Pharmacogenetic and microRNA mechanisms of beta blocker use on bone

Motivated by studies showing an association between beta blocker (BB) use and positive bone outcomes, a pilot randomized control trial (RCT) was performed at the Mayo Clinic which randomized postmenopausal women to placebo, propranolol (40 or 80 mg twice daily), atenolol (50 mg/day), or nebivolol (5 mg/day) to determine changes in bone turnover markers (BTMs) and in bone mineral density (BMD) over 20 weeks. Pharmacogenetic effects and microRNA-mediated mechanisms involving beta adrenergic receptor and related genes have previously been found. We sought to validate these effects and discover new candidates in an ancillary study to the pilot clinical trial. We genotyped all participants and performed microRNA (miRNA) sequencing at baseline and at 20 weeks for 24 participants from the atenolol or placebo groups. We discovered several variants in ADRB1, ADRB2, and HDAC4 which showed significant pharmacogenetic effects with BMD at multiple sites and with BTMs. Our miRNA results showed a significant treatment effect for miR-19a-3p over time with atenolol use in the low-responder group compared to placebo. Overall, the longitudinal miRNA analysis showed a large number of miRNAs which were up-regulated over the trial in the low responders but not the high responders compared to placebo, of which miR-19a-3p was one example. Finally, we compared the response to atenolol treatment for cardiovascular traits (pulse, blood pressure) with the response for the bone resorption marker, CTX, and found a largely independent effect. Our results have implications for personalized therapy and for understanding mechanisms of BB treatment effect on bone.