Περίληψη:
Although 21 pancreatic cancer susceptibility loci have been identified
in individuals of European ancestry through genome-wide association
studies (GWASs), much of the heritability of pancreatic cancer risk
remains unidentified. A recessive genetic model could be a powerful tool
for identifying additional risk variants. To discover recessively
inherited pancreatic cancer risk loci, we performed a re-analysis of the
largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium
(PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4),
including 8,769 cases and 7,055 controls of European ancestry. Six
single nucleotide polymorphisms (SNPs) showed associations with
pancreatic cancer risk according to a recessive model of inheritance. We
replicated these variants in 3,212 cases and 3,470 controls collected
from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results
of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921
(8p23.2) and rs147904962 (17q21.31) showed specific recessive effects
(p<10(-5)) compared with the additive effects (p>10(-3)), although none
of the six SNPs reached the conventional threshold for genome-wide
significance (p < 5x10(-8)). Additional bioinformatic analysis explored
the functional annotations of the SNPs and indicated a possible
relationship between rs36018702 and expression of the BCL2L11 and BUB1
genes, which are known to be involved in pancreatic biology. Our
findings, while not conclusive, indicate the importance of considering
non-additive genetic models when performing GWAS analysis. The SNPs
associated with pancreatic cancer in this study could be used for
further meta-analysis for recessive association of SNPs and pancreatic
cancer risk and might be a useful addiction to improve the performance
of polygenic risk scores.
Συγγραφείς:
Lu, Ye
Gentiluomo, Manuel
Macauda, Angelica
Gioffreda,
Domenica
Gazouli, Maria
Petrone, Maria C.
Kelemen, Dezso and
Ginocchi, Laura
Morelli, Luca
Papiris, Konstantinos and
Greenhalf, William
Izbicki, Jakob R.
Kiudelis, Vytautas and
Mohelnikova-Duchonova, Beatrice
Bueno-de-Mesquita, Bas
Vodicka,
Pavel
Brenner, Hermann
Diener, Markus K.
Pezzilli, Raffaele
and Ivanauskas, Audrius
Salvia, Roberto
Szentesi, Andrea and
Aoki, Mateus Nobrega
Nemeth, Balazs C.
Sperti, Cosimo and
Jamroziak, Krzysztof
Chammas, Roger
Oliverius, Martin and
Archibugi, Livia
Ermini, Stefano
Novak, Janos
Kupcinskas,
Juozas
Strouhal, Ondrej
Soucek, Pavel
Cavestro, Giulia M.
and Milanetto, Anna C.
Vanella, Giuseppe
Neoptolemos, John P.
and Theodoropoulos, George E.
van Laarhoven, Hanneke W. M. and
Mambrini, Andrea
Moz, Stefania
Kala, Zdenek
Lovecek, Martin
and Basso, Daniela
Uzunoglu, Faik G.
Hackert, Thilo
Testoni,
Sabrina G. G.
Hlavac, Viktor
Andriulli, Angelo
Lucchesi,
Maurizio
Tavano, Francesca
Carrara, Silvia
Hegyi, Peter and
Arcidiacono, Paolo G.
Busch, Olivier R.
Lawlor, Rita T. and
Puzzono, Marta
Boggi, Ugo
Guo, Feng
Malecka-Panas, Ewa and
Capurso, Gabriele
Landi, Stefano
Talar-Wojnarowska, Renata and
Strobel, Oliver
Gao, Xin
Vashist, Yogesh
Campa, Daniele and
Canzian, Federico
