Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density

Kathleen T. Nevola; Archana Nagarajan; Alexandra C. Hinton; Katerina Trajanoska; Melissa M. Formosa; Angela Xuereb-Anastasi; Nathalie Van Der Velde; Bruno H. Stricker; Fernando Rivadeneira; Nicholas R. Fuggle; Leo D. Westbury; Elaine M. Dennison; Cyrus Cooper; Douglas P. Kiel; Katherine J. Motyl; Christine W. Lary

doi:10.1210/jendso/bvab092

Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density

Kathleen T. Nevola, Archana Nagarajan, Alexandra C. Hinton, Katerina Trajanoska, Melissa M. Formosa, Angela Xuereb-Anastasi, Nathalie Van Der Velde, Bruno H. Stricker, Fernando Rivadeneira, Nicholas R. Fuggle, Leo D. Westbury, Elaine M. Dennison, Cyrus Cooper, Douglas P. Kiel, Katherine J. Motyl, Christine W. Lary^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

3 Citations (Scopus)

Abstract

Context: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. Objective: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study. Methods: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD. Results: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings. Conclusion: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.

Original language	English
Article number	bvab092
Journal	Journal of the Endocrine Society
Volume	5
Issue number	8
DOIs	https://doi.org/10.1210/jendso/bvab092
Publication status	Published - 1 Aug 2021

Bibliographical note

Funding Information:
This work was supported by the COBRE in Mesenchymal and Neural Regulation of Metabolic Networks (National Institutes of Health (NIH) grant Nos. NIH/NIGMS P20GM121301 to L.L., NIH/NIAMS K01AR067858 to K.J.M., NIH/NIAMS R01 AR041398 to D.P.K., and Framingham Contract Number (No. 75N92019D00031). The MOFS was supported by the Research and Innovation Development Trust (RIDT) of the University of Malta, The Malta Community Chest Fund, and the European Union Strategic Educational Pathways Scholarship scheme (STEPS). The Rotterdam Study was supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NWO); The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. This study was supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant No. 6130.0031), the Hague; an unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project No. KB-15-004-003), The Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. The Hertfordshire Cohort Study is supported by the Medical Research Council University Unit Partnership (grant No. MRC-MC-UP-A620-1014). Code for FHS analyses can be found at https://github.com/knevola/ MMC/tree/master/Aim2-Genetic-Influences-scripts.

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.

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10.1210/jendso/bvab092

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Nevola, K. T., Nagarajan, A., Hinton, A. C., Trajanoska, K., Formosa, M. M., Xuereb-Anastasi, A., Van Der Velde, N., Stricker, B. H., Rivadeneira, F., Fuggle, N. R., Westbury, L. D., Dennison, E. M., Cooper, C., Kiel, D. P., Motyl, K. J., & Lary, C. W. (2021). Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density. Journal of the Endocrine Society, 5(8), Article bvab092. https://doi.org/10.1210/jendso/bvab092

@article{3a0b44e556bd4eab9e03af40519612ff,

title = "Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density",

abstract = "Context: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. Objective: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study. Methods: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD. Results: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings. Conclusion: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures. ",

author = "Nevola, \{Kathleen T.\} and Archana Nagarajan and Hinton, \{Alexandra C.\} and Katerina Trajanoska and Formosa, \{Melissa M.\} and Angela Xuereb-Anastasi and \{Van Der Velde\}, Nathalie and Stricker, \{Bruno H.\} and Fernando Rivadeneira and Fuggle, \{Nicholas R.\} and Westbury, \{Leo D.\} and Dennison, \{Elaine M.\} and Cyrus Cooper and Kiel, \{Douglas P.\} and Motyl, \{Katherine J.\} and Lary, \{Christine W.\}",

