95%CI 1.10,1.22，p = 6.1 × 10−7)，rs2232079(T)（TFBS变体，OR 0.88，95%CI 0.83,0.93，p = 6.4 × 10−6）和rs10025845 (A)（TFBS 变体，OR 1.88，95%CI 1.50,1.12，p = 1.32 × 10−5）。关联最显着的 SNP rs2472632 位于一个增强子中，预计该增强子会靶向含有 34 个癌基因的卷曲螺旋结构域。我们的结果通过对调控区域的多态性进行集中分析，并证明功能优先顺序对识别与 PDAC 风险相关的位点的有用性，为 PDAC 遗传风险因素提供了新的见解。