@article {8508, title = {Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink.}, journal = {Clin Pharmacol Ther}, volume = {106}, year = {2019}, month = {2019 12}, pages = {1353-1361}, abstract = {

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n~=~2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P~<~5~{\texttimes}~10 ) 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 genomewide significant in the severe myopathy (creatine kinase~>~10~{\texttimes}~upper limit of normal or rhabdomyolysis) group (P~=~2.55~{\texttimes}~10 ; odds ratio 5.15; 95\% confidence interval 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 = {Adverse Drug Reaction Reporting Systems, Case-Control Studies, Databases, Factual, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver-Specific Organic Anion Transporter 1, Muscular Diseases, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Reproducibility of Results, Risk Factors, Severity of Illness Index, United Kingdom}, issn = {1532-6535}, doi = {10.1002/cpt.1557}, author = {Carr, Daniel F and Francis, Ben and Jorgensen, Andrea L and Zhang, Eunice and Chinoy, Hector and Heckbert, Susan R and Bis, Joshua C and Brody, Jennifer A and Floyd, James S and Psaty, Bruce M and Molokhia, Mariam and Lapeyre-Mestre, Maryse and Conforti, Anita and Alfirevic, Ana and van Staa, Tjeerd and Pirmohamed, Munir} } @article {8102, title = {Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.}, journal = {PLoS One}, volume = {14}, year = {2019}, month = {2019}, pages = {e0218115}, abstract = {

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.

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 >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.

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.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0218115}, 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, P{\"a}r 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} }