Article

Identifying genomic and developmental causes of adverse drug reactions in children

Children's Mercy Hospitals & Clinics, Division of Clinical Pharmacology, 2401 Gillham Road, Kansas City, MO 64110, USA.
Pharmacogenomics (Impact Factor: 3.43). 11/2010; 11(11):1591-602. DOI: 10.2217/pgs.10.146
Source: PubMed

ABSTRACT Adverse drug reactions are a concern for all clinicians who utilize medications to treat adults and children; however, the frequency of adult and pediatric adverse drug reactions is likely to be under-reported. In this age of genomics and personalized medicine, identifying genetic variation that results in differences in drug biotransformation and response has contributed to significant advances in the utilization of several commonly used medications in adults. In order to better understand the variability of drug response in children however, we must not only consider differences in genotype, but also variation in gene expression during growth and development, namely ontogeny. In this article, recommendations for systematically approaching pharmacogenomic studies in children are discussed, and several examples of studies that investigate the genomic and developmental contribution to adverse drug reactions in children are reviewed.

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Available from: J Steven Leeder, Sep 05, 2015
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    • "The highly polymorphic CYP2D6 gene is of particular pharmacogenetic interest owing to its implications for metabolism of a variety of drugs (Becker and Leeder, 2010). We detected a total of eight predicted G4s in this gene (Supplementary Table 1; Figure 1C) with one present 437 bp upstream from the transcriptional start site in the promoter region which could potentially influence transcriptional regulation. "
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    Frontiers in Pharmacology 07/2014; 5:160. DOI:10.3389/fphar.2014.00160 · 3.80 Impact Factor
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    • "Can understanding genetic regulation of response and disposition of drugs in children be used to improve drug safety by better understanding how adverse drug reactions develop, how these reactions can be modified or prevented and which children are at specific risk for adverse drug reactions? While all three approaches should and are being pursued, it is likely that the most immediately fruitful results will come from applying pharmacogenomics to enhancing drug safety (Becker and Leeder, 2010; Hawcutt et al., 2013; Stevens et al., 2013). "
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    ABSTRACT: Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children.
    Frontiers in Genetics 04/2014; 5:78. DOI:10.3389/fgene.2014.00078
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    ABSTRACT: Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P(trend) = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P(trend) = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.
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