title: SNPs in bone-related miRNAs are associated with the osteoporotic phenotype.
abstract: Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.
authors.affiliation: IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII), Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: De-Ugarte
authors.affiliation: IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII), Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Caro-Molina
authors.affiliation: IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII), Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodríguez-Sanz
authors.affiliation: Department of Genetics and Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: García-Pérez
authors.affiliation: Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL/Hospital de Torrelavega, Universidad de Cantabria. RETICEF, Santander, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Olmos
authors.affiliation: Unidad Metabólica Ósea, Hospital Universitario Insular, Universidad de Las Palmas de Gran Canaria, Canarias, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sosa-Henríquez
authors.affiliation: Departamento de Medicina (USE), UGC Medicina Interna, Hospital Universitario Virgen Macarena, Seville, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Pérez-Cano
authors.affiliation: Servicio de Metabolismo Óseo y Mineral, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gómez-Alonso
authors.affiliation: CETIR Grup Mèdic, RETICEF, Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Del Rio
authors.affiliation: Servicio COT, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Mateo-Agudo
authors.affiliation: Servicio de Medicina Interna, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Blázquez-Cabrera
authors.affiliation: Departamento de Medicina Interna, H. Marqués de Valdecilla, Universidad de Cantabria, IDIVAL, RETICEF, Santander, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: González-Macías
authors.affiliation: Servicio de Reumatología. Hospital Universitario de Salamanca, RETICEF (ISCIII), IBSAL (Biomedical Research Institute of Salamanca), Salamanca, Spain.
authors.forename: Javier Del
authors.initials: JD
authors.lastname: Pino-Montes
authors.affiliation: UGC Endocrinologia y Nutrición. Hospital Universitario San Cecilio. Granada, RETICEF, Ibs, Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Muñoz-Torres
authors.affiliation: Unidad de Enfermedades Metabólicas Óseas. Servicio de Medicina Interna. Fundacion Jimenez Diaz, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Diaz-Curiel
authors.affiliation: Hospital de la Santa Creu I Sant Pau. Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Malouf
authors.affiliation: Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, INCLIVA, Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cano
authors.affiliation: Hospital Universitario Río Hortega, Valladolid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Pérez-Castrillon
authors.affiliation: IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII), Barcelona, Spain.
authors.forename: Xavier
authors.identifier: http://orcid.org/0000-0002-5537-1859
authors.initials: X
authors.lastname: Nogues
authors.affiliation: IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII), Barcelona, Spain. ngarcia@imim.es.
authors.forename: Natalia
authors.initials: N
authors.lastname: Garcia-Giralt
authors.affiliation: IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII), Barcelona, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Diez-Perez
mesh_terms: D000368:Aged; D000483:Alleles; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D002113:Calcification, Physiologic; D002478:Cells, Cultured; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D009690:Nucleic Acid Conformation; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D059467:Transcriptome
chemical_list: D035683:MicroRNAs