Abstract
MicroRNAs (miRNAs) regulate posttranscriptional gene expression usually by binding to 3'-untranslated regions (3'-UTRs) of target message RNAs (mRNAs). Hence genetic polymorphisms on 3'-UTRs of mRNAs may alter binding affinity between miRNAs target 3'-UTRs, thereby altering translational regulation of target mRNAs and/or degradation of mRNAs, leading to differential protein expression of target genes. Based on a database that catalogues predicted polymorphisms in miRNA target sites (poly-miRTSs), we selected 568 polymorphisms within 3'-UTRs of target mRNAs and performed association analyses between these selected poly-miRTSs and osteoporosis in 997 white subjects who were genotyped by Affymetrix Human Mapping 500K arrays. Initial discovery (in the 997 subjects) and replication (in 1728 white subjects) association analyses identified three poly-miRTSs (rs6854081, rs1048201, and rs7683093) in the fibroblast growth factor 2 (FGF2) gene that were significantly associated with femoral neck bone mineral density (BMD). These three poly-miRTSs serve as potential binding sites for 9 miRNAs (eg, miR-146a and miR-146b). Further gene expression analyses demonstrated that the FGF2 gene was differentially expressed between subjects with high versus low BMD in three independent sample sets. Our initial and replicate association studies and subsequent gene expression analyses support the conclusion that these three polymorphisms of the FGF2 gene may contribute to susceptibility to osteoporosis, most likely through their effects on altered binding affinity for specific miRNAs. © 2011 American Society for Bone and Mineral Research.
Highlights
Osteoporosis is a problem of excessive skeletal fragility leading to large numbers of low-trauma fractures among the elderly
The strongest association signal for femoral neck bone mineral density (BMD) was detected at poly-miRTS rs1712 in the F-box protein 5 (FBXO5) gene ( p 1⁄4 2.54E-03); this poly-miRTS is located at a predicted binding site for miR-549
This study reports the important role of polymorphisms in 3’UTRs of message RNAs (mRNAs) in determining variations in BMD
Summary
Osteoporosis is a problem of excessive skeletal fragility leading to large numbers of low-trauma fractures among the elderly. Genetic mutations that alter protein sequences and polymorphisms that regulate gene expression (ie, regulatory polymorphisms) are two naturally occurring genetic variations that are identified and characterized often when studying the genetics of complex diseases/traits.[4,5]. The initial discovery and replication (in an independent sample 1,728 white subjects) association studies (DNA level), along with subsequent gene expression analyses (RNA level), identified three singlenucleotide polymorphisms (SNPs) in the 3’-UTR of the fibroblast growth factor 2 (FGF2) gene as putative binding sites for miRNAs that may contribute to the risk of osteoporosis
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