title: Identification of miRSNPs associated with the risk of multiple myeloma.
abstract: Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.|Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Angelica
authors.initials: A
authors.lastname: Macauda
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.|Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Diego
authors.initials: D
authors.lastname: Calvetti
authors.affiliation: The Pirbright Institute, Pirbright, Woking, Surrey, GU24 0NF, United Kingdom.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maccari
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.affiliation: Institute of Regional Health Research, and Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.|Research Unit of Molecular Diagnostics and Clinical Research, Laboratory Center, Hospital of Southern Jutland, Aabenraa, Denmark.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Andersen
authors.affiliation: National Research Centre for the Working Environment, Copenhagen, DK-2100, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: UO Hematology, Department of Internal and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Buda
authors.affiliation: Department of Hematology, Semmelweis University, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Varkonyi
authors.affiliation: Department of Hematology, Catalan Institute of Oncology (ICO) and IDIBELL, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Sureda
authors.affiliation: Department of Hematology, Hospital Universitario 12 de Octubre, Complutense School of Medicine, CNIO, Madrid, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Martinez Lopez
authors.affiliation: Holycross Medical Center, Kielce, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Watek
authors.affiliation: Medical University, Wrocław, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Butrym
authors.affiliation: Department of Hematology, University Hospital of Salamanca, Salamanca, Spain.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Sarasquete
authors.affiliation: Department of Hematology, Specialist District Hospital, Rzeszow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Dudziński
authors.affiliation: Department of Hematology, Cracow University Hospital, Cracow, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Jurczyszyn
authors.affiliation: Department of Lymphoid Malignancies Maria Sklodowska-Curie Memorial Institute and Oncology Centre Warsaw, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Druzd-Sitek
authors.affiliation: Department of Hematology, University Hospital, Bydgoszcz, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kruszewski
authors.affiliation: Department of Hematology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: Edyta
authors.initials: E
authors.lastname: Subocz
authors.affiliation: UO Hematology, Department of Internal and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Petrini
authors.affiliation: Department of Hematology, Medical University of Lodz, Łódź, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Iskierka-Jażdżewska
authors.affiliation: Department of Hematology, Rydygier Hospital, Cracow, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Raźny
authors.affiliation: Department of Hematology, Semmelweis University, Budapest, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szombath
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal.
authors.forename: Herlander
authors.initials: H
authors.lastname: Marques
authors.affiliation: Department of Hematology, Cracow University Hospital, Cracow, Poland.
authors.forename: Daria
authors.initials: D
authors.lastname: Zawirska
authors.affiliation: Department of Hematology, Copernicus Hospital, Torun, Poland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Chraniuk
authors.affiliation: Department of Hematology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Halka
authors.affiliation: Clinic of Immunology, Laboratory Center, Hospital of Southern Jutland, Sønderborg, Denmark.
authors.forename: Svend Erik
authors.initials: SE
authors.lastname: Hove Jacobsen
authors.affiliation: Department of Internal Diseases, Hypertension and Occupational Medicine, Medical University, Wroclaw, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Mazur
authors.affiliation: Department of Hematology, University Hospital of Salamanca, Salamanca, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: García Sanz
authors.affiliation: INSERM UMR 1052/CNRS 5286, Université Claude Bernard Lyon I, Lyon, 69622, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.affiliation: Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), IDIBELL, CIBERESP and Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Laboratory of Clinical and Transplant Immunology and Genetics, Copernicus Memorial Hospital, Łódź, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Stępień
authors.affiliation: Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Katia
authors.initials: K
authors.lastname: Beider
authors.affiliation: Azienda USL Toscana Nord Ovest, U.O Dipartimento di Ematologia, Livorno, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pelosini
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal.|Barretos Cancer Hospital, Molecular Oncology Research Center, Barretos, Brazil.
authors.forename: Rui
authors.initials: R
authors.lastname: Manuel Reis
authors.affiliation: Department of Hematology and Bone marrow Transplantation, Silesian Medical University, Katowice, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Krawczyk-Kulis
authors.affiliation: Department of Hematology, Copernicus Hospital, Torun, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Rymko
authors.affiliation: Laboratoire d'hématologie, Pôle biologie, Institut Universitaire du Cancer de Toulouse-Oncopole 1, Avenue Irène Joliot-Curie, Toulouse 31059, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Avet-Loiseau
authors.affiliation: Institut Curie, 26 rue d'Ulm, Paris, F-75005, France.|PSL Research University, Paris, F-75005, France.|Inserm, U900, Paris, F-75005, France.|Mines Paris Tech, Fontainebleau, Paris, F-77305, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
authors.affiliation: Department of Hematology, St. John's Cancer Center, Lublin, Poland.
authors.forename: Norbert
authors.initials: N
authors.lastname: Grząśko
authors.affiliation: Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Ostrovsky
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jamroziak
authors.affiliation: Department of Haematology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark.
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Vangsted
authors.affiliation: Department of Hematology and Medical Oncology, IMIB, University Hospital Morales Meseguer, Murcia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Jerez
authors.affiliation: Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Tomczak
authors.affiliation: Department of Hematology, Sea Hospital, Gdynia, Poland.
authors.forename: Jan Maciej
authors.initials: JM
authors.lastname: Zaucha
authors.affiliation: Department of Hematology, Semmelweis University, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Kadar
authors.affiliation: Centro Pfizer, Universidad de Granada, Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), Granada, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Sainz
authors.affiliation: Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics*; D009194:Myeloma Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012306:Risk
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D009194:Myeloma Proteins; D012333:RNA, Messenger; C085016:multiple myeloma M-proteins
keywords: Genetic susceptibility; Multiple myeloma; SNP; miRNA