note = "Funding Information: This work was supported by the COBRE in Mesenchymal and Neural Regulation of Metabolic Networks (National Institutes of Health (NIH) grant Nos. NIH/NIGMS P20GM121301 to L.L., NIH/NIAMS K01AR067858 to K.J.M., NIH/NIAMS R01 AR041398 to D.P.K., and Framingham Contract Number (No. 75N92019D00031). The MOFS was supported by the Research and Innovation Development Trust (RIDT) of the University of Malta, The Malta Community Chest Fund, and the European Union Strategic Educational Pathways Scholarship scheme (STEPS). The Rotterdam Study was supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NWO); The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. This study was supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant No. 6130.0031), the Hague; an unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project No. KB-15-004-003), The Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. The Hertfordshire Cohort Study is supported by the Medical Research Council University Unit Partnership (grant No. MRC-MC-UP-A620-1014). Code for FHS analyses can be found at https://github.com/knevola/ MMC/tree/master/Aim2-Genetic-Influences-scripts. Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.",

year = "2021",

month = aug,

day = "1",

doi = "10.1210/jendso/bvab092",

language = "English",

volume = "5",

journal = "Journal of the Endocrine Society",

issn = "2472-1972",

publisher = "Endocrine Society",

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Nevola, KT, Nagarajan, A, Hinton, AC, Trajanoska, K, Formosa, MM, Xuereb-Anastasi, A, Van Der Velde, N, Stricker, BH , Rivadeneira, F, Fuggle, NR, Westbury, LD, Dennison, EM, Cooper, C, Kiel, DP, Motyl, KJ & Lary, CW 2021, 'Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density', Journal of the Endocrine Society, vol. 5, no. 8, bvab092. https://doi.org/10.1210/jendso/bvab092

TY - JOUR

T1 - Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density

AU - Nevola, Kathleen T.

AU - Nagarajan, Archana

AU - Hinton, Alexandra C.

AU - Trajanoska, Katerina

AU - Formosa, Melissa M.

AU - Xuereb-Anastasi, Angela

AU - Van Der Velde, Nathalie

AU - Stricker, Bruno H.

AU - Rivadeneira, Fernando

AU - Fuggle, Nicholas R.

AU - Westbury, Leo D.

AU - Dennison, Elaine M.

AU - Cooper, Cyrus

AU - Kiel, Douglas P.

AU - Motyl, Katherine J.

AU - Lary, Christine W.

N1 - Funding Information: This work was supported by the COBRE in Mesenchymal and Neural Regulation of Metabolic Networks (National Institutes of Health (NIH) grant Nos. NIH/NIGMS P20GM121301 to L.L., NIH/NIAMS K01AR067858 to K.J.M., NIH/NIAMS R01 AR041398 to D.P.K., and Framingham Contract Number (No. 75N92019D00031). The MOFS was supported by the Research and Innovation Development Trust (RIDT) of the University of Malta, The Malta Community Chest Fund, and the European Union Strategic Educational Pathways Scholarship scheme (STEPS). The Rotterdam Study was supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NWO); The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. This study was supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant No. 6130.0031), the Hague; an unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project No. KB-15-004-003), The Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. The Hertfordshire Cohort Study is supported by the Medical Research Council University Unit Partnership (grant No. MRC-MC-UP-A620-1014). Code for FHS analyses can be found at https://github.com/knevola/ MMC/tree/master/Aim2-Genetic-Influences-scripts. Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.

PY - 2021/8/1

Y1 - 2021/8/1

N2 - Context: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. Objective: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study. Methods: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD. Results: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings. Conclusion: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.

AB - Context: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. Objective: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study. Methods: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD. Results: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings. Conclusion: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.

UR - https://www.scopus.com/pages/publications/85111927308

U2 - 10.1210/jendso/bvab092

DO - 10.1210/jendso/bvab092

M3 - Article

C2 - 34195528

AN - SCOPUS:85111927308

SN - 2472-1972

VL - 5

JO - Journal of the Endocrine Society

JF - Journal of the Endocrine Society

IS - 8

M1 - bvab092

ER -

Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density

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