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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, <jats:italic>p<\/jats:italic>\u2009=\u20095.5\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, <jats:italic>p<\/jats:italic>\u2009=\u20096.1\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, <jats:italic>p<\/jats:italic>\u2009=\u20096.4\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, <jats:italic>p<\/jats:italic>\u2009=\u20091.32\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the <jats:italic>coiled-coil domain containing 34<\/jats:italic> 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.<\/jats:p>","DOI":"10.1186\/s40246-024-00576-x","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T13:02:44Z","timestamp":1706878964000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk"],"prefix":"10.1186","volume":"18","author":[{"given":"Pelin","family":"\u00dcnal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bas","family":"Bueno-de-Mesquita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casper H. 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