A Genome-wide Association Study of Circulating Levels of Atorvastatin and Its Major Metabolites.

Clinical Pharmacology and Therapeutics
Richard M TurnerMunir Pirmohamed

Abstract

Atorvastatin (ATV) is frequently prescribed and generally well  tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L), and 2-OH ATV L was performed in 590 patients who had been hospitalized with a non-ST elevation acute coronary syndrome 1 month earlier and were on high-dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2-OH ATV/ATV (P = 7.25 × 10-16 ) and 2-OH ATV L/ATV L (P = 3.95 × 10-15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (P = 6.18 × 10-7 ), and SLCO1B1 rs4149056 with increased ATV (P = 2.21 × 10-6 ) and 2-OH ATV (P = 1.09 × 10-6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (n = 149), all of these associations remained, except for 2-OH ATV and rs4149056 (P = 0.057). Clinically, rs4149056 was associated with increased muscular symptoms (odds ratio (OR) 3.97; 95% confidence interval (CI) 1.29-12.27; P = 0.016) and ATV intolerance (OR 1.55; 95% CI 1.09-2.1...Continue Reading

References

Apr 10, 2002·The Journal of Biological Chemistry·Oliver BurkLeszek Wojnowski
Apr 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Thomayant PrueksaritanontThomas A Baillie
Jul 26, 2005·Pharmacogenetics and Genomics·Sarah C SimMagnus Ingelman-Sundberg
Nov 17, 2006·Pharmacogenetics and Genomics·Marja K PasanenMikko Niemi
May 3, 2007·Clinical Pharmacology and Therapeutics·M K PasanenM Niemi
Feb 26, 2008·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Ine Blankenberg SkottheimAnders Asberg
May 29, 2009·Clinical Pharmacology and Therapeutics·J E KeskitaloM Niemi
Oct 2, 2009·Clinical Pharmacology and Therapeutics·S RiedmaierU M Zanger
Jun 3, 2010·Nature Reviews. Genetics·Jonathan Marchini, Bryan Howie
Jul 17, 2010·Bioinformatics·Randall J PruimCristen J Willer
Sep 3, 2010·Nature·UNKNOWN International HapMap 3 ConsortiumJean E McEwen
Feb 12, 2011·Annals of Human Genetics·Laura J HorsfallDallas M Swallow
Aug 20, 2011·Frontiers in Pharmacology·Stephan RiedmaierUlrich M Zanger
Dec 6, 2011·Nature Methods·Olivier DelaneauJean-François Zagury
Apr 19, 2012·Clinical Pharmacology and Therapeutics·Kathrin KleinUlrich M Zanger
May 5, 2012·Pharmacogenetics and Genomics·Sung Kweon ChoJae Yong Chung
Apr 13, 2013·Molecular Diagnosis & Therapy·Camilla StormoMarianne K Kringen
May 30, 2013·Nature Genetics·UNKNOWN GTEx Consortium
Jul 24, 2013·Circulation. Cardiovascular Genetics·Marianne K DeGorterRichard B Kim
Aug 27, 2013·European Journal of Clinical Pharmacology·Leena ChoiBrian S Caffo
Jun 5, 2014·Clinical Pharmacology and Therapeutics·A AlfirevicM Pirmohamed
Nov 5, 2014·British Journal of Clinical Pharmacology·Mary A De VeraDiane Lacaille
May 28, 2015·European Journal of Human Genetics : EJHG·Katherine S RuthJohn R B Perry
Sep 29, 2015·Molecular Pharmaceutics·Tom J J SchirrisFrans G M Russel
Sep 30, 2015·Clinical Pharmacology and Therapeutics·R S GammalUNKNOWN Clinical Pharmacogenetics Implementation Consortium
Jun 9, 2016·Genome Biology·William McLarenFiona Cunningham

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Citations

Feb 3, 2021·Cardiovascular Drugs and Therapy·E F MagavernM Pirmohamed
Feb 11, 2021·Personalized Medicine·Brian TomlinsonChristopher Wk Lam
Nov 17, 2020·Frontiers in Genetics·Ping Siu KeeSimran D S Maggo
Nov 18, 2020·Genes·Victoria RollinsonMunir Pirmohamed
May 7, 2021·Nature Reviews. Cardiology·Julio D Duarte, Larisa H Cavallari

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