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SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients.
Türkmen, Deniz; Bowden, Jack; Masoli, Jane A H; Melzer, David; Pilling, Luke C.
Afiliación
  • Türkmen D; Epidemiology & Public Health Group, Department of Clinical & Biomedical Science, Faculty of Health & Life Sciences, University of Exeter, Exeter EX4 4QD, UK.
  • Bowden J; Exeter Diabetes Group (ExCEED), Department of Clinical & Biomedical Science, Faculty of Health & Life Sciences, University of Exeter, Exeter EX4 4QD, UK.
  • Masoli JAH; Department of Genetics, Novo Nordisk Research Centre Oxford, Innovation Building, Old Road Campus, Oxford OX3 7BN, UK.
  • Melzer D; Epidemiology & Public Health Group, Department of Clinical & Biomedical Science, Faculty of Health & Life Sciences, University of Exeter, Exeter EX4 4QD, UK.
  • Pilling LC; Department of Healthcare for Older People, Royal Devon University Healthcare NHS Foundation Trust, Exeter EX2 5DW, UK.
Int J Mol Sci ; 25(8)2024 Apr 17.
Article en En | MEDLINE | ID: mdl-38674010
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Hidroximetilglutaril-CoA Reductasas / Transportador 1 de Anión Orgánico Específico del Hígado / Secuenciación del Exoma Límite: Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Hidroximetilglutaril-CoA Reductasas / Transportador 1 de Anión Orgánico Específico del Hígado / Secuenciación del Exoma Límite: Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article Pais de publicación: Suiza