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Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

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 m...

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Main Authors: Ünal, Pelin (Author) , Lu, Ye (Author) , Bueno-de-Mesquita, Bas (Author) , van Eijck, Casper H. J. (Author) , Talar-Wojnarowska, Renata (Author) , Szentesi, Andrea (Author) , Gazouli, Maria (Author) , Kreivenaite, Edita (Author) , Tavano, Francesca (Author) , Małecka-Wojciesko, Ewa (Author) , Erőss, Bálint (Author) , Oliverius, Martin (Author) , Bunduc, Stefania (Author) , Nóbrega Aoki, Mateus (Author) , Vodickova, Ludmila (Author) , Boggi, Ugo (Author) , Giaccherini, Matteo (Author) , Kondrackiene, Jurate (Author) , Chammas, Roger (Author) , Palmieri, Orazio (Author) , Theodoropoulos, George E. (Author) , Bijlsma, Maarten F. (Author) , Basso, Daniela (Author) , Mohelnikova-Duchonova, Beatrice (Author) , Soucek, Pavel (Author) , Izbicki, Jakob R. (Author) , Kiudelis, Vytautas (Author) , Vanella, Giuseppe (Author) , Arcidiacono, Paolo Giorgio (Author) , Włodarczyk, Barbara (Author) , Hackert, Thilo (Author) , Schöttker, Ben (Author) , Uzunoglu, Faik G. (Author) , Bambi, Franco (Author) , Goetz, Mara (Author) , Hlavac, Viktor (Author) , Brenner, Hermann (Author) , Perri, Francesco (Author) , Carrara, Silvia (Author) , Landi, Stefano (Author) , Hegyi, Péter (Author) , Dijk, Frederike (Author) , Maiello, Evaristo (Author) , Capretti, Giovanni (Author) , Testoni, Sabrina Gloria Giulia (Author) , Petrone, Maria Chiara (Author) , Stocker, Hannah (Author) , Ermini, Stefano (Author) , Archibugi, Livia (Author) , Gentiluomo, Manuel (Author) , Cavestro, Giulia Martina (Author) , Pezzilli, Raffaele (Author) , Di Franco, Gregorio (Author) , Milanetto, Anna Caterina (Author) , Sperti, Cosimo (Author) , Neoptolemos, John P. (Author) , Morelli, Luca (Author) , Vokacova, Klara (Author) , Pasquali, Claudio (Author) , Lawlor, Rita T. (Author) , Bazzocchi, Francesca (Author) , Kupcinskas, Juozas (Author) , Capurso, Gabriele (Author) , Campa, Daniele (Author) , Canzian, Federico (Author)
Format: Article (Journal)
Language:English
Published: 02 February 2024
In: Human genomics
Year: 2024, Volume: 18, Pages: 1-12
ISSN:1479-7364
DOI:10.1186/s40246-024-00576-x
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1186/s40246-024-00576-x
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Author Notes:Pelin Ünal, Ye Lu, Bas Bueno-de-Mesquita, Casper H.J. van Eijck, Renata Talar-Wojnarowska, Andrea Szentesi, Maria Gazouli, Edita Kreivenaite, Francesca Tavano, Ewa Małecka-Wojciesko, Bálint Erőss, Martin Oliverius, Stefania Bunduc, Mateus Nóbrega Aoki, Ludmila Vodickova, Ugo Boggi, Matteo Giaccherini, Jurate Kondrackiene, Roger Chammas, Orazio Palmieri, George E. Theodoropoulos, Maarten F. Bijlsma, Daniela Basso, Beatrice Mohelnikova-Duchonova, Pavel Soucek, Jakob R. Izbicki, Vytautas Kiudelis, Giuseppe Vanella, Paolo Giorgio Arcidiacono, Barbara Włodarczyk, Thilo Hackert, Ben Schöttker, Faik G. Uzunoglu, Franco Bambi, Mara Goetz, Viktor Hlavac, Hermann Brenner, Francesco Perri, Silvia Carrara, Stefano Landi, Péter Hegyi, Frederike Dijk, Evaristo Maiello, Giovanni Capretti, Sabrina Gloria Giulia Testoni, Maria Chiara Petrone, Hannah Stocker, Stefano Ermini, Livia Archibugi, Manuel Gentiluomo, Giulia Martina Cavestro, Raffaele Pezzilli, Gregorio Di Franco, Anna Caterina Milanetto, Cosimo Sperti, John P. Neoptolemos, Luca Morelli, Klara Vokacova, Claudio Pasquali, Rita T. Lawlor, Francesca Bazzocchi, Juozas Kupcinskas, Gabriele Capurso, Daniele Campa and Federico Canzian

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520 |a 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. 
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