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GATM gene variants and statin myopathy risk
M. Pirmohamed Arising from L. M. Mangravite et al. Nature502,377–380 (2013); doi:10.1038/nature12508Mangravite et al. identified six expression quantitative loci (eQTLs) that interacted with simvastatin exposure by using 480 lymphoblastoid cell lines exposed to β-hydroxy simvastatin acid in vitro. One of these SNPs (rs9806699) within the glycine amidinotransferase (GATM) gene was shown to have an association with statin-induced myopathy in two independent cohorts (n = 172 myopathy cases), conferring a protective effect (odds ratio = 0.61, 95% confidence interval = 0.39–0.95, P = 0.03). Our genotyping...
Source: Nature - September 17, 2014 Category: Research Authors: D. F. CarrA. AlfirevicR. JohnsonH. ChinoyT. van StaaM. Pirmohamed Tags: Brief Communication Arising Source Type: research

Mangravite et al. reply
M. Krauss Replying to D. F. Carr et al.Nature513, http://dx.doi.org/10.1038/nature13628 (2014); J. S. Floyd et al.Nature513, http://dx.doi.org/10.1038/nature13629 (2014)Our study tested for associations of single-nucleotide polymorphisms (SNPs) at the GATM loci with statin-induced myopathy based on the finding that one of these SNPs (rs986699) was associated with statin-induced expression of GATM in a panel of human lymphoblastoid cell lines, and the fact that GATM encodes the enzyme responsible for synthesis of creatine, a major source of energy in skeletal muscle. Significant associations with incidence of myopathy...
Source: Nature - September 17, 2014 Category: Research Authors: Lara M. MangraviteBarbara E. EngelhardtMatthew StephensRonald M. Krauss Tags: Brief Communication Arising Source Type: research

A statin-dependent QTL for GATM expression is associated with statin-induced myopathy
ker, Jemma C. Hopewell, Sarah Parish, Jane Armitage, Rory Collins, Russell A. Wilke, Deborah A. Nickerson, Matthew Stephens & Ronald M. Krauss Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on eith...
Source: Nature - August 28, 2013 Category: Research Authors: Lara M. MangraviteBarbara E. EngelhardtMarisa W. MedinaJoshua D. SmithChristopher D. BrownDaniel I. ChasmanBrigham H. MechamBryan HowieHeejung ShimDevesh NaidooQiPing FengMark J. RiederYii.-Der I. ChenJerome I. RotterPaul M. RidkerJemma C. HopewellSarah P Tags: Letter Source Type: research