While 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 encouraging results, the predictive value of these SNPs for the development of asthma is yet to be tested prospectively in a general population sample. However, the exponential expansion of our information and knowledge of SNPs and their effects, coupled with advances in microarray technology, has positioned us on the brink of a very different approach to clinical medicine: the routine assessment of an individual’s SNP profile in clinical decision making. Although much work remains, the prospect of real-time clinical genotyping for selected conditions is on us!
The potential clinical benefits of genotyping are several fold: early detection of disease; predicting prognosis; selecting the most appropriate therapy; estimating risk to allow more appropriate environmental modification; predicting adverse events; and discovering novel biological mechanisms. The challenges are also numerous, and include the following: costs; issues of fatalism/invincibility; protection of privacy; education of the public and their health-care providers; and the biological uncertainty associated with the modest risks imparted by a particular genotype.
An important aspect of the Human Genome Project was the massive governmental and industry-sponsored effort to develop a dense set of SNP markers throughout the human genome. This effort was spurred on by the realization that a dense set of SNP markers could yield critical information to determine specific functional SNPs and combinations of SNPs that form the genetic basis of complex diseases. The SNP Consortium and the International HapMap Project (http://www.hapmap.org), as well as research conducted by individual laboratories throughout the world, have generated enormous SNP-based resources to allow biologists to better investigate complex genetic diseases.
Determination of the base sequence of DNA at a specific SNP site is called genotyping. For research discovery purposes, there are a number of high through-put technologies available to optimize the genotyping of large numbers of individuals for one SNP at a time. Genotyping by microarray allows the opposite approach—the simultaneous determination of multiple SNPs from an individual—and it is this strategy that promises to influence the practice of medicine. Microarrays allow the fixation of hundreds or thousands of specific oligonucleotide probes in a precise configuration or array onto a small-format solid support, such as a microscope slide, where they can be identified.
We are all the same! We are all different! Any two humans are approximately 99.9% identical at the DNA sequence level, yet substantial, often medically relevant phenotypic differences exist between individuals. A significant proportion of these phenotypic differences are caused by this relatively small amount of genetic variation interacting with environmental factors. A clinically important element of phenotypic variation relates to susceptibility to disease and response to therapy. In this review, we examine the potential for using the assessment of genetic variation, by genotyping, for risk prediction and individualized therapy in pulmonary disorders. To date, the revolution in molecular genetics has had a relatively minor influence on the practice of respiratory medicine. Examples where it has influenced practice include the following: (1) genotyping for a single-nucleotide polymorphism (SNP) in the gene encoding Factor V Leiden that increases risk for serious thromboembolic disease; (2) genotyping for mutations associated with cystic fibrosis (CF) for diagnosis and genetic counseling2; and (3) genotyping non-small cell carcinomas to predict response to chemotherapy. Genotyping has had a greater impact on the identification of respiratory pathogens, offering exquisite sensitivity and the potential for rapid diagnosis and determination of virulence and drug resistance; however, this subject is beyond the scope of the present review.