Magdaléna Neřoldová1, Viktor Stránecký2, Kateřina Hodaňová2, Hana Hartmannová2, Lenka Piherová2, Anna Přistoupilová2, Lenka Mrázová3, Michal Vrablík4, Věra Adámková5, Jaroslav A Hubáček3, Milan Jirsa1, Stanislav Kmoch2. 1. Laboratory of Experimental Hepatology, Center for Experimental Medicine, Institute for Clinical & Experimental Medicine, Prague, Czech Republic. 2. Institute of Inherited Metabolic Diseases, First Medical Faculty, Charles University, Prague, Czech Republic. 3. Laboratory for Atherosclerosis Research, Center for Experimental Medicine, Institute for Clinical & Experimental Medicine, Prague, Czech Republic. 4. Third Medical Department, First Faculty of Medicine, Charles University & General Faculty Hospital, Prague, Czech Republic. 5. Preventive Cardiology Department, Institute for Clinical & Experimental Medicine, Prague, Czech Republic.
Abstract
AIM: Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. METHODS: We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. RESULTS: In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. CONCLUSION: These findings support the role of rare variants and nominate loci for follow-up studies.
AIM: Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. METHODS: We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis. RESULTS: In the novel candidate gene CLCN1, we identified a heterozygote truncating mutation p.R894* in four patients. In addition, we detected predictably pathogenic case-specific variants in MYOT, CYP3A5, SH3TC2, FBXO32 and RBM20. CONCLUSION: These findings support the role of rare variants and nominate loci for follow-up studies.
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Authors: 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 Journal: PLoS One Date: 2019-06-26 Impact factor: 3.240