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Pharmacogenomic effects of β-blocker use on femoral neck bone mineral density

Pharmacogenomic effects of β-blocker use on femoral neck bone mineral density
Pharmacogenomic effects of β-blocker use on femoral neck bone mineral density
Context: recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to non-users, 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 polymorphisms (SNPs) 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 four genetic findings using data from the Rotterdam Study, the BPROOF Study, the MOFS, and the Hertfordshire Cohort Study.

Design: we used sex-stratified linear mixed models to determine SNPs 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 single nucleotide polymorphisms (SNPs) from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNPs may impact FN BMD.

Results: one polymorphism (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 polymorphisms, which further validated our findings.

Conclusions: this analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.
beta blocker, bone, genomics, miRNA, pharmacogenomics, β-blocker
2472-1972
Nevola, Kathleen T.
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Nagarajan, Archana
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Hinton, Alexandra C.
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Trajanoska, Katerina
fa445c07-4fc2-4fbf-bf03-e5077c6d6c19
Formosa, Melissa M.
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Xuereb-Anastasi, Angela
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van der Velde, Nathalie
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Stricker, Bruno H.
6ab95e7a-7feb-4d0a-8cb6-41a6d64f9a29
Rivadeneira, Fernando
8441b9d3-6d8e-4b33-8827-dd70d80db200
Fuggle, Nicholas
9ab0c81a-ac67-41c4-8860-23e0fdb1a900
Westbury, Leo
5ed45df3-3df7-4bf9-bbad-07b63cd4b281
Dennison, Elaine
ee647287-edb4-4392-8361-e59fd505b1d1
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Kiel, Douglas P.
ff4d761f-9e48-415b-aae2-0c45381fd05f
Motyl, Katherine J.
f9f146a1-e22f-499c-88ee-d855d17a0ce2
Lary, Christine W.
60d30069-8722-4fff-abcb-31b096bba17f
Nevola, Kathleen T.
77f3f0b7-05c7-49ae-8cb6-38fafada5261
Nagarajan, Archana
b4834086-e1c3-48af-844a-c7a687998403
Hinton, Alexandra C.
15b1ad49-b566-42c2-a79c-806cc64554ed
Trajanoska, Katerina
fa445c07-4fc2-4fbf-bf03-e5077c6d6c19
Formosa, Melissa M.
0aa68d84-ad13-435e-9b29-829964352d22
Xuereb-Anastasi, Angela
57a41656-15c8-41c9-bcab-e5e383942b1c
van der Velde, Nathalie
54e7631d-a9a1-4752-a9a9-e6249f1322b3
Stricker, Bruno H.
6ab95e7a-7feb-4d0a-8cb6-41a6d64f9a29
Rivadeneira, Fernando
8441b9d3-6d8e-4b33-8827-dd70d80db200
Fuggle, Nicholas
9ab0c81a-ac67-41c4-8860-23e0fdb1a900
Westbury, Leo
5ed45df3-3df7-4bf9-bbad-07b63cd4b281
Dennison, Elaine
ee647287-edb4-4392-8361-e59fd505b1d1
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Kiel, Douglas P.
ff4d761f-9e48-415b-aae2-0c45381fd05f
Motyl, Katherine J.
f9f146a1-e22f-499c-88ee-d855d17a0ce2
Lary, Christine W.
60d30069-8722-4fff-abcb-31b096bba17f

Nevola, Kathleen T., Nagarajan, Archana, Hinton, Alexandra C., Trajanoska, Katerina, Formosa, Melissa M., Xuereb-Anastasi, Angela, van der Velde, Nathalie, Stricker, Bruno H., Rivadeneira, Fernando, Fuggle, Nicholas, Westbury, Leo, Dennison, Elaine, Cooper, Cyrus, Kiel, Douglas P., Motyl, Katherine J. and Lary, Christine W. (2021) Pharmacogenomic effects of β-blocker use on femoral neck bone mineral density. Journal of the Endocrine Society, 5 (8), [bvab092]. (doi:10.1210/jendso/bvab092).

Record type: Article

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 non-users, 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 polymorphisms (SNPs) 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 four genetic findings using data from the Rotterdam Study, the BPROOF Study, the MOFS, and the Hertfordshire Cohort Study.

Design: we used sex-stratified linear mixed models to determine SNPs 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 single nucleotide polymorphisms (SNPs) from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNPs may impact FN BMD.

Results: one polymorphism (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 polymorphisms, which further validated our findings.

Conclusions: this analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.

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Accepted/In Press date: 7 May 2021
e-pub ahead of print date: 15 May 2021
Published date: 1 August 2021
Keywords: beta blocker, bone, genomics, miRNA, pharmacogenomics, β-blocker

Identifiers

Local EPrints ID: 449425
URI: http://eprints.soton.ac.uk/id/eprint/449425
ISSN: 2472-1972
PURE UUID: 23a2b901-72de-4f9a-8e3f-b75e2ebb74ad
ORCID for Elaine Dennison: ORCID iD orcid.org/0000-0002-3048-4961
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709

Catalogue record

Date deposited: 28 May 2021 16:31
Last modified: 26 Nov 2021 02:40

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Contributors

Author: Kathleen T. Nevola
Author: Archana Nagarajan
Author: Alexandra C. Hinton
Author: Katerina Trajanoska
Author: Melissa M. Formosa
Author: Angela Xuereb-Anastasi
Author: Nathalie van der Velde
Author: Bruno H. Stricker
Author: Fernando Rivadeneira
Author: Nicholas Fuggle
Author: Leo Westbury
Author: Elaine Dennison ORCID iD
Author: Cyrus Cooper ORCID iD
Author: Douglas P. Kiel
Author: Katherine J. Motyl
Author: Christine W. Lary

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