학술논문
Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk
Document Type
article
Author
Ye Lu; Chiara Corradi; Manuel Gentiluomo; Evangelina López de Maturana; George E. Theodoropoulos; Susanne Roth; Evaristo Maiello; Luca Morelli; Livia Archibugi; Jakob R. Izbicki; Patricia Sarlós; Vytautas Kiudelis; Martin Oliverius; Mateus Nóbrega Aoki; Yogesh Vashist; Casper H. J. van Eijck; Maria Gazouli; Renata Talar-Wojnarowska; Andrea Mambrini; Raffaele Pezzilli; Bas Bueno-de-Mesquita; Péter Hegyi; Pavel Souček; John P. Neoptolemos; Gregorio Di Franco; Cosimo Sperti; Emanuele F. Kauffmann; Viktor Hlaváč; Faik G. Uzunoğlu; Stefano Ermini; Ewa Małecka-Panas; Maurizio Lucchesi; Giuseppe Vanella; Frederike Dijk; Beatrice Mohelníková-Duchoňová; Franco Bambi; Maria Chiara Petrone; Krzysztof Jamroziak; Feng Guo; Katerina Kolarova; Giovanni Capretti; Anna Caterina Milanetto; Laura Ginocchi; Martin Loveček; Marta Puzzono; Hanneke W. M. van Laarhoven; Silvia Carrara; Audrius Ivanauskas; Konstantinos Papiris; Daniela Basso; Paolo G. Arcidiacono; Ferenc Izbéki; Roger Chammas; Pavel Vodicka; Thilo Hackert; Claudio Pasquali; Maria L. Piredda; Eithne Costello-Goldring; Giulia Martina Cavestro; Andrea Szentesi; Francesca Tavano; Barbara Włodarczyk; Hermann Brenner; Edita Kreivenaite; Xin Gao; Stefania Bunduc; Roel C. H. Vermeulen; Martin A. Schneider; Anna Latiano; Domenica Gioffreda; Sabrina G. G. Testoni; Juozas Kupcinskas; Rita T. Lawlor; Gabriele Capurso; Núria Malats; Daniele Campa; Federico Canzian
Source
Frontiers in Genetics, Vol 12 (2021)
Subject
Language
English
ISSN
1664-8021
92537464
92537464
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.