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

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226 Applying Pharmacogenomics in Therapeuticssuch as albuterol, levalbuterol, pirbuterol, and ipratropium. 29–31 In addition, albuteroland ipratropium 29 are a common combination of short-acting inhaled bronchodilatorsused in COPD patients. In contrast, the long-acting bronchodilators, such as salmeterol,formoterol, and arformoterol, 32–35 are characterized by a long maintenanceperiod of effective symptom improvement (24 hours). Therefore, these drugs are notused for acute shortness of breath.Anti-Inflammatory DrugsAnti-inflammatory drugs help reduce and prevent inflammation inside the airways.Commonly used inhaled corticosteroids include mometasone, fluticasone,budesonide, and beclomethasone, 36–40 in addition to corticosteroid pills such asprednisone and methylprednisolone. 41–43 Combinations of long-acting bronchodilatorsand corticosteroids, such as Advair ® (fluticasone and salmeterol), 36,44 are alsoused in some patients to prevent exacerbations of COPD.Genetics and Pharmacogenetics of COPDCOPD is a heterogeneous syndrome, possibly caused by the interactions of bothgenetic susceptibility and environmental factors. Although cigarette smoking is theprimary environmental risk factor for developing COPD, 19 only about 15% of smokersdevelop clinically significant COPD, suggesting that there are other factors andpotential genetic factors that contribute to the pathogenesis of COPD. 45 Genomicresearch on the genetic basis for COPD has identified the genes that are associatedwith COPD pathogenesis and heterogeneity by scanning variations in the genescoding protease/anti-protease systems. 46 For example, it is generally accepted thatCOPD is associated with an abnormal inflammatory response. 47 Therefore, manydifferent immune response mediators, such as TNF-α (tumor necrosis factor alpha)and TNF-β (tumor necrosis factor beta), have been implicated in the pathogenesisof COPD. 46,48,49 TNF-α mediated inflammation is thought to play a key role in therespiratory and systemic features of COPD. 46,50,51 An SNP in the promoter regionof the TNF-α gene directly affects the regulation of gene expression, and thus isan eQTL. This SNP has been shown to be associated with COPD phenotypes inAsian individuals, 52–54 but not in European individuals, 55,56 potentially explainingthe ethnic disparities of this disease. 57 More recently, a population-based GWAS hasidentified genetic risk loci for COPD, in which a susceptibility locus on chromosome19q13 was identified in a total of 3499 cases and 1922 control subjects from fourcohorts, 58 further extending previous GWAS findings in smaller cohorts. 59 Notably, arecent analysis of 6633 individuals with moderate-to-severe COPD and 5704 controlindividuals confirmed association at three known loci: CHRNA3 (encoding nicotinecholinergic receptor alpha 3), FAM13A (encoding family with sequence similarity13, member A), and HHIP (encoding hedgehog interacting protein), in addition tonovel loci near RIN3 (encoding Ras and Rab interactor 3) with significant evidenceof association, as well as MMP12 (encoding matrix metallopeptidase 12) and TGFB2(encoding transforming growth factor, beta 2). 60The goal of understanding the genetic defects in patients with COPD will be notonly to redefine the disease phenotypes based on the genetic information, but also toalternatively approach patients based on the understanding of COPD pathogenesis,
Applying Pharmacogenomics in the Therapeutics of Pulmonary Diseases227which may lead to improved clinical outcomes. To date, the majority of COPD pharmacogeneticand pharmacogenomic studies published have focused on immediatebronchodilator responsiveness (BDR) as a clinical outcome, given that short-actingβ-agonists, acting as bronchodilators to quickly relieve acute shortness of breath,are the most commonly prescribed drugs for COPD. 9,29–31 In a genome-wide linkageanalysis using short tandem repeat markers, regions on chromosomes 3 and 4have revealed some evidence for linkage to BDR, 61 suggesting that BDR is likely anactionable phenotype of COPD 62 that may identify responder subgroups to bronchodilatorswith different clinical outcomes.Specifically, most studies have focused on the roles of common genetic variantsin the ADRB2 gene (encoding β2-adrenergic receptor) on BDR, although the findingshave been inconclusive so far. 63 In a Japanese COPD cohort study, ADRB2polymorphism was demonstrated to be a determinant of preferential BDR to eitherβ2-agonists or anticholinergics in patients with COPD. 64 Furthermore, althougha significant correlation between BDR measures to salbutamol and to oxitropiumwas observed, there were individuals who responded preferentially to one of thetwo agents. 64 The genetic effects of ADRB2 polymorphisms may explain someof the variability in response to therapeutic doses of short-acting β2-agonists inpatients with COPD. 65 The present findings suggest that the ADBR2 gene haplotypesmay affect the severity of obstructive ventilatory impairment but not theimmediate response to salbutamol during acute exacerbations of COPD. 66 Yet inanother recent pharmacogenomic study, there was little evidence for the associationbetween ADRB2 variants and response to indacaterol (an ultra-long-actingβ2-agonist), 67 suggesting that ADRB2 genetic variation is unlikely to play a significantrole in differential response to indacaterol treatment in COPD patients. 68These inconclusive results highlight the difficulties in translating these findings toclinically relevant outcomes of COPD.AsthmaBrief BackgroundAsthma is a disorder that causes the airways of the lungs to swell and narrow(i.e., airway obstruction), leading to various phenotypes or groupings of clinicalcharacteristics. 69 Common symptoms of asthma are wheezing, shortness of breath,chest tightness, and coughing. 70 When an asthma attack occurs, the lining of theair passages swells and the muscles surrounding the airways become tight, causedby some combination of airway smooth muscle constriction and inflammation ofthe bronchi, 70 which reduces the amount of air that can pass through the airway.Previous studies indicate that inflammatory processes associated with type 2 helperT-cell (Th2) immunity are present in approximately half of the population withasthma. 71 In particular, cytokines, interleukin-4 (IL-4), and interleukin-13 (IL-13)that signal through two different but overlapping receptors have been implicated inasthma. 72–75An estimated 300 million people have asthma worldwide. 70 In the United States,asthma prevalence increased from 7.3% in 2001 to 8.4% in 2010, with 25.7 millionpersons suffering from asthma. 76 Children aged 0–17 years had higher asthma
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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