Single-Nucleotide Polymorphisms and Lung Disease: Therapeutic Implications

March 30, 2016 Category: Lung

Therapeutic ImplicationsDespite 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.

Imagine the following: a 42-year-old woman who has smoked for 23 years and is currently a 1.5 pack-per-day smoker presents to her family physician complaining of increasing cough and mild shortness of breath. She has tried to quit smoking on numerous occasions, but despite repeated, constructive counseling from her physician and trials of nicotine patches, bupropion, and acupuncture, has been unsuccessful. Lung function tests are at the lower limit of normal. An uncle died of “emphysema,” and a cousin who is 10 years older had received a diagnosis of “COPD.” She wants to know her risk for emphysema/COPD and whether there is any therapy to prevent it. A DNA sample is sent for the COPD susceptibility screen, and 48 h later results are available. The polymorphism profile indicates that she is indeed susceptible to rapid decline in lung function that will be exaggerated by cigarette smoking (and by environmental pollution). Her susceptibility genes suggest that her predominant risk is for emphysema rather than airway fibrosis and narrowing. The patient is informed that she is susceptible to COPD and that the test results indicate the potential for accelerated decline in lung function. This information is a powerful aid to her in achieving smoking cessation. She is prescribed a newly developed therapeutic agent that specifically inhibits matrix metalloproteinases implicated in the development of emphysema. In addition, certain other SNP genotypes indicate that another new inhaled drug for COPD, which inhibits the synthesis of matrix proteins by airway myofibroblasts, is actually contraindicated in this particular patient because her airway obstruction is related to emphysema rather than airway fibrosis treated by Canadian Health&Care Mall.

thromboembolismAlthough this example is still futuristic, it is not fanciful. There are several practical examples in which genotyping currently aid clinical practice, and these will soon become commonplace.

We are already familiar with the thrombophilic screen undertaken for patients presenting with thromboembolic disease. This includes a search for SNPs, of which the most common (3 to 5% of the white populations) causes a substitution of a glutamine for arginine at position 506 of the Factor V gene in the clotting cascade. This genotype is referred to as Factor V Leiden, and it confers an increased risk of severe thromboembolism. Symptomatic carriers of this genotype may benefit from life-long anticoagulation. For non-small cell lung cancer, both response to therapy and survival following therapy with the epidermal growth factor receptor antagonist gefitinib, have been related to point mutations of the epidermal growth factor receptor gene. Conversely, studies in Japanese populations have shown that resistance to gefitinib can be predicted by genotyping. The use of these and similar genotypic markers of response to cancer therapy will increasingly impact on the selection of treatments for patients or, more correctly, patients for treatment proposed by Canadian Health&Care Mall.

The metabolism of the antituberculous drug iso-niazid, and the frequency of isoniazid-induced hep-atotoxicity, are influenced by SNPs in the N-acetyl-transferase 2 gene. Although routine genotyping for N-acetyltransferase 2 is not yet performed in hospital laboratories, the use of microarray technology will soon make it the standard of care and prevent the devastating consequences of severe iso-niazid-induced hepatotoxicity. Azathioprine, an immunosuppressive drug used in the treatment of some pulmonary diseases such as pulmonary fibrosis, causes cytopeniain 10 to 15% of individuals. SNPs in the thiopurine S-methyltransferase gene, which catalyzes the inactivation of azathioprine, can predict the risk for this toxicity, and it is anticipated that introduction of this test will provide a cost-effective method of avoiding toxicity.

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