A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance

Margherita Bigossi; Cyrielle Maroteau; Adem Y. Dawed; Alasdair Taylor; Sundararajan Srinivasan; Alaa' Lufti Melhem; Ewan R. Pearson; Roberto Pola; Colin N. A. Palmer; Moneeza K. Siddiqui

doi:10.1093/ehjcvp/pvad040

A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance

Margherita Bigossi, Cyrielle Maroteau, Adem Y. Dawed, Alasdair Taylor, Sundararajan Srinivasan, Alaa' Lufti Melhem, Ewan R. Pearson, Roberto Pola, Colin N. A. Palmer, Moneeza K. Siddiqui (Lead / Corresponding author)

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Abstract

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.

Original language	English
Pages (from-to)	536–545
Number of pages	10
Journal	European Heart Journal: Cardiovascular Pharmacotherapy
Volume	9
Issue number	6
Early online date	30 May 2023
DOIs	https://doi.org/10.1093/ehjcvp/pvad040
Publication status	Published - Sept 2023

Keywords

Pharmacogenomics
SLCO1B1
Statins
Adverse drug reactions
Precision medicine
Musculoskeletal symptoms

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10.1093/ehjcvp/pvad040Licence: CC BY-NC

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Bigossi, M., Maroteau, C., Dawed, A. Y., Taylor, A., Srinivasan, S., Melhem, A. L., Pearson, E. R., Pola, R., Palmer, C. N. A., & Siddiqui, M. K. (2023). A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance. European Heart Journal: Cardiovascular Pharmacotherapy, 9(6), 536–545. https://doi.org/10.1093/ehjcvp/pvad040

@article{1cfa0244b95741e0ad73a1754e8bf955,

title = "A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance",

abstract = "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.",

keywords = "Pharmacogenomics, SLCO1B1, Statins, Adverse drug reactions, Precision medicine, Musculoskeletal symptoms",

author = "Margherita Bigossi and Cyrielle Maroteau and Dawed, {Adem Y.} and Alasdair Taylor and Sundararajan Srinivasan and Melhem, {Alaa' Lufti} and Pearson, {Ewan R.} and Roberto Pola and Palmer, {Colin N. A.} and Siddiqui, {Moneeza K.}",

note = "Funding Information: This research was partly funded by the National Institute for Health Research (NIHR) (INSPIRED 16/136/102) using aid from the UK government to support global health research. GoDARTS was funded and supported by the Wellcome Trust (Award 072960 and 084726) and the UK Medical Research Council (Award G0601261). SHARE is NHS Scotland Research (NRS) infrastructure initiative and it was funded by the Chief Scientists Office of the Scottish Government. Additional Funding and initiation of the spare blood retention at NHS Tayside was supported by the Wellcome Trust Biomedical Resource (award number 099177/Z/12/Z). PREDICTION-ADR has received funding form the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under Grant Agreement no. 602108. The UK Biobank was primarily funded by the Wellcome Trust and the Medical Research Council. Approval for the study and permission to access the data was granted by the UK Biobank Resource under Application Number 20405 that is open access. Copyright: {\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2023",

month = sep,

doi = "10.1093/ehjcvp/pvad040",

language = "English",

volume = "9",

pages = "536–545",

journal = "European Heart Journal: Cardiovascular Pharmacotherapy",

issn = "2055-6845",

publisher = "Oxford University Press",

number = "6",

}

TY - JOUR

T1 - A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance

AU - Bigossi, Margherita

AU - Maroteau, Cyrielle

AU - Dawed, Adem Y.

AU - Taylor, Alasdair

AU - Srinivasan, Sundararajan

AU - Melhem, Alaa' Lufti

AU - Pearson, Ewan R.

AU - Pola, Roberto

AU - Palmer, Colin N. A.

AU - Siddiqui, Moneeza K.

N1 - Funding Information: This research was partly funded by the National Institute for Health Research (NIHR) (INSPIRED 16/136/102) using aid from the UK government to support global health research. GoDARTS was funded and supported by the Wellcome Trust (Award 072960 and 084726) and the UK Medical Research Council (Award G0601261). SHARE is NHS Scotland Research (NRS) infrastructure initiative and it was funded by the Chief Scientists Office of the Scottish Government. Additional Funding and initiation of the spare blood retention at NHS Tayside was supported by the Wellcome Trust Biomedical Resource (award number 099177/Z/12/Z). PREDICTION-ADR has received funding form the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant Agreement no. 602108. The UK Biobank was primarily funded by the Wellcome Trust and the Medical Research Council. Approval for the study and permission to access the data was granted by the UK Biobank Resource under Application Number 20405 that is open access. Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

KW - Pharmacogenomics

KW - SLCO1B1

KW - Statins

KW - Adverse drug reactions

KW - Precision medicine

KW - Musculoskeletal symptoms

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DO - 10.1093/ehjcvp/pvad040

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C2 - 37253618

SN - 2055-6845

VL - 9

SP - 536

EP - 545

JO - European Heart Journal: Cardiovascular Pharmacotherapy

JF - European Heart Journal: Cardiovascular Pharmacotherapy

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ER -

A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance

Abstract

Keywords

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Scotland India Diabetes Health Informatics Unit (joint with Madras Diabetes Research Foundation)

PREDICTION-ADR: Personalisation of tREatment In Cardiovascular Disease Through Next Generation Sequencing - Adverse Drug Reactions (Joint with University of Uppsala, University of Liverpool and University of Utrecht)

The Tayside Bioresource: Leveraging Electronic Medical Records to Deliver Personalised Medicine (Biomedical Resource Grant)

Health Informatics Centre

Cite this

A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

Scotland India Diabetes Health Informatics Unit (joint with Madras Diabetes Research Foundation)

PREDICTION-ADR: Personalisation of tREatment In Cardiovascular Disease Through Next Generation Sequencing - Adverse Drug Reactions (Joint with University of Uppsala, University of Liverpool and University of Utrecht)

The Tayside Bioresource: Leveraging Electronic Medical Records to Deliver Personalised Medicine (Biomedical Resource Grant)

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Health Informatics Centre

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