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.
14 May 2016 - 17 May 2016