Maine Medical Center, Medical Education, Maine Medical Center Research Institute
Humans, Pharmacogenetics, MicroRNAs, Bone Density, Pharmacogenomic Testing, Adrenergic beta-Antagonists, Osteosclerosis
Osteoporosis is a debilitating and costly disease. Recent studies have shown that beta blocker (BB) users have higher bone mineral density (BMD) and decreased risk of fracture as compared to non-users. This association is thought to be due to suppression of adrenergic signaling in osteoblasts, which leads to increased BMD in rodent models; however the mechanism in humans is unknown. We used the Framingham Heart Study/Osteoporosis Substudy to investigate pharmacogenetic effects from variants in the ?1AR and ?2AR genes and to discover potential microRNA (miRNA) mechanisms of the effect of BB use on BMD. Framingham Offspring cohort participants had clinical data, dual-energy X-ray absorptiometry (DXA) scans, miRNA and mRNA profiling of whole blood, and high density genotype data imputed to the Haplotype Reference Consortium (HRC). We found nine miRNAs associated with BB use and increased BMD as well as a miRNA network associated with BMD and BB use containing two of these nine miRNAs, miR-19a-3p and miR-186-5p, the first of which has been previously shown to directly target the ?1AR mRNA transcript. To validate these miRNA associations, we show that these two miRNAs have significantly higher expression in individuals without incident fracture compared to those with incident fracture in an external data set. We have found rs1801252, a serine->glycine missense variant at positon 49 in ADRB1 to show a significant interaction with BB use on Femoral Neck BMD in women (p=0.048). Several variants in ADRB2 have also shown significant interaction effects with BB use in women and men. These pharmacogenetic and miRNA associations for BB use on BMD provide a starting point for understanding molecular mechanisms involved and for clinical biomarker discovery.
Nevola, Kathleen T.; Kiel, Douglas P.; Zullo, Andrew R.; Foessl, Ines; Obermayer-Pietsch, Barbara; Motyl, Katherine; and Lary, Christine W., "Pharmacogenetic and MicroRNA Effects of Beta Blocker Association with Increased Bone Mineral Density in Humans" (2020). Costas T. Lambrew Research Retreat 2020. 92.