SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients
dc.contributor.author | Türkmen, D | |
dc.contributor.author | Bowden, J | |
dc.contributor.author | Masoli, JAH | |
dc.contributor.author | Melzer, D | |
dc.contributor.author | Pilling, LC | |
dc.date.accessioned | 2024-06-06T14:59:55Z | |
dc.date.issued | 2024-04-17 | |
dc.date.updated | 2024-06-06T14:23:35Z | |
dc.description.abstract | The solute carrier organic anion transporter family member 1B1 (SLCO1B1) encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in SLCO1B1, such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare SLCO1B1 variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both SLCO1B1*5 alone and the SLCO1B1*15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, p = 6 × 10-8; beta*15 = 0.03 mmol/L, p = 3 × 10-4), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, p = 0.04; HR*15 = 1.05, p = 0.04). SLCO1B1*15 and SLCO1B1*20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, p = 0.003; HR*20 = 1.25, p = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in SLCO1B1 increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further SLCO1B1 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation. | en_GB |
dc.description.sponsorship | Ministry of National Education, Republic of Turkey | en_GB |
dc.description.sponsorship | University of Exeter Medical School | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | National Institute for Health and Care Research (NIHR) | en_GB |
dc.format.extent | 4426- | |
dc.format.medium | Electronic | |
dc.identifier.citation | Vol. 25(8), article 4426 | en_GB |
dc.identifier.doi | https://doi.org/10.3390/ijms25084426 | |
dc.identifier.grantnumber | MR/X011372/1 | en_GB |
dc.identifier.grantnumber | NIHR302270 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/136173 | |
dc.identifier | ORCID: 0000-0003-2628-3304 (Bowden, Jack) | |
dc.identifier | ORCID: 0000-0002-3332-8454 (Pilling, Luke C) | |
dc.identifier | ScopusID: 54892844700 | 57195139356 (Pilling, Luke C) | |
dc.identifier | ResearcherID: E-4917-2013 (Pilling, Luke C) | |
dc.language.iso | en | en_GB |
dc.publisher | MDPI | en_GB |
dc.relation.url | https://github.com/lukepilling/twistR | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/38674010 | en_GB |
dc.rights | © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | en_GB |
dc.subject | SLCO1B1 | en_GB |
dc.subject | cholesterol | en_GB |
dc.subject | clinical response | en_GB |
dc.subject | epidemiology | en_GB |
dc.subject | exome sequencing variants | en_GB |
dc.subject | pharmacogenomics | en_GB |
dc.subject | statin | en_GB |
dc.title | SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2024-06-06T14:59:55Z | |
dc.identifier.issn | 1661-6596 | |
exeter.article-number | ARTN 4426 | |
exeter.place-of-publication | Switzerland | |
dc.description | This is the final version. Available from MDPI via the DOI in this record | en_GB |
dc.description | Data Availability Statement: Participant-level data are available on application to the UK Biobank (www.ukbiobank.ac.uk/register-apply, accessed on 20 March 2024). The TWIST R package is available on GitHub (https://github.com/lukepilling/twistR, accessed on 20 March 2024) but contains no individual-level data. | en_GB |
dc.identifier.eissn | 1422-0067 | |
dc.identifier.journal | International Journal of Molecular Sciences | en_GB |
dc.relation.ispartof | Int J Mol Sci, 25(8) | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_GB |
dcterms.dateAccepted | 2024-04-16 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2024-04-17 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2024-06-06T14:55:55Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2024-06-06T15:00:03Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2024-04-17 |
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Except where otherwise noted, this item's licence is described as © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).