Polymerase Γ Gene POLG determines the risk of sodium valproate-induced liver toxicity
Stewart, Joanna D.; Horvath, Rita; Baruffini, Enrico; Ferrero, Iliana; Bulst, Stefanie; Watkins, Paul B.; Fontana, Robert John; Day, Christopher P.; Chinnery, Patrick F.
2010-11
Citation
Stewart, Joanna D.; Horvath, Rita; Baruffini, Enrico; Ferrero, Iliana; Bulst, Stefanie; Watkins, Paul B.; Fontana, Robert J.; Day, Christopher P.; Chinnery, Patrick F. (2010). "Polymerase Γ Gene POLG determines the risk of sodium valproate-induced liver toxicity P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science who also receives funding from the Medical Research Council (UK), the UK Parkinson's Disease Society, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust. Telethon-Italy Foundation (Grant No. GGP07019) to I.F. R.H. and S.B. are supported by the Deutsche Forschungsgemeinschaft HO 2505/2-1. The Muscle Tissue Culture Collection is part of the German network on muscular dystrophies (MD-NET, service structure S1, 01GM0601) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany). The Muscle Tissue Culture Collection is a partner of EuroBioBank ( www.eurobiobank.org ) and TREAT-NMD (EC, 6th FP, proposal 036825). R.H. is also supported by the Newcastle upon Tyne Hospitals NHS Charity (RES0211/7262) Potential conflict of interest: Nothing to report. ." Hepatology 52(5): 1791-1796. <http://hdl.handle.net/2027.42/78232>
Abstract
Sodium valproate (VPA) is widely used throughout the world to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy. VPA toxicity is an uncommon but potentially fatal cause of idiosyncratic liver injury. Rare mutations in POLG , which codes for the mitochondrial DNA polymerase Γ (polΓ), cause Alpers-Huttenlocher syndrome (AHS). AHS is a neurometabolic disorder associated with an increased risk of developing fatal VPA hepatotoxicity. We therefore set out to determine whether common genetic variants in POLG explain why some otherwise healthy individuals develop VPA hepatotoxicity. We carried out a prospective study of subjects enrolled in the Drug Induced Liver Injury Network (DILIN) from 2004 to 2008 through five US centers. POLG was sequenced and the functional consequences of VPA and novel POLG variants were evaluated in primary human cell lines and the yeast model system Saccharomyces cerevisiae . Heterozygous genetic variation in POLG was strongly associated with VPA-induced liver toxicity (odds ratio = 23.6, 95% confidence interval [CI] = 8.4-65.8, P = 5.1 × 10 −7 ). This was principally due to the p.Q1236H substitution which compromised polΓ function in yeast. Therapeutic doses of VPA inhibited human cellular proliferation and high doses caused nonapoptotic cell death, which was not mediated through mitochondrial DNA depletion, mutation, or a defect of fatty acid metabolism. Conclusion: These findings implicate impaired liver regeneration in VPA toxicity and show that prospective genetic testing of POLG will identify individuals at high risk of this potentially fatal consequence of treatment. (HEPATOLOGY 2010;52:1791-1796)Publisher
Wiley Subscription Services, Inc., A Wiley Company
ISSN
0270-9139 1527-3350
Other DOIs
PMID
21038416
Types
Article
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