| Title: | SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients |
| Journal: | International Journal of Molecular Sciences |
| Published: | 17 Apr 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38674010/ |
| DOI: | https://doi.org/10.3390/ijms25084426 |
| Citations: | 1 (1 in last 2 years) as of 8 Aug 2024 |
Publication 9882
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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.</p>
14 Keywords
- Aged
- Atorvastatin
- Exome Sequencing
- Female
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Liver-Specific Organic Anion Transporter 1
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Simvastatin
- Treatment Outcome
- UK Biobank
- United Kingdom
5 Authors
- Deniz Türkmen
- Jack Bowden
- Jane A. H. Masoli
- David Melzer
- Luke C. Pilling
1 Application
| Application ID | Title |
|---|---|
| 14631 | Genetic and environmental influences on ageing well |
Enabling scientific discoveries that improve human health