Pharmacogenetics and Asthma

Asthma has been called a syndrome rather than a disease because of the multiplicity of types that share a common collection of symptoms. Both genetics and environment play important roles in the development of asthma and it has long been understood that the timing of exposure to triggers such as pollen, mold and animal dander can produce either a protective or inducive effect.

Environment determines the phenotype, while genetics determines the genotype, of a patient. In the last decade, research has focussed on the genetics of asthma and the elusive asthma gene. It has turned out that there are over 60 genes involved in asthma, and that no single gene or its variant is solely responsible for (or associated with) asthma.

It was noted that morbidity and mortality related to asthma is greater among African-Americans and Puerto Ricans than Caucasians and Mexican-Americans, and that the difference could be explained by genetics.1 Twice as many African-Americans have nocturnal asthma than do any other ethnic groups.2 There is also a substantial variation, calculated to be as much as 60 - 80%, in response to treatment that is attributed to genetic factors.3.4. The response to medication ranges from so-called hyper-responsive patients to those who have negative responses (including anaphylactic or life-threatening responses) – i.e., patients whose asthma is worsened after they take specific medication.5

See Table 1.

Increase in peak flow after medication Patient classified as
more than 40% hyper-responder
between 15% and 40% good responder
between 5% and 15% moderate responder
no change non-responder
drop in peak flow negative responder

Table 1: Classification according to response to pharmacotherapy

The realization that in asthma there was marked heterogeneity in disease severity and response to therapy set researchers looking for genetic markers that would identify the different responders for the three major drug classes used in the treatment of asthma – bronchodilators, inhaled corticosteroids and leukotriene modifiers. This has led to a new field called pharmacogenetics, which studies the interaction of genes and the beneficial or adverse responses to pharmacologic therapies. 6, 7 The results of a genotypic study of patients in seven academic medical centres showed that patients with the genotype B16 Arg/Arg or B16 Gly/ Gly not only respond differently to albuterol, but also exhibit a different response to a methacholine challenge. Gly/Gly patients required 2.4 times the methacholine dose to decrease FEV1 (forced expiratory volume in one second) by 20%. A statistical comparison showed that the difference due to genotype was significant. 9 A study of Puerto Ricans and Mexicans showed that the Arg allele in Puerto Ricans produced a greater bronchodilator response to albuterol than in Mexicans. 10 A British study 11 of patients between the ages of 3 and 22 years showed that those who had the single Arg16 variant and used either albuterol (salbutamol) or salmeterol (a long-acting bronchodilator or LABA) on a daily basis had a 30% greater risk of exacerbations than those who did not have this variant. The risk increased to 70% for patients with two copies of the gene.

A Cochrane review of salmeterol analysed 26 clinical trials involving over 60,000 asthma patients, excluding any trials that involved inhaled corticosteroids (ICS). It found a statistically significant odds ratio (OR 9.52) for asthma-related deaths connected with salmeterol compared with albuterol or placebo. 12 The toxicity of LABAs is not understood though it is known that African-Americans are more likely to respond negatively than Caucasians.

The SMART study 13 (the Salmeterol Asthma Multicenter Research Trial) of 2005 found that when used as sole therapy, salmeterol could result in life-threatening exacerbations or death in a few individuals, particularly those of African-American descent. For this reason, the study was abruptly terminated. Hence the Food and Drug Administration requirement for a black box warning on all LABAs. Increased exacerbations were also found in a subset of non-Hispanic white and African Americans in a genetic study of patients prescribed LABAs. 14 Compared with other ethnic groups using LABAs, African-Americans were twice as likely to require increased use of short-acting beta-agonists, systemic corticosteroids, emergency visits or hospitalization with a prolonged diminution of peak expiratory flow. 15 The Long-Acting Beta Agonist Response by Genotype (LARGE) trial published in The Lancet 9 showed that when a LABA such as salmeterol is combined with an ICS, then, regardless of the genotypic variations in an individual's beta-2 adrenergic receptors, the individual will respond positively to combination therapy. But ICS do not completely mitigate the risk of exacerbations imposed by LABAs.

