TY  - JOUR
AU  - Giaccherini, Matteo
AU  - Gori, Leonardo
AU  - Gentiluomo, Manuel
AU  - Farinella, Riccardo
AU  - Cervena, Klara
AU  - Skieceviciene, Jurgita
AU  - Dijk, Frederike
AU  - Capurso, Gabriele
AU  - Vezakis, Antonis
AU  - Archibugi, Livia
AU  - Chammas, Roger
AU  - Hussein, Tamás
AU  - Tavano, Francesca
AU  - Hegyi, Péter
AU  - Lovecek, Martin
AU  - Izbicki, Jakob
AU  - Brenner, Hermann
AU  - Mohelnikova-Duchonova, Beatrice
AU  - Dell'Anna, Giuseppe
AU  - Kupcinskas, Juozas
AU  - Ermini, Stefano
AU  - Aoki, Mateus Nóbrega
AU  - Neoptolemos, John P
AU  - Gazouli, Maria
AU  - Pasquali, Claudio
AU  - Pezzilli, Raffaele
AU  - Talar-Wojnarowska, Renata
AU  - Oliverius, Martin
AU  - Al-Saeedi, Mohammed
AU  - Lucchesi, Maurizio
AU  - Furbetta, Niccolò
AU  - Carrara, Silvia
AU  - van Eijck, Casper H J
AU  - Maleckas, Almantas
AU  - Milanetto, Anna Caterina
AU  - Lawlor, Rita T
AU  - Schöttker, Ben
AU  - Boggi, Ugo
AU  - Morelli, Luca
AU  - Ginocchi, Laura
AU  - Ponz de Leon, Ruggero
AU  - Sperti, Cosimo
AU  - Zerbi, Alessandro
AU  - Arcidiacono, Paolo Giorgio
AU  - Uzunoglu, Faik G
AU  - Bunduc, Stefania
AU  - Holleczek, Bernd
AU  - Gioffreda, Domenica
AU  - Małecka-Wojciesko, Ewa
AU  - Kiudelis, Mindaugas
AU  - Szentesi, Andrea
AU  - van Laarhoven, Hanneke W M
AU  - Soucek, Pavel
AU  - Götz, Mara
AU  - Erőss, Bálint
AU  - Cavestro, Giulia Martina
AU  - Basso, Daniela
AU  - Perri, Francesco
AU  - Landi, Stefano
AU  - Canzian, Federico
AU  - Campa, Daniele
TI  - 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.
JO  - Carcinogenesis
VL  - 44
IS  - 8-9
SN  - 0143-3334
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2023-01812
SP  - 642-649
PY  - 2023
N1  - 2023 Dec 2;44(8-9):642-649
AB  - 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=2.46x10 -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=1.53x10 -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 GWAS studies in light of functional data.
KW  - Pancreatic ductal adenocarcinoma (Other)
KW  - association study (Other)
KW  - genetic susceptibility (Other)
KW  - missense (Other)
KW  - single nucleotide polymorphisms (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37670727
DO  - DOI:10.1093/carcin/bgad056
UR  - https://inrepo02.dkfz.de/record/282532
ER  -