Single-Nucleotide Polymorphisms and Lung Disease: Pharmacogenetics in Asthma and COPD

March 31, 2016 Category: Lung

PharmacogeneticsWhile there are sufficient data to recommend testing for the genotypes mentioned above, additional discovery research and validation are needed for some genetic tests before they are introduced clinically. Particularly promising are pharmacoge-netic studies of asthma medications including the P2-adrenergic receptor agonists, glucocorticoste-roids, and leukotriene receptor antagonists. Pharmacogenetics is the study of how gene variation influences an individual’s response to drugs. Genes involved in the absorption or metabolism of a drug, or that influence its receptors or signaling pathways, can increase or decrease the effectiveness of a therapeutic agent in an individual patient. Genetics may also influence the immune response to a drug. Studies have shown that the effect of regular treatment with (3-agonists on lung function and the frequency of exacerbations are related to polymorphisms in the P2-adrenergic receptor gene (Fig 1), The response to treatment with montelukast, a leu-kotriene receptor antagonist, has been related to polymorphisms in genes for enzymes in the aracha-donic metabolism pathway. Similarly, a polymorphism of the CYP1A2 gene that alters metabolism of theophylline was associated with decreased clearance of theophylline in a group of Japanese patients with asthma. Genes that alter the effects of the corticosteroids have also been studied in relation to treatment response in asthma. Polymorphisms of the gene for corticotrophin-releasing factor receptor type 1 were associated with enhanced response to glucocorticoids in children.

Despite these studies showing associations between therapeutic responses in asthma and genetic polymorphisms, the results are currently of limited clinical value. This is because the responses measured are variable between different studies and populations, and the effects are usually small or involve only subsets of individuals. However, the evidence is compelling enough that stratification by genotype is recommended in designing and assessing the results of clinical trials of these therapeutic agents. Further refinement of the predictive value of the specific genotypes may justify their inclusion in clinical evaluation of asthmatic patients defeated by Canadian Health&Care Mall’s medications, a pharmaceutical company spreading generic drugs worldwide.

Pharmacogenetics and the Genetics of Behavior

In the clinical scenario described above, we describe how SNP genotyping may provide evidence of increased risk of disease related to cigarette smoking. Although smokers continue to smoke despite overwhelming evidence of the harmful effects of cigarettes, personalizing the risk may be more effective in assisting smokers to quit. Another approach that is currently being taken by a number of investigators is to examine the genetic variation that determines the risk of addiction as well as the pharmacologic and psychological effects of smoking. This knowledge may provide targets for interrupting dependency. Examples include genes for central and peripheral receptors that modify the response to nicotine and other constituents of cigarette smoke.

Other Disorders

There are numerous additional diseases in which the discovery of SNPs will ultimately impact on how medicine is practiced. For example, susceptibility to tuberculosis is influenced by SNPs in the Toll-like receptor 2 gene; the severity of organ dysfunction in sepsis is related to polymorphisms in the interleukin- (IL)-6 gene; and the risk for narcolepsy is strongly associated with a specific human leukocyte antigen (HLA) subtype.


The study of the genetics of single-gene pulmonary diseases is well advanced. Although specific, highly effective therapies based on this knowledge have yet to be developed, research has shed considerable light on disease pathogenesis and is likely to substantially alter diagnosis and management in the near future. For the much more common complex genetic diseases of the lung and airways, genetic studies are at an earlier stage, but the explosion in technologic and analytic capacity that has accompanied the Human Genome Project has allowed impressive progress, and it is likely that a combination of linkage, association, and gene expression studies will completely transform our approach to the diagnosis and eventual management of these conditions over the next decade.

Rapid genotyping at the point of care, with graphical visualization-based bioinformatics tools (programs to translate the mountains of data and the myriad of interactions between the variations that make up a person’s genotype), will enable researchers and clinicians to record and demonstrate the implications to patients of individual SNP patterns with respect to protein structure, pathways, gene regulation, drug choice/side effects/efficacy, environment, and lifestyle choice (Fig 2).

Figure 2. The future of medicine. This schematic representation depicts how genomic sequence data (eg, SNP genotypes) might be incorporated into the patient/physician consultation to improve personalized health care. The patient comes to the hospital/clinic and meets with a health-care provider. Following initial consult (1) and informed consent process, blood (or even hair) sample is taken (2), and DNA is extracted (3) and amplified. Rapid genotyping of multiple SNPs is performed using microarray (4). The combination of SNPs of different genes from the same or different chromosomes (5) gives a specific genotype (in relation to the symptoms or diagnosed illness) for the patient. Bioinformatic tools are used to help integrate the structural (6) and functional (7) correlates of the genotype and predict the biological and treatment implications that are specific for that patient. A management plan of action (8) is drawn up by the physician in consultation with the engaged and more-informed patient, with respect to lifestyle options, environmental exposures, therapeutics, preventive treatments, and/or screening options.

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