Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Applying Pharmacogenomics in the Therapeutics of Pulmonary Diseases
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to react to asthma triggers and cause serious asthma symptoms. The main types of
anti-inflammatory drugs for asthma control are steroids or corticosteroids. Other
anti-inflammatory drugs include mast cell stabilizers, leukotriene modifiers, and
immunomodulators. 88–90 Inhaled steroids for better asthma control include flunisolide,
mometasone, triamcinolone acetonide, fluticasone, budesonide, and beclomethasone.
91–94 There are also some combinations of a steroid and long-acting
bronchodilator, such as Advair (fluticasone and salmeterol), Dulera ® (mometasone
and formoterol), and Symbicort ® (budesonide and formoterol). 44,95,96
Genetics and Pharmacogenetics of Asthma
Genetics is believed to partially contribute to the risk of asthma. Notably, recent
advances in genotyping technology have allowed GWAS and meta-analyses of
GWAS on asthma, which have begun to shed light on both common and distinct
pathways that contribute to asthma. 97 For example, associations with genetic
variants in IL-33 (encoding interleukin-33), 98 TSLP (encoding thymic stromal
lymphopoietin), 99,100 and IL1RL1 (encoding interleukin 1 receptor-like 1) 101 highlight
a central role of the innate immune response pathways that promote the activation
and differentiation of T-helper 2 cells in the pathogenesis of both asthma
and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding
the ORMDL3 (encoding ORM1-like 3), is specifically associated with risk for the
onset of asthma in childhood. 102,103
Despite the availability of several classes of asthma drugs and their overall
effectiveness, a significant portion of patients fail to respond to these therapeutic
agents. Evidence suggests that genetic factors may partly mediate the heterogeneity
in asthma treatment response. 104,105 The responses to treatments such as β2-agonists,
leukotriene modifiers, and inhaled corticosteroids have demonstrated substantial
interindividual variability. 105 Although many studies are limited by small sample
sizes and results remain to be confirmed in larger replication cohorts, several candidate
genes have been identified to be associated with variable response to common
asthma drugs. 106 High-throughput technologies are also allowing for large-scale
genetic investigations. Thus, the future is promising for a personalized treatment of
asthma, which will improve therapeutic outcomes, minimize side effects, and lead
to more cost-effective care. Some major pharmacogenomic findings in the context of
asthma are summarized.
Similar to what has been found in COPD, genetic variants in ADRB2 were
observed to be associated with the variability in response to β2-agonists in patients
with asthma. In a meta-analysis examining the association between ADRB2 polymorphisms
and the response to inhaled β2-adrenergic agonists in children with
asthma, a significant association was made between favorable therapeutic response
in asthmatic children and the Arg/Arg genotype at position 16 of the ADRB2 gene,
compared with the genotype Arg/Gly or Gly/Gly. 107 Therefore, clinical genotyping
for ADRB2 polymorphisms may help determine whether asthmatic children are drug
resistant to β2-adrenergic agonists. In contrast, in another cohort of pediatric asthmatics,
children whose genotypes were homozygous for ADRB2 Gly16Gly had a
more rapid response to β2-agonist treatment. 108 However, the effect of the ADRB2
Arg16Gly polymorphisms appeared to be drug specific, with apparently no effect for