February 10 2011
DTC Genomics tests, Using your results: Pediatric seizure medication safety/prevention example
A research article published in November shows that people who have the 'GT' genotype for the single-nucleotide polymorphism (SNP) in the mitochondrial polymerase gamma (POLG) gene have a 23-fold increase in liver toxicity. For those who have two copies 'TT', the risk is even higher. As such, these genotypes confer tremendous risk on about 12 percent of people of European/Caucasian descent, and somewhat smaller percentages of people of Asian or African descent.
This most-recent work is merely the latest and strongest evidence to-date. It confirms and strengthens evidence that has been accumulating in other independent studies published over the past few years (see links below).
• rs3087374 (POLG; 3708G>T; Q1236H) on Chr. 15
Your genotype at this SNP is ready and waiting for you to examine, in your raw file download from 23andme and other DTC genomics companies that use Illumina microarray chips. The DTC companies do not tell you anything about it, but the information is there for you or your child's doctor to use.
In other words, there is no real reason to go and get some expensive single-purpose DNA test when you already have the information among the 580,000+ results that you received already when you got your DTC genomics testing done--a tremendous 20-megabyte amount of actionable, multi-purpose information of life-long value for a very modest price.
Bear in mind that a 23-times increase in risk here is not "23-times-rare-equals-still-rare-and-negligible". It means greater than 50% chance of having severe and potentially life-threatening toxicity if placed on a valproic acid type seizure medication (Depakene, Depakote, Epival, Valcote, Convulex, Epilim, etc.).
The fact that a 50%+ chance of severe liver injury may arise with as many as 12% of people who are exposed to these drugs does not mean that they are bad medications. After all, severe, frequent seizures can be life-threatening in their own right, and it is essential to select a drug regimen that can effectively suppress seizure activity.
But it does mean that simple cheap DNA testing--including the DNA SNP variations that are provided in multi-purpose DTC chip tests--can yield major improvements in safety, by enabling pediatricians (pediatric neurologists) and parents to avoid exposures to needless risks and proceed directly to individualize the medication choices, selecting meds that do not carry those risks for this particular child, in view of her genomic information.
(Bear in mind, too, that POLG polymorphisms are important not only for pediatric seizures and their treatment, but also are important in Parkinson's Disease and chemotherapy-associated peripheral neuropathies in adults and other conditions.)
Douglas McNair, MD PhD, Senior VP, is one of three Cerner Engineering Fellows and is responsible for innovations in decision support and very-large-scale datamining. McNair joined Cerner in 1986, first as VP of Cerner's Knowledge Systems engineering department; then as VP of Regulatory Affairs; then as General Manager for Cerner's Detroit and Kansas City branches. Subsequently, he was Chief Research Officer, responsible for Cerner's clinical research operations. In 1987, McNair was co-inventor and co-developer of Discern Expert®, a decision-support engine that today is used in more than 2,000 health care facilities around the world. Between 1977 and 1986, McNair was a faculty member of Baylor College of Medicine in the Departments of Medicine and Pathology. He is a diplomate of the American Board of Pathology and the American Board of Internal Medicine.
Luoma P, et al. Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease. Neurol 2007;69:1152-9.
McFarland R. Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase ?. Arch Dis Child 2008;93;151-3.
Milone M, Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist. 2010;16:84-91.
Saneto R, et al. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders. Seizure. 2010;19:140-6.
Stewart J, et al. Polymerase ? gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010 Nov;52:1791-6. (download .pdf)