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Bone Abstracts (2016) 5 P234 | DOI: 10.1530/boneabs.5.P234

Genetics and Epigenetics

SNP regulation of miRNA expression and its association with osteoporosis

Laura De-Ugarte1, Enrique Caro-Molina1, Maria Rodríguez-Sanz1, M A García-Pérez2, J M Olmos3, Manuel Sosa-Henríquez4, Ramon Pérez-Cano14, Carlos Gómez-Alonso5, Luis Del Rio6, Jesus Mateo-Agudo7, Laura Navarro-Casado8, Jesus González-Macías3, Javier Del Pino-Montes9, Manuel Muñoz-Torres10, Manuel Diaz-Curiel11, Jorge Malouf12, J L Pérez-Catrillón13, Xavier Nogues1, Natalia Garcia-Giralt1 & Adolfo Diez-Perez1


1IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 2Department of Genetics, University of Valencia, Research Foundation, Institute of Health Research INCLIVA, Valencia, Spain; 3Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain; 4Universidad de Las Palmas de Gran Canaria, Hospital Universitario Insular, Las Palmas de Gran Canaria, Spain; 5Servicio de Metabolismo Óseo y Mineral, Hospital Universitario Central de Asturias, Oviedo, Spain; 6CETIR Centre Médic, Barcelona, Spain; 7Servicio de Cirugía Ortopédica y Traumatología, Hospital Universitario Miguel Servet, Zaragoza, Spain; 8Medicina Interna C Hospitalario Universitario de Albacete, Albacete, Spain; 9Servicio de Reumatología Hospital Universitario de Salamanca, Salamanca, Spain; 10UGC Endocrinología y Nutrición, Hospital Universitario San Cecilio, Complejo Hospitalario Universitario de Granada, Granada, Spain; 11Servicio de Medicina Interna/Enfermedades Metabólicas Óseas Fundacion Jimenez Diaz, Madrid, Spain; 12Mineral Metabolism Unit, Internal Medicine Department, Hospital de Sant Pau, Barcelona, Spain; 13Hospital Universitario Río Hortega, Valladolid, Spain; 14Medicina Interna Hospital, Universitario Virgen Macarena, Sevilla, Spain.

Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotype variability. The aim of this study was to identify osteoporosis-related SNPs by affecting the expression levels of mature microRNAs.

The first approach was to perform an association analysis of putative functional SNPs located in pri-miRNA sequences of bone-related microRNAs with the lumbar spine and femoral neck (FN) bone mineral density (BMD). In this regard, OSTEOMED2 cohort was created by recruiting postmenopausal women from several Spanish regions (n=2183).

Multivariate linear regression models were fitted to assess the association between genotyped SNPs and BMD. Potential confounders considered for adjustment were densitometer devices, body mass index and age.

Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with FN BMD. Allele A (minority allele) for the rs6430498 and allele A (majority allele) for the rs12512664 were found associated with lower BMD values.

Further, we measured these BMD-associated microRNAs in whole trabecular bone from osteoporotic FN fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone.

Finally, a correlation was observed among genotypes of rs6430498 and rs12512664 and the expression levels of the miR-3679 and miR-4274 in human osteoblastic cells, respectively. In both cases, the allele A was associated with higher microRNA expression levels.

In conclusion, two novel osteoblast-expressed microRNAs, miR-3679 and miR-4274, have been associated with BMD and its overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of regulation abnormalities in bone disorders as well as for identifying possible new treatment targets.