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

The solute carrier organic anion transporter family member 1B1 () encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in , 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 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 5 alone and the 15 haplotype increased LDL during treatment (beta5 = 0.08 mmol/L, = 6 × 10; beta15 = 0.03 mmol/L, = 3 × 10), as did the likelihood of discontinuing statin prescriptions (hazard ratio5 = 1.12, = 0.04; HR*15 = 1.05, = 0.04). 15 and 20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR15 = 1.22, = 0.003; HR20 = 1.25, = 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 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 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation.