dc.contributor.author | Bigossi, M | |
dc.contributor.author | Maroteau, C | |
dc.contributor.author | Dawed, AY | |
dc.contributor.author | Taylor, A | |
dc.contributor.author | Srinivasan, S | |
dc.contributor.author | Melhem, AL | |
dc.contributor.author | Pearson, ER | |
dc.contributor.author | Pola, R | |
dc.contributor.author | Palmer, CNA | |
dc.contributor.author | Siddiqui, MK | |
dc.date.accessioned | 2024-04-08T07:11:49Z | |
dc.date.available | 2023-05-29 | |
dc.date.available | 2024-04-08T07:11:49Z | |
dc.date.issued | 2023-05-30 | |
dc.identifier.citation | Margherita Bigossi, Cyrielle Maroteau, Adem Y Dawed, Alasdair Taylor, Sundararajan Srinivasan, Alaa’ Lufti Melhem, Ewan R Pearson, Roberto Pola, Colin N A Palmer, Moneeza K Siddiqui, A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 9, Issue 6, September 2023, Pages 536–545, https://doi.org/10.1093/ehjcvp/pvad040 | en_US |
dc.identifier.issn | 2055-6837 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/95964 | |
dc.description.abstract | Background and aims
The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentrations of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study, we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance.
Methods and results
A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside, Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance [general statin intolerance (GSI): ORGSI 2.42; 95% confidence interval (CI): 1.29–4.31, P = 0.003; statin-related myopathy: ORSRM 2.51; 95% CI: 1.28–4.53, P = 0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85; 95% CI: 1.03–6.65, P = 0.02]. In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99; 95% CI: 1.01–3.95, P = 0.048; ORGRS 1.76; 95% CI: 1.16–2.69, P = 0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared with Val174Ala (GSI: HRVal174Ala 2.49; 95% CI: 1.09–5.68, P = 0.03; HRGRS 2.44; 95% CI: 1.46–4.08, P < 0.001). Finally, sequence kernel association testing confirmed that rare variants in SLCO1B1 are associated with the risk of intolerance (P = 0.02).
Conclusion
We provide evidence that a GRS based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early-onset statin intolerance. | en_US |
dc.format.extent | 536 - 545 | |
dc.publisher | Oxford University Press | en_US |
dc.relation.ispartof | EUROPEAN HEART JOURNAL-CARDIOVASCULAR PHARMACOTHERAPY | |
dc.rights | This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com | |
dc.subject | Pharmacogenomics | en_US |
dc.subject | SLCO1B1 | en_US |
dc.subject | Statins | en_US |
dc.subject | Adverse drug reactions | en_US |
dc.subject | Precision medicine | en_US |
dc.subject | Musculoskeletal symptoms | en_US |
dc.title | A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance | en_US |
dc.type | Article | en_US |
dc.rights.holder | © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. | |
dc.identifier.doi | 10.1093/ehjcvp/pvad040 | |
pubs.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:001016508300001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=612ae0d773dcbdba3046f6df545e9f6a | en_US |
pubs.issue | 6 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 9 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |