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

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224 Applying Pharmacogenomics in TherapeuticsAPPLYING PHARMACOGENOMICS TO PULMONARY DISORDERSSimilar to other complex diseases, pharmacogenetic and pharmacogenomic studieson pulmonary diseases aim to implicate genetic variants responsible for interindividualresponses to drugs, with the ultimate goal of realizing personalized care ofpatients with pulmonary diseases. Given the strong associations of immune responsegenes with many pulmonary diseases, pharmacogenetic research in pulmonarydiseases has often been focused on these candidate genes. With the availability ofwhole-genome approaches, pharmacogenomic studies have also been carried outin a whole-genome, unbiased fashion. Specifically, several pulmonary disorders orsyndromes, specifically chronic obstructive pulmonary disease (COPD), asthma,and pulmonary artery hypertension (PAH), which have attracted abundant genetic,pharmacogenetic, and/or pharmacogenomic research efforts, are reviewed in the followingsections with an emphasis on clinical applications. Table 9.1 summarizes thegenetic and pharmacogenomic loci as reviewed for these pulmonary disorders.Chronic Obstructive Pulmonary DiseaseBrief BackgroundCOPD is characterized by the progressive development of airflow limitation that isnot fully reversible. 8 COPD is a heterogeneous disorder or syndrome with multipledisease subphenotypes, including two main conditions: emphysema and chronicbronchitis. 8 In emphysema, the walls between many air sacs in the lungs are damaged,resulting in narrowing of the small airways and breakdown of lung tissues. 9,10In contrast, in chronic bronchitis, the lining of the airways is constantly irritated andinflamed, thus worsening airflow obstruction by luminal obstruction of small airways,epithelial remodeling, and alteration of airway surface tension, predisposingto collapse. 11–13 The results of these damages cause progressive loss of lung function,TABLE 9.1Summary of Genes Associated with Pulmonary Diseasesand Pharmacogenomic LociDisorder COPD Asthma PHGenes associated with diseaserisk and pathogenesisTNF-α/TNF-β IL-33 BMPR2CHRNA3 TSLP ACVRL1FAM13A IL1RL1 SMAD1, SMAD4,SMAD9HHIP ORMDL3 BMPR1BRIN3CAV1MMP12KCNK3TGFB2TRPC6Pharmacogenomic loci ADRB2 ADRB2GSNORBMPR2ACVRL1Note: COPD, chronic obstructive pulmonary disease; PH, pulmonary hypertension.
Applying Pharmacogenomics in the Therapeutics of Pulmonary Diseases225leading to various symptoms such as coughing that produces large amounts ofmucus, wheezing, shortness of breath, and chest tightness among other symptoms. 14The prevalence of COPD is substantial with >300 millions of estimated patientsin 2010 worldwide. 15 Overall, the number of deaths from COPD has decreasedslightly from 3.1 million to 2.9 million between 1990 and 2010, 16 making it thefourth leading cause of death globally. 17 COPD is also a major cause of disabilityand the third leading cause of death in the United States. The total number of globalCOPD is expected to continually increasing, as the population continues to get older.The World Health Organization (WHO) predicts that COPD will become the thirdleading cause of death worldwide by 2030. 18Independently of other risk factors, regular cigarette smoking is the leading causeof COPD, accounting for approximately 80% of cases. 19 Most COPD cases are thosewho used to smoke or are current smokers. In multivariate analysis, cigarette smokers,as compared with nonsmokers, were at higher risk for developing COPD withdose–response effects. 19 Total deaths from COPD are projected to increase by morethan 30% in the next 10 years unless urgent actions are taken to reduce the underlyingrisk factors, especially tobacco use. 18 Long-term exposure to other lung irritantsin the environment, 20,21 such as indoor and outdoor air pollution, occupational dustsand chemicals (vapors, irritants, and fumes), and frequent lower respiratory infectionsduring childhood are also risk factors that contribute to the pathogenesis anddevelopment of COPD. In addition, genetic susceptibility of individuals could beused to explain why not all smokers would develop COPD. 22 For example, a smallproportion of COPD cases (about 1–5%) have been known to have α1-antitrypsindeficiency. 23,24 This risk is even higher if an individual who is α1-antitrypsin deficientalso smokes regularly. 23Therapy for COPDAlthough COPD cannot be cured completely, drug treatment for COPD and subsequentexacerbations of respiratory symptoms must be included in an effective strategyfor COPD management, in which the major therapeutic approaches include riskfactor reduction, such as smoking cessation and treatment with bronchodilators andcorticosteroid therapy. When selecting a treatment plan, the benefits and risks to theindividual and to the community must be taken into account. To date, none of theexisting medications for COPD have been shown to modify the long-term decline inlung function, which is the hallmark of this syndrome. Therefore, pharmacotherapyfor COPD is primarily meant to decrease symptoms and complications. In particular,bronchodilator medications, which include β-agonists, anticholinergics, theophylline,25–27 and a combination of one or more of these drugs, as well as glucocorticosteroids,28 are central to the symptomatic management of stable COPD and controlof exacerbations.BronchodilatorsBronchodilators help open the airways in the lungs by relaxing smooth muscle aroundthe airways. Bronchodilators can be classified as short or long acting. The short- actingbronchodilators, sometimes called “quick-reliever” can quickly decrease shortness ofbreath for about 4 to 6 hours. Common short-acting bronchodilators include β-agonists,
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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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Pharmacoeconomics of Pharmacogenomi
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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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