دورية أكاديمية
A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance.
| العنوان: | A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance. |
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| المؤلفون: | Bigossi M; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK.; Section of Internal Medicine and Thromboembolic Diseases, Department of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy., Maroteau C; Human Genetics Centre of Excellence, Novo Nordisk Research Centre Oxford, Oxford OX3 7FZ, UK., Dawed AY; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK., Taylor A; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK., Srinivasan S; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK., Melhem AL; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK., Pearson ER; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK., Pola R; Section of Internal Medicine and Thromboembolic Diseases, Department of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy., Palmer CNA; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK., Siddiqui MK; Pat McPherson Centre for Pharmacogenetics & Pharmacogenomics, Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, DundeeDD1 9SY, UK. |
| المصدر: | European heart journal. Cardiovascular pharmacotherapy [Eur Heart J Cardiovasc Pharmacother] 2023 Sep 20; Vol. 9 (6), pp. 536-545. |
| نوع المنشور: | Meta-Analysis; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 101669491 Publication Model: Print Cited Medium: Internet ISSN: 2055-6845 (Electronic) NLM ISO Abbreviation: Eur Heart J Cardiovasc Pharmacother Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Oxford : Oxford University Press, [2015]- |
| مواضيع طبية MeSH: | Hydroxymethylglutaryl-CoA Reductase Inhibitors*/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors*/therapeutic use , Muscular Diseases*/chemically induced , Muscular Diseases*/diagnosis , Muscular Diseases*/genetics, Humans ; Genotype ; Liver-Specific Organic Anion Transporter 1/genetics ; Phenotype ; Risk Factors |
| مستخلص: | 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. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.) |
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| معلومات مُعتمدة: | 099177/Z/12/Z United Kingdom WT_ Wellcome Trust; 16/136/102 United Kingdom DH_ Department of Health; 072960 United Kingdom WT_ Wellcome Trust; 084726 United Kingdom WT_ Wellcome Trust; G0601261 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: SLCO1B1; Adverse drug reactions; Musculoskeletal symptoms; Pharmacogenomics; Precision medicine; Statins |
| المشرفين على المادة: | 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) 0 (Liver-Specific Organic Anion Transporter 1) 0 (SLCO1B1 protein, human) |
| تواريخ الأحداث: | Date Created: 20230530 Date Completed: 20230923 Latest Revision: 20230925 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC10509567 |
| DOI: | 10.1093/ehjcvp/pvad040 |
| PMID: | 37253618 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2055-6845 |
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| DOI: | 10.1093/ehjcvp/pvad040 |