Clinical Pharmacogenetics in Pediatric Patients

Anwar Husain; Jennifer A. Loehle; David W. Hein


Pharmacogenomics. 2007;8(10):1403-1411. 

In This Article


Asthma is the most common chronic disorder in children and adolescents, the leading cause of hospitalizations in children aged under 15 years, and the leading cause of school absences. Early intervention and continuous therapy for pediatric patients have been speculated to alter the course of the disease. Although most people with asthma will gain some benefit from various treatment modalities, there is a wide spectrum of response to each of these agents. Adverse drug reactions remain a serious problem, with failed efficacy and safety concerns being observed with three (bronchodilating β-agonist therapy, anti-inflammatory inhaled corticosteroids, and leukotriene modifiers) major treatment modalities.[30,31,32]

Inhaled glucocorticoids are currently the preference for long-term control of moderate and severe persistent asthma, despite the observed variation in response to such steroid therapy. Children as a patient group are at greater risk for adverse effects from long-term steroid therapy, further complicating decisions of the best course of treatment for asthmatic children.[33] Other drugs commonly used in treating asthma include inhaled β2 agonists such as albuterol, which act by stimulating the β2 adrenergic receptor (B2AR) and leukotriene (LT) modifiers such as montelukast, which acts as a potent, selective LT antagonist. Polymorphisms have been identified within the molecular proteins and enzymes involved in the pathways by which such drugs bring about their effects that may influence interindividual variation in patient response.

B2AR agonists are currently the most widely used drugs in the treatment of asthma. The exact genetic determinants of the variation in response to these drugs have yet to be fully characterized. Martinez et al. looked at the association between common polymorphisms in the B2AR gene and response to albuterol therapy in children with asthma, and reported that patients homozygous for the 46 G>A (R16) were 5.3-times, and heterozygotes 2.3-times, more likely to respond to albuterol than patients homozygous for the G16 allele.[34] Consistent with these results, Lima et al. demonstrated a significantly greater response to albuterol in individuals homozygous for the R16 allele versus either heterozygous individuals or individuals homozygous for the G16 allele.[35] The R16 allele has also been linked with apparent increased tachyplaxis as indicated by a decline in peak expiratory flow with regular use of albuterol.[36] A prospective study demonstrated that R16 homozygotes had improved peak expiratory flow when withdrawn from as needed β-agonist use with albuterol, while G16 patients had an improvement in peak flow when they were treated with regular albuterol.[37] Further understanding of the mechanisms for these associations, as well as prospective replication with long-acting β-agonists, is needed.[38] Although this SNP may be a sufficient marker of poorer response to therapy, it is possible that it is only in linkage disequilibrium with another polymorphism or that an even greater degree of prediction might be obtained by examining associations linked to collections of SNPs, or haplotypes. One of the most common haplotypes containing 46G>A (G16R) was associated with a decreased response to β-agonists.[39]

Corticosteroids have multiple beneficial effects in patients with asthma through a potent anti-inflammatory response. However, the drugs are known to have multiple adverse effects, especially in children, related to adrenal suppression, decreased growth velocity and decreased bone density. More than any other asthma therapy, inhaled corticosteroids stand to benefit the most from pharmacogenetic research in terms of reducing adverse effects while maximizing therapeutic response. Tantisira et al. suggested a relationship between the response to inhaled corticosteroids and a polymorphism of the corticotrophin-releasing hormone receptor 1 (CRHR1), a gene possibly involved in modulation of endogenous glucorticoid production and enhancing allergen-induced airway inflammation and lung mechanical dysfunction.[40] Another gene that has been associated with inhaled corticosteroid responsiveness is TBX21, which encodes for the transcription factor T-bet (T-box expressed in T cells), responsible for the induction of Th1 cells and the repression of Th2 cells from naive T lymphocytes. Tantisira and colleagues tested the effect of the TBX21 variant on the efficacy of long-term inhaled corticosteroid therapy.[41] They demonstrated a significant interaction between the H33Q SNP (rs2240017) and inhaled corticosteroid use resulting in improvement of airway responsiveness to nonasthmatic levels.

The third and most recently developed therapeutic arm for asthma is the leukotriene modifiers. These are recommended as an alternative to low-dose inhaled corticosteroids for patients with mild-persistent asthma and as an alternative add-on therapy to corticosteroid treatment in patients with moderate and severe persistent asthma. LT antagonist therapy has been shown to bring about increased forced expiratory volume in 1 second (FEV1) and peak flow, reduced bronchial hyper-responsiveness and inflammatory markers, reduced asthma exacerbation rates, and has permitted the reduction of inhaled corticosteroids in some patients.[42]

Response to LT antagonists and modifiers varies among individuals, prompting pharmacogenetic research into the basis of such variation. Polymorphisms in candidate genes in the LT biosynthesis and activity pathways have been analyzed for possible association with observed therapeutic phenotypes. Polymorphisms in the 5-lipoxygenase (-LO) promoter gene and in the LT C4 synthase (LTC4S) gene, as well as the LT A4 hydrolase (LTA4) and multidrug resistance protein 1 (MRP1), have been studied and determined to play important roles in the response to LT modifier therapy. 5-LO is the first committed step in the pathway to synthesize LTs. Polymorphisms in the region of nucleotide repeats located upsteam of the coding region have been shown to reduce the efficiency of gene transcription. The possible association of the arachidonate 5-lipoxygenase (ALOX5) variable number tandem repeat (VNTR) polymorphism with the response to ABT-761, a zileutron-like ALOX5 inhibitor, was examined in 114 patients taking high-dose ABT-761 versus 107 patients receiving placebo.[43] Patients homozygous for the major allele or heterozygous for one of the minor variant alleles demonstrated an approximate 20% change in FEV1 at the end of the treatment period. By contrast, ten patients homozygous for the minor allele did not benefit from ABT-761 therapy, similar to that observed with patients receiving placebo.

Lima and colleagues examined possible associations between multiple genetic variants within several leukotriene pathway candidate genes and interpatient variability in montelukast response[44] Associations were found between individual SNPs in the ALOX5 and MRP1 genes and changes in FEV1. Individuals with the variant LTC4S -444A>C promoter polymorphisms had a 73 or 80% reduced risk, respectively, for asthma exacerbations compared with individuals homozygous for the reference genotype. By contrast, individuals heterozygous or homozygous for a single LTA4 SNP had a fourfold increased risk for asthma exacerbation. The association observed with the LTC4S-444A>C variant is consistent with some studies[45,46,47] but not others.[48,49]


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