Leukotrienes (LT) are potent bronchoconstrictors, a thousand times more powerful than histamine. They mediate diverse features in both asthma and allergy.16 They are involved in inflammatory cell chemotaxis and intensely affect smooth muscle contraction. They are generated from the metabolism of arachidonic acid found in leukocytes. While their molecular regulation is not yet fully understood, they have been targeted by leukotriene inhibitors/modifiers/receptor antagonists (LTRA). LTRAs work by targeting the activity of cysteinyl leukotrienes and are used as adjunct treatment in the management of severe, persistent asthma. Two classes of LT modifiers are the LTRA (montelukast and zafirlukast) and the 5-lipoxygenase (5-LO) inhibitor (zileuton). It has been estimated that only 25% - 30% of individuals respond positively to montelukast.17 Genetics, in particular, determines the response to montelukast in patients with moderate, persistent, atopic asthma. 18, 19 The LT pathway is encoded in key proteins in at least six genes. Further, there are multiple loci within the many leukotriene pathway genes related to asthma severity and response to treatment. Studies have shown that genetic variation in activating proteins, binding proteins and LT receptors influence the response to LT modifiers. The researchers concluded that a variety of genes and novel variants influence the pharmacokinetics and the bioavailability of LTRAs. A study of 250 children with asthma found that an African-American heritagewas likely to have influenced both the severity of asthma and the response to LTRA therapy. 20 126 children, ages 6 to 17 years, were studied for their response to LTRAs and ICS. 21 Specifying response as a minimum 7.5% improvement in FEV1

  •     17% responded to both medications
  •     23% responded to the ICS only
  •     5% responded to the LTRA alone
  •     55% responded to neither LTRA or ICS

The BADGER (Best Add-on Therapy Giving Effective Response) pediatric trial found that Hispanics and Caucasians showed a therapeutic response (endpoints included less lung function decline, reduced exacerbations and more days without symptoms) to the addition of LABA to ICS while African-Americans did not.22

ICS are considered the gold standard of treatment for asthma. However, there is a small group of individuals who are steroid-resistant or refractory to any dose of ICS despite being on optimal prescribed therapy. These are the difficult-to-treat patients. ICS then are not free from genetic responses. There are fifteen genes that can predict the category of glucocorticoid response with an accuracy of 84%, and fourteen candidate genes were selected for study in adult and pediatric patients.8

A significant association was seen between corticotropin-releasing hormone receptor 1 (CRHR1) and the FEV1 response to ICS. Individuals with a variant of CRHR1 (a particular allele Rs242942) had 2.5 times the improvement in FEV1, but the CRHR1 variants in other adults taking ICS showed no protective association against a decline in lung function. The researchers concluded that additional factors come into play to determine the FEV1 response variability to ICS. A recent study involving pediatric asthma patients who had been prescribed ICS, found a specific CYP3A4 genotype in those with improved control of asthma symptoms, indicating that this genotype may be a biomarker for effective response to ICS.23

The goal of pharmacogenetics is to predict, using a genetic profile, which medications will work with individual patients, and which contribute to airway responsiveness, exacerbations and lung function. This will likely eliminate the current trial-and-error approach and result in a maximal therapeutic response with a minimum of side effects. While there is much more research that needs to be done before the goal of tailored, individualized or personalized medicine is achieved, where only specific beneficial therapies are prescribed, it may not provide the complete answer – after all, the role of the environment and the resulting phenotype is yet to be analysed and clarified. In the meantime, the asthma educator can ensure awareness of these individual genetic responses to medications by regularly asking patients about their response to therapy.

References

  1. Ortega VE, Meyers DA. Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. J Allergy Clin Immunol. 2014 Jan;133(1):16-26. doi: 10.1016/j.jaci.2013. 10.040.
  2. Levin AM, Wang Y, et al. Nocturnal asthma and the importance of race/ethnicity and genetic ancestry. Am J Respir Crit Care Med. 2014 Aug 1;190(3):266-73. doi: 10.1164/rccm.201402-0204OC.
  3. Drazen JM1, Silverman EK, Lee TH. Heterogeneity of therapeutic responses in asthma. Br Med Bull. 2000;56(4):1054-70.
  4. Lima JJ. Treatment heterogeneity in asthma: genetics of response to leukotriene modifiers. Mol Diagn Ther. 2007;11(2):97-104.
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  19. Lima JJ, Zhang S, et al. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med. 2006 Feb 15;173(4):379-85.
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  23. Stockmann C, Fassl B, Gaedigk R, et al. Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control. J Pediatr. 2013;162(6):1222. e1–1227. e2.