Abstract
Background: Clinical trials have shown zoledronic acid as a potent bisphosphonate in preventing bone loss, but with varying potency between patients. Human osteoclasts ex vivo reportedly displayed a variable sensitivity to zoledronic acid > 200-fold, determined by the half-maximal inhibitory concentration (IC50), with cigarette smoking as one of the reported contributors to this variation. To reveal the molecular basis of the smoking-mediated variation on treatment sensitivity, we performed a DNA methylome profiling on whole blood cells from 34 healthy female blood donors. Multiple regression models were fitted to associate DNA methylation with ex vivo determined IC50 values, smoking, and their interaction adjusting for age and cell compositions. Results: We identified 59 CpGs displaying genome-wide significance (p < 1e−08) with a false discovery rate (FDR) < 0.05 for the smoking-dependent association with IC50. Among them, 3 CpGs have p < 1e−08 and FDR < 2e−03. By comparing with genome-wide association studies, 15 significant CpGs were locally enriched (within < 50,000 bp) by SNPs associated with bone and body size measures. Furthermore, through a replication analysis using data from a published multi-omics association study on bone mineral density (BMD), we could validate that 29 out of the 59 CpGs were in close vicinity of genomic sites significantly associated with BMD. Gene Ontology (GO) analysis on genes linked to the 59 CpGs displaying smoking-dependent association with IC50, detected 18 significant GO terms including cation:cation antiporter activity, extracellular matrix conferring tensile strength, ligand–gated ion channel activity, etc. Conclusions: Our results suggest that smoking mediates individual sensitivity to zoledronic acid treatment through epigenetic regulation. Our novel findings could have important clinical implications since DNA methylation analysis may enable personalized zoledronic acid treatment.
| Original language | English |
|---|---|
| Article number | 42 |
| Journal | Clinical Epigenetics |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - 13 Mar 2023 |
Bibliographical note
Publisher Copyright:© 2023, The Author(s).
Funding
We wish to thank Henning Boldt for performing the DNA methylation measurements and Salah Masmoudi for setting up the database allowing us to compare the results of DNA methylation with demographic and experimental information of the corresponding participants. We acknowledge Malka Kitayner (PhD) for her analytical support. We also wish to thank Jacob Bastholm Olesen for excellent technical assistance. This work was promoted and facilitated by the membership of David Karasik and Kent Søe in the COST Action CA18139 GEMSTONE [59] (Genomics of MusculoSkeletal traits Translational Network), in particular their membership of Working Group 4 [60]. We wish to acknowledge funding from the Research Counsel of Lillebaelt Hospital; the Region of Southern Denmark (15/24819); the Department of Regional Health Research, University of Southern Denmark; the Mrs Astrid Thaysen Fund (ATL 16/02); and the Aase & Ejnar Danielsen Fund (10-001835 and 19-10-0352). The replication study was partially supported or benefited by grants from the National Institutes of Health, United States (R01AR069055, R01AG061917, U19AG055373, and P20GM109036). DK was supported by grant ISF-1121/19 from Israel Science Foundation.
| Funders | Funder number |
|---|---|
| Department of Regional Health Research, University of Southern Denmark | |
| Mrs Astrid Thaysen Fund | ATL 16/02 |
| Region of Southern Denmark | 15/24819 |
| Research Counsel of Lillebaelt Hospital | |
| National Institutes of Health | R01AG061917, R01AR069055, P20GM109036, ISF-1121/19, U19AG055373 |
| European Cooperation in Science and Technology | |
| Aase og Ejnar Danielsens Fond | 19-10-0352, 10-001835 |
| Israel Science Foundation |
Keywords
- Antiresorptives
- Association studies
- DNA methylation
- Epigenetics
- Osteoclasts
- Smoking
- Zoledronic acid
