Linked Life Data

21038416

Source:http://linkedlifedata.com/resource/pubmed/id/21038416

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-11-1
pubmed:abstractText
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 ? (pol?), 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??). This was principally due to the p.Q1236H substitution which compromised pol? 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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1527-3350
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
52
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1791-6
pubmed:meshHeading
pubmed-meshheading:21038416-Adolescent, pubmed-meshheading:21038416-Adult, pubmed-meshheading:21038416-Amino Acid Substitution, pubmed-meshheading:21038416-Bipolar Disorder, pubmed-meshheading:21038416-Child, pubmed-meshheading:21038416-Child, Preschool, pubmed-meshheading:21038416-DNA-Directed DNA Polymerase, pubmed-meshheading:21038416-Diffuse Cerebral Sclerosis of Schilder, pubmed-meshheading:21038416-GABA Agents, pubmed-meshheading:21038416-Genetic Variation, pubmed-meshheading:21038416-Headache, pubmed-meshheading:21038416-Hepatocytes, pubmed-meshheading:21038416-Humans, pubmed-meshheading:21038416-Liver, pubmed-meshheading:21038416-Middle Aged, pubmed-meshheading:21038416-Polymorphism, Single Nucleotide, pubmed-meshheading:21038416-Risk Assessment, pubmed-meshheading:21038416-Seizures, pubmed-meshheading:21038416-Valproic Acid, pubmed-meshheading:21038416-Young Adult
pubmed:year
2010
pubmed:articleTitle
Polymerase ? gene POLG determines the risk of sodium valproate-induced liver toxicity.
pubmed:affiliation
Mitochondrial Research Group, Institute of Human Genetics, Newcastle University, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural