Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.
<h4>Aims</h4>Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifyi...
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doaj-2ad0f040dcd841839a2fd08139da53902021-03-04T12:38:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01146e021811510.1371/journal.pone.0218115Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.James S FloydKatarzyna M BlochJennifer A BrodyCyrielle MaroteauMoneeza K SiddiquiRichard GregoryDaniel F CarrMariam MolokhiaXiaoming LiuJoshua C BisAmmar AhmedXuan LiuPär HallbergQun-Ying YuePatrik K E MagnussonDiane BrissonKerri L WigginsAlanna C MorrisonEtienne KhouryPaul McKeigueBruno H StrickerMaryse Lapeyre-MestreSusan R HeckbertArlene M GallagherHector ChinoyRichard A GibbsEmmanuelle Bondon-GuittonRussell TracyEric BoerwinkleDaniel GaudetAnita ConfortiTjeerd van StaaColleen M SitlaniKenneth M RiceAnke-Hilse Maitland-van der ZeeMia WadeliusAndrew P MorrisMunir PirmohamedColin A N PalmerBruce M PsatyAna AlfirevicPREDICTION-ADR Consortium and EUDRAGENE<h4>Aims</h4>Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.<h4>Methods and results</h4>SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.<h4>Conclusions</h4>In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.https://doi.org/10.1371/journal.pone.0218115 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
James S Floyd Katarzyna M Bloch Jennifer A Brody Cyrielle Maroteau Moneeza K Siddiqui Richard Gregory Daniel F Carr Mariam Molokhia Xiaoming Liu Joshua C Bis Ammar Ahmed Xuan Liu Pär Hallberg Qun-Ying Yue Patrik K E Magnusson Diane Brisson Kerri L Wiggins Alanna C Morrison Etienne Khoury Paul McKeigue Bruno H Stricker Maryse Lapeyre-Mestre Susan R Heckbert Arlene M Gallagher Hector Chinoy Richard A Gibbs Emmanuelle Bondon-Guitton Russell Tracy Eric Boerwinkle Daniel Gaudet Anita Conforti Tjeerd van Staa Colleen M Sitlani Kenneth M Rice Anke-Hilse Maitland-van der Zee Mia Wadelius Andrew P Morris Munir Pirmohamed Colin A N Palmer Bruce M Psaty Ana Alfirevic PREDICTION-ADR Consortium and EUDRAGENE |
spellingShingle |
James S Floyd Katarzyna M Bloch Jennifer A Brody Cyrielle Maroteau Moneeza K Siddiqui Richard Gregory Daniel F Carr Mariam Molokhia Xiaoming Liu Joshua C Bis Ammar Ahmed Xuan Liu Pär Hallberg Qun-Ying Yue Patrik K E Magnusson Diane Brisson Kerri L Wiggins Alanna C Morrison Etienne Khoury Paul McKeigue Bruno H Stricker Maryse Lapeyre-Mestre Susan R Heckbert Arlene M Gallagher Hector Chinoy Richard A Gibbs Emmanuelle Bondon-Guitton Russell Tracy Eric Boerwinkle Daniel Gaudet Anita Conforti Tjeerd van Staa Colleen M Sitlani Kenneth M Rice Anke-Hilse Maitland-van der Zee Mia Wadelius Andrew P Morris Munir Pirmohamed Colin A N Palmer Bruce M Psaty Ana Alfirevic PREDICTION-ADR Consortium and EUDRAGENE Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. PLoS ONE |
author_facet |
James S Floyd Katarzyna M Bloch Jennifer A Brody Cyrielle Maroteau Moneeza K Siddiqui Richard Gregory Daniel F Carr Mariam Molokhia Xiaoming Liu Joshua C Bis Ammar Ahmed Xuan Liu Pär Hallberg Qun-Ying Yue Patrik K E Magnusson Diane Brisson Kerri L Wiggins Alanna C Morrison Etienne Khoury Paul McKeigue Bruno H Stricker Maryse Lapeyre-Mestre Susan R Heckbert Arlene M Gallagher Hector Chinoy Richard A Gibbs Emmanuelle Bondon-Guitton Russell Tracy Eric Boerwinkle Daniel Gaudet Anita Conforti Tjeerd van Staa Colleen M Sitlani Kenneth M Rice Anke-Hilse Maitland-van der Zee Mia Wadelius Andrew P Morris Munir Pirmohamed Colin A N Palmer Bruce M Psaty Ana Alfirevic PREDICTION-ADR Consortium and EUDRAGENE |
author_sort |
James S Floyd |
title |
Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. |
title_short |
Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. |
title_full |
Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. |
title_fullStr |
Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. |
title_full_unstemmed |
Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. |
title_sort |
pharmacogenomics of statin-related myopathy: meta-analysis of rare variants from whole-exome sequencing. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2019-01-01 |
description |
<h4>Aims</h4>Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.<h4>Methods and results</h4>SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.<h4>Conclusions</h4>In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable. |
url |
https://doi.org/10.1371/journal.pone.0218115 |
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