Journal Article

SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients

Türkmen, Deniz, Masoli, Jane A. H., Bowden, Jack, Melzer, David, Pilling, Luke C.

2024

Overview

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.

• Publisher: MDPI AG
• Subject: Aged / Atorvastatin - therapeutic use / Biobanks / Biological Specimen Banks / Biomarkers / Cardiovascular disease / Exome Sequencing - methods / Female / Humans / Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects / Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use / Ischemia / Liver-Specific Organic Anion Transporter 1 - genetics / Male / Middle Aged / Patients / Polymorphism, Single Nucleotide / Simvastatin - therapeutic use / Statins / Stroke / Treatment Outcome / Trends / UK Biobank / United Kingdom / Vitamin D