Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink

Daniel F. Carr; Ben Francis; Andrea L. Jorgensen; Eunice Zhang; Hector Chinoy; Susan R. Heckbert; Joshua C. Bis; Jennifer A. Brody; James S. Floyd; Bruce M. Psaty; Mariam Molokhia; Maryse Lapeyre-Mestre; Anita Conforti; Ana Alfirevic; Tjeerd van Staa; Munir Pirmohamed

doi:10.1002/cpt.1557

Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink

Daniel F. Carr, Ben Francis, Andrea L. Jorgensen, Eunice Zhang, Hector Chinoy, Susan R. Heckbert, Joshua C. Bis, Jennifer A. Brody, James S. Floyd, Bruce M. Psaty, Mariam Molokhia, Maryse Lapeyre-Mestre, Anita Conforti, Ana Alfirevic, Tjeerd van Staa, Munir Pirmohamed

Research output: Contribution to journal › Article › peer-review

Abstract

Statins can be associated with myopathy. We have undertaken a Genome-wide Association Study (GWAS) to discover and validate genetic risk-factors for statin-induced myopathy in a “real-world” setting. 135 statin myopathy patients recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome v1.0 Bead Chip, and compared to the Wellcome Trust Case-Control Consortium (n=2501). Nominally statistically significant SNP signals in the GWAS (p<5x10-5) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genome-wide significant in the severe myopathy (CK>10xULN or rhabdomyolysis) group (p=2.55x10-9; OR 5.15, 95%CI 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk-factor for statin myopathy. No other novel genetic risk-factors with a similar effect size were identified.

Original language	English
Journal	Clinical Pharmacology & Therapeutics
Early online date	20 Jun 2019
DOIs	https://doi.org/10.1002/cpt.1557
Publication status	Published - 2019

Keywords

statin
myopathy
genome wide association study
adverse dug reaction

Access to Document

10.1002/cpt.1557Licence: CC BY

MMRG: Manchester Myositis Research Group
Chinoy, H. (PI), Lamb, J. (PI), Ollier, W. (PI), Rothwell, S. (CoI), Lilleker, J. (CoI), Oldroyd, A. (PGR student), Snedden, A. (PGR student), Platt, H. (Support team) & New, P. (Support team)
1/01/10 → …
Project: Research

File

Cite this

Carr, D. F., Francis, B., Jorgensen, A. L., Zhang, E., Chinoy, H., Heckbert, S. R., Bis, J. C., Brody, J. A., Floyd, J. S., Psaty, B. M., Molokhia, M., Lapeyre-Mestre, M., Conforti, A., Alfirevic, A., van Staa, T., & Pirmohamed, M. (2019). Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink. Clinical Pharmacology & Therapeutics. https://doi.org/10.1002/cpt.1557

@article{5b678fc6470541b4aa6f2a3a8a241157,

title = "Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink",

abstract = "Statins can be associated with myopathy. We have undertaken a Genome-wide Association Study (GWAS) to discover and validate genetic risk-factors for statin-induced myopathy in a “real-world” setting. 135 statin myopathy patients recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome v1.0 Bead Chip, and compared to the Wellcome Trust Case-Control Consortium (n=2501). Nominally statistically significant SNP signals in the GWAS (p<5x10-5) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genome-wide significant in the severe myopathy (CK>10xULN or rhabdomyolysis) group (p=2.55x10-9; OR 5.15, 95%CI 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk-factor for statin myopathy. No other novel genetic risk-factors with a similar effect size were identified. ",

keywords = "statin, myopathy, genome wide association study, adverse dug reaction",

author = "Carr, {Daniel F.} and Ben Francis and Jorgensen, {Andrea L.} and Eunice Zhang and Hector Chinoy and Heckbert, {Susan R.} and Bis, {Joshua C.} and Brody, {Jennifer A.} and Floyd, {James S.} and Psaty, {Bruce M.} and Mariam Molokhia and Maryse Lapeyre-Mestre and Anita Conforti and Ana Alfirevic and {van Staa}, Tjeerd and Munir Pirmohamed",

year = "2019",

doi = "10.1002/cpt.1557",

language = "English",

journal = "Clinical Pharmacology & Therapeutics",

issn = "0009-9236",

publisher = "Springer Nature",

}

Carr, DF, Francis, B, Jorgensen, AL, Zhang, E, Chinoy, H, Heckbert, SR, Bis, JC, Brody, JA, Floyd, JS, Psaty, BM, Molokhia, M, Lapeyre-Mestre, M, Conforti, A, Alfirevic, A, van Staa, T & Pirmohamed, M 2019, 'Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink', Clinical Pharmacology & Therapeutics. https://doi.org/10.1002/cpt.1557

TY - JOUR

T1 - Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink

AU - Carr, Daniel F.

AU - Francis, Ben

AU - Jorgensen, Andrea L.

AU - Zhang, Eunice

AU - Chinoy, Hector

AU - Heckbert, Susan R.

AU - Bis, Joshua C.

AU - Brody, Jennifer A.

AU - Floyd, James S.

AU - Psaty, Bruce M.

AU - Molokhia, Mariam

AU - Lapeyre-Mestre, Maryse

AU - Conforti, Anita

AU - Alfirevic, Ana

AU - van Staa, Tjeerd

AU - Pirmohamed, Munir

PY - 2019

Y1 - 2019

N2 - Statins can be associated with myopathy. We have undertaken a Genome-wide Association Study (GWAS) to discover and validate genetic risk-factors for statin-induced myopathy in a “real-world” setting. 135 statin myopathy patients recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome v1.0 Bead Chip, and compared to the Wellcome Trust Case-Control Consortium (n=2501). Nominally statistically significant SNP signals in the GWAS (p<5x10-5) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genome-wide significant in the severe myopathy (CK>10xULN or rhabdomyolysis) group (p=2.55x10-9; OR 5.15, 95%CI 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk-factor for statin myopathy. No other novel genetic risk-factors with a similar effect size were identified.

AB - Statins can be associated with myopathy. We have undertaken a Genome-wide Association Study (GWAS) to discover and validate genetic risk-factors for statin-induced myopathy in a “real-world” setting. 135 statin myopathy patients recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome v1.0 Bead Chip, and compared to the Wellcome Trust Case-Control Consortium (n=2501). Nominally statistically significant SNP signals in the GWAS (p<5x10-5) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genome-wide significant in the severe myopathy (CK>10xULN or rhabdomyolysis) group (p=2.55x10-9; OR 5.15, 95%CI 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk-factor for statin myopathy. No other novel genetic risk-factors with a similar effect size were identified.

KW - statin

KW - myopathy

KW - genome wide association study

KW - adverse dug reaction

U2 - 10.1002/cpt.1557

DO - 10.1002/cpt.1557

M3 - Article

C2 - 31220337

AN - SCOPUS:85070066260

SN - 0009-9236

JO - Clinical Pharmacology & Therapeutics

JF - Clinical Pharmacology & Therapeutics

ER -

Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink

Abstract

Keywords

Access to Document

Fingerprint

Projects

MMRG: Manchester Myositis Research Group

Cite this