Author:
Lu Ye,Corradi Chiara,Gentiluomo Manuel,López de Maturana Evangelina,Theodoropoulos George E.,Roth Susanne,Maiello Evaristo,Morelli Luca,Archibugi Livia,Izbicki Jakob R.,Sarlós Patricia,Kiudelis Vytautas,Oliverius Martin,Aoki Mateus Nóbrega,Vashist Yogesh,van Eijck Casper H. J.,Gazouli Maria,Talar-Wojnarowska Renata,Mambrini Andrea,Pezzilli Raffaele,Bueno-de-Mesquita Bas,Hegyi Péter,Souček Pavel,Neoptolemos John P.,Di Franco Gregorio,Sperti Cosimo,Kauffmann Emanuele F.,Hlaváč Viktor,Uzunoğlu Faik G.,Ermini Stefano,Małecka-Panas Ewa,Lucchesi Maurizio,Vanella Giuseppe,Dijk Frederike,Mohelníková-Duchoňová Beatrice,Bambi Franco,Petrone Maria Chiara,Jamroziak Krzysztof,Guo Feng,Kolarova Katerina,Capretti Giovanni,Milanetto Anna Caterina,Ginocchi Laura,Loveček Martin,Puzzono Marta,van Laarhoven Hanneke W. M.,Carrara Silvia,Ivanauskas Audrius,Papiris Konstantinos,Basso Daniela,Arcidiacono Paolo G.,Izbéki Ferenc,Chammas Roger,Vodicka Pavel,Hackert Thilo,Pasquali Claudio,Piredda Maria L.,Costello-Goldring Eithne,Cavestro Giulia Martina,Szentesi Andrea,Tavano Francesca,Włodarczyk Barbara,Brenner Hermann,Kreivenaite Edita,Gao Xin,Bunduc Stefania,Vermeulen Roel C. H.,Schneider Martin A.,Latiano Anna,Gioffreda Domenica,Testoni Sabrina G. G.,Kupcinskas Juozas,Lawlor Rita T.,Capurso Gabriele,Malats Núria,Campa Daniele,Canzian Federico
Abstract
Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case–Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07–1.17, p = 3.03 × 10−6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
Funder
Associazione Italiana per la Ricerca sul Cancro
Subject
Genetics (clinical),Genetics,Molecular Medicine