Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. Floyd, J. S, Bloch, K. M, Brody, J. A, Maroteau, C., Siddiqui, M. K, Gregory, R., Carr, D. F, Molokhia, M., Liu, X., Bis, J. C, Ahmed, A., Liu, X., Hallberg, P., Yue, Q., Magnusson, P. K E, Brisson, D., Wiggins, K. L, Morrison, A. C, Khoury, E., McKeigue, P., Stricker, B. H, Lapeyre-Mestre, M., Heckbert, S. R, Gallagher, A. M, Chinoy, H., Gibbs, R. A, Bondon-Guitton, E., Tracy, R., Boerwinkle, E., Gaudet, D., Conforti, A., van Staa, T., Sitlani, C. M, Rice, K. M, Maitland-van der Zee, A., Wadelius, M., Morris, A. P, Pirmohamed, M., Palmer, C. A N, Psaty, B. M, & Alfirevic, A. PLoS One, 14:e0218115, 2019.
doi  abstract   bibtex   
\textlessp\textgreater\textbfAIMS: 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.\textless/p\textgreater\textlessp\textgreater\textbfMETHODS AND RESULTS: 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 \textgreater4 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.\textless/p\textgreater\textlessp\textgreater\textbfCONCLUSIONS: 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.\textless/p\textgreater
@article{floyd_pharmacogenomics_2019,
	title = {Pharmacogenomics of statin-related myopathy: {Meta}-analysis of rare variants from whole-exome sequencing.},
	volume = {14},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0218115},
	abstract = {{\textless}p{\textgreater}\textbf{AIMS: }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.{\textless}/p{\textgreater}{\textless}p{\textgreater}\textbf{METHODS AND RESULTS: }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 {\textgreater}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.{\textless}/p{\textgreater}{\textless}p{\textgreater}\textbf{CONCLUSIONS: }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.{\textless}/p{\textgreater}},
	journal = {PLoS One},
	author = {Floyd, James S and Bloch, Katarzyna M and Brody, Jennifer A and Maroteau, Cyrielle and Siddiqui, Moneeza K and Gregory, Richard and Carr, Daniel F and Molokhia, Mariam and Liu, Xiaoming and Bis, Joshua C and Ahmed, Ammar and Liu, Xuan and Hallberg, Pär and Yue, Qun-Ying and Magnusson, Patrik K E and Brisson, Diane and Wiggins, Kerri L and Morrison, Alanna C and Khoury, Etienne and McKeigue, Paul and Stricker, Bruno H and Lapeyre-Mestre, Maryse and Heckbert, Susan R and Gallagher, Arlene M and Chinoy, Hector and Gibbs, Richard A and Bondon-Guitton, Emmanuelle and Tracy, Russell and Boerwinkle, Eric and Gaudet, Daniel and Conforti, Anita and van Staa, Tjeerd and Sitlani, Colleen M and Rice, Kenneth M and Maitland-van der Zee, Anke-Hilse and Wadelius, Mia and Morris, Andrew P and Pirmohamed, Munir and Palmer, Colin A N and Psaty, Bruce M and Alfirevic, Ana},
	year = {2019},
	pages = {e0218115}
}
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