Frontiers in Genetics (Aug 2021)

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

  • Ye Lu,
  • Ye Lu,
  • Chiara Corradi,
  • Manuel Gentiluomo,
  • Evangelina López de Maturana,
  • George E. Theodoropoulos,
  • Susanne Roth,
  • Evaristo Maiello,
  • Luca Morelli,
  • Livia Archibugi,
  • Livia Archibugi,
  • 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,
  • 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,
  • Giuseppe Vanella,
  • Giuseppe Vanella,
  • Frederike Dijk,
  • Beatrice Mohelníková-Duchoňová,
  • Franco Bambi,
  • Maria Chiara Petrone,
  • Krzysztof Jamroziak,
  • Feng Guo,
  • Feng Guo,
  • Katerina Kolarova,
  • Giovanni Capretti,
  • 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,
  • Roger Chammas,
  • Pavel Vodicka,
  • Pavel Vodicka,
  • Pavel Vodicka,
  • Thilo Hackert,
  • Claudio Pasquali,
  • Maria L. Piredda,
  • Eithne Costello-Goldring,
  • Giulia Martina Cavestro,
  • Andrea Szentesi,
  • Andrea Szentesi,
  • Francesca Tavano,
  • Barbara Włodarczyk,
  • Hermann Brenner,
  • Hermann Brenner,
  • Hermann Brenner,
  • Edita Kreivenaite,
  • Xin Gao,
  • Xin Gao,
  • Stefania Bunduc,
  • Stefania Bunduc,
  • Roel C. H. Vermeulen,
  • Martin A. Schneider,
  • Anna Latiano,
  • Domenica Gioffreda,
  • Sabrina G. G. Testoni,
  • Juozas Kupcinskas,
  • Rita T. Lawlor,
  • Gabriele Capurso,
  • Gabriele Capurso,
  • Gabriele Capurso,
  • Núria Malats,
  • Daniele Campa,
  • Federico Canzian

DOI
https://doi.org/10.3389/fgene.2021.693933
Journal volume & issue
Vol. 12

Abstract

Read online

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.

Keywords