PHL 437/Pharmacogenomics First Lecture (Asthma I) By Abdelkader Ashour, Ph.D. Phone:

Pharmacogenomics, Introduction  Definition  Pharmacogenomics (PG) is a field of study that examines the relationship between genetic variability (or polymorphisms) and the response (both therapeutic and/or adverse) to therapeutic interventions  PG holds out the promise of allowing clinicians to prospectively choose therapies that have the greatest likelihood to be effective for individual patients and to avoid those which may have a high likelihood of producing adverse effects  PG also offers a new tool for discovering new targets for drug development  A polymorphism is a variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population  Two major types of sequence variation have been associated with variation in human phenotype: single nucleotide polymorphisms (SNPs) and insertions/deletions  Single base pair substitutions that are present at frequencies of 1% or greater in a population are termed SNPs  SNPs in the coding region are classified as nonsynonymous (or missense) if the base pair change results in an AA substitution, or synonymous (or sense) if the base pair substitution within a codon does not alter the encoded AA. Base pair substitutions that lead to a stop codon are termed nonsense mutations

Genes: DNA to RNA to Protein DNA Precursor RNA mRNA Protein Transcription Translation Splicing (35,000 genes in total) Intron

Anatomy of a Gene DNA  AAAAAAAAA RNA transcript mRNA PromoterExonsIntron Transcription Processing Coding Region Start

Asthma, Introduction  Asthma is a common disorder, accounting in the USA for 1-3% of all office visits, 500,000 hospital admissions per year, more pediatric hospital admissions than any other single illness, and more than 5000 deaths annually Asthma is the most common chronic disabling disease of childhood, but it affects all age groups  The clinical hallmarks of asthma are recurrent, episodic bouts of coughing, shortness of breath, chest tightness and wheezing In mild asthma, symptoms occur only occasionally, e.g., on exposure to allergens or certain pollutants, on exercise or after a viral upper respiratory infection More severe forms of asthma are associated with frequent attacks of wheezing dyspnea, especially at night and even chronic limitation of activity  It is physiologically characterized by increased responsiveness of the trachea and bronchi to various stimuli and by widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy

Asthma, Introduction, contd.  Asthma pathologic features include contraction of airway smooth muscle, mucosal thickening from edema (with abnormally thick, viscid plugs of mucus) and cellular infiltration (inflammatory cells; eosinophils, mast cells, macrophages and lymphocytes)  There is a strong correlation between increasing IgE levels and the prevalence of asthma  Airway inflammation is thought to be triggered by innate and/or adapted immune responses  Although there may be multiple "triggers" for an inflammatory response (such as mast cell secretion), there is general agreement that a lymphocyte-directed eosinophilic bronchitis is a hallmark of asthma  Lymphocytes that participate in asthma pathology are biased toward the T-helper type 2 phenotype, leading to increases in production of IL-4, IL-5, and IL-13  The chronic inflammatory response, over time, leads to epithelial shedding and reorganization, mucous hypersecretion, and airway wall remodeling (subepithelial fibrosis and smooth muscle hyperplasia)  The pharmacotherapy of asthma centers on controlling the disease with drugs that inhibit airway inflammation. Other drugs that relax bronchial smooth muscle are used for more immediate and direct relief of the symptoms of asthma

Drugs Used in Treatment of Asthma  There is a large amount of interindividual variability in both therapeutic and adverse responses to asthma therapies  Commonly, some patients respond to a given treatment, while others fail to respond  Genetic variability can account for 50% to 60% of this variability