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 TITLE=Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk JOURNAL=Frontiers in Genetics VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.693933 DOI=10.3389/fgene.2021.693933 ISSN=1664-8021 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.