Pharmacogenomics of pediatric asthma

Abstract

CONTEXT:Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below.EVIDENCE ACQUISITION:A search of PubMed, Google scholar, E-Medicine, BMJ and Mbase was done using the key words “pharmacogenomics of asthma”, “pharmacogenomics of β-agonist, glucocorticoids, leukotriene modifiers, theophylline, muscarinic antagonists in asthma”.RESULTS:Presently, there are limited examples of gene polymorphism that can influence response to asthma therapy. Polymorphisms that alter response to asthma therapy include Arg16Gly, Gln27Glu, Thr164Ile for β-agonist receptor, polymorphism of glucocorticoid receptor gene, CRHR1 variants and polymorphism of LTC4S, ALOX5. Polymorphic variants of muscarinic receptors, PDE4 and CYP450 gene variants.CONCLUSION:It was concluded that genetic variation can improve the response to asthma therapy. However, no gene polymorphism has been associated with consistent results in different populations. Therefore, asthma pharmacogenomic studies in different populations with a large number of subjects are required to make possible tailoring the asthma therapy according to the genetic characteristic of individual patient.

Pharmacogenomic of asthma in children

“…Other gene variants associated with airway inflammation via the nitric oxide pathway have also been associated with BDR. 22 β2-Agonists work by binding to receptors ADRβ2, which are G-proteincoupled receptors on the cell surface. The ARβ2 contains several polymorphisms, including Arg16Gly and Gln27Glu, which are functionally relevant.…”

Variability in Laboratory Immune Parameters Is Associated with Stress Hormone Receptor Polymorphisms

“…SNP of both Gly16Arg and Gln27Glu are associated with asthma risk as well as response to therapy [19,20]. Polymorphisms in Gln27Glu have also been associated with the severity of existing cardiovascular disease [21].…”

Clinically Relevant Pharmacogenomic Testing in Pediatric Practice

“…15 Locus B16 of the gene encoding the beta2 receptor is a significant SNP locus; patients with arginine at this locus are more likely to respond and respond more quickly to beta-agonists than do those with glycine at the locus. 3,16 About one sixth of Caucasians and one fifth of African Americans are homozygous for arginine at B16. 15 …”

“…3 Individuals with increased leukotriene C4 synthase activity have a stronger response to pharmacologic modification of the leukotriene pathway. 5 Carrying even a single variant allele results in a decreased response to treatment with a leukotriene modifiers 16 ; however, carriers of the variant allele are also at a decreased risk for asthma exacerbations (homozygous CC individuals have a 73% to 80% reduced risk for acute asthma exacerbations). 3 …”

“…15 However, nearly a third of children taking inhaled corticosteroids do not experience objective improvement of their asthma-related airway reactivity, and corticosteroids can be associated with serious adverse effects in children. 16 The corticotrophin-releasing hormone receptor 1 (CRHR1) has been extensively studied for genetic polymorphisms that may influence response to corticosteroids. Many variants in CRHR1 have demonstrated associations with corticosteroid efficacy, but a robust biomarker is yet to emerge.…”