A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma
Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, w...
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
August-September 2023
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| In: |
Carcinogenesis
Year: 2023, Jahrgang: 44, Heft: 8/9, Pages: 642-649 |
| ISSN: | 1460-2180 |
| DOI: | 10.1093/carcin/bgad056 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/carcin/bgad056
|
| Verfasserangaben: | Matteo Giaccherini, Leonardo Gori, Manuel Gentiluomo, Riccardo Farinella, Klara Cervena, Jurgita Skieceviciene, Frederike Dijk, Gabriele Capurso, Antonis Vezakis, Livia Archibugi, Roger Chammas, Tamás Hussein, Francesca Tavano, Péter Hegyi, Martin Lovecek, Jakob R. Izbicki, Hermann Brenner, Beatrice Mohelnikova-Duchonova, Giuseppe Dell’Anna, Juozas Kupcinskas, Stefano Ermini, Mateus Nóbrega Aoki, John P. Neoptolemos, Maria Gazouli, Claudio Pasquali, Raffaele Pezzilli, Renata Talar-Wojnarowska, Martin Oliverius, Mohammed Al-Saeedi, Maurizio Lucchesi, Niccolò Furbetta, Silvia Carrara, Casper H J van Eijck, Almantas Maleckas, Anna Caterina Milanetto, Rita T. Lawlor, Ben Schöttker, Ugo Boggi, Luca Morelli, Laura Ginocchi, Ruggero Ponz de Leon Pisani, Cosimo Sperti, Alessandro Zerbi, Paolo Giorgio Arcidiacono, Faik G. Uzunoglu, Stefania Bunduc, Bernd Holleczek, Domenica Gioffreda, Ewa Małecka-Wojciesko, Mindaugas Kiudelis, Andrea Szentesi, Hanneke W.M. van Laarhoven, Pavel Soucek, Mara Götz, Bálint Erőss, Giulia Martina Cavestro, Daniela Basso, Francesco Perri, Stefano Landi, Federico Canzian and Daniele Campa |
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| 245 | 1 | 2 | |a A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma |c Matteo Giaccherini, Leonardo Gori, Manuel Gentiluomo, Riccardo Farinella, Klara Cervena, Jurgita Skieceviciene, Frederike Dijk, Gabriele Capurso, Antonis Vezakis, Livia Archibugi, Roger Chammas, Tamás Hussein, Francesca Tavano, Péter Hegyi, Martin Lovecek, Jakob R. Izbicki, Hermann Brenner, Beatrice Mohelnikova-Duchonova, Giuseppe Dell’Anna, Juozas Kupcinskas, Stefano Ermini, Mateus Nóbrega Aoki, John P. Neoptolemos, Maria Gazouli, Claudio Pasquali, Raffaele Pezzilli, Renata Talar-Wojnarowska, Martin Oliverius, Mohammed Al-Saeedi, Maurizio Lucchesi, Niccolò Furbetta, Silvia Carrara, Casper H J van Eijck, Almantas Maleckas, Anna Caterina Milanetto, Rita T. Lawlor, Ben Schöttker, Ugo Boggi, Luca Morelli, Laura Ginocchi, Ruggero Ponz de Leon Pisani, Cosimo Sperti, Alessandro Zerbi, Paolo Giorgio Arcidiacono, Faik G. Uzunoglu, Stefania Bunduc, Bernd Holleczek, Domenica Gioffreda, Ewa Małecka-Wojciesko, Mindaugas Kiudelis, Andrea Szentesi, Hanneke W.M. van Laarhoven, Pavel Soucek, Mara Götz, Bálint Erőss, Giulia Martina Cavestro, Daniela Basso, Francesco Perri, Stefano Landi, Federico Canzian and Daniele Campa |
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| 500 | |a Gesehen am 12.12.2023 | ||
| 520 | |a Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10−9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10−6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data. | ||
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