Role of Pharmacogenetics in personalizing glucocorticoid treatment in Asthma- is it important to work in this direction, an opinion


Asthma is a chronic respiratory inflammatory disease that affects more than 300 million people in the world and imposes a huge burden on the society with respect to morbidity, mortality and the cost of health care system. Many different therapies are available for the treatment of asthma such as inhaled corticosteroids (ICS), ?2-adrenergic receptor agonists and anticholinergics, monoclonal antibodies. These therapies involve different biological pathways which include different types of genes with variations. In spite of these combination of therapies, a sub group of refractory asthmatic patient shows poor control of symptoms and also exacerbation (Ortega et al., 2015). Further, these therapies often show life threatening adverse events. Therefore, the variations in therapeutic benefits and adverse events provide a platform for developing the genetic profiling for the precision medicines and the pharmacogenetic Identification of genetic loci related to therapeutic responsiveness will help to develop the individualised medicine. Glucocorticoids are the most effective first line medication for asthma management (Tse et al., 2011) and it can be administered orally, through injections, and through inhalers in chronic therapy. Therapy with glucocorticoids shows substantial inter patient variation and may poses serious adverse events. It was noted that small portion of asthmatic patients treated with the ICS had a poor lung-function improvement. Studies have identified that the two corticotropin-releasing hormone gene (CRHR1) single nucleotide polymorphism (SNP) and three SNPs in heat shock organizing protein gene (STIP1) are associated with the response to lung function in ICS therapy (Tantisira et al., 2004, Hawkins et al., 2009). The glucocorticoid path way is also shown to interact with other pathway with different genes and thus effects the response of ICS when given alone or combining with a short-acting beta agonist (SABA) or a long-acting beta agonist (LABA). Enzyme Adenylyl cyclase type 9 of ?2-adrenergic receptor pathway encoded by gene ADCY9 (coding SNP, Met772Ile; reference sequence 2230739) is found to be associated with bronchodilation effect of balbuterol (SABA) in patients treated with ICS from the Childhood Asthma Management Program (CAMP) of Genome Wide Association Study (GWAS) (Tantisira et al., 2005). Further, genetic loci identified for the metabolism of ICS is also important for the therapeutic effectiveness. In a gene study of CYP3A5, CYP3A4, and CYP3A7 in asthmatic children, it was identified that the specific genotype of CYP4A4 had better control of asthma symptoms (Stockmann et al., 2013). In addition, association between the ICS treatment related changes in lung function and promoter SNP in the glucocorticoid-induced transcript-1 gene (GLCCI1, reference sequence 37972) is identified in GWAS in CAMP cohort (Tantisira et al., 2011). Although multiple genes are found to be associated to have influence on ISC responsiveness, however, a maximum of 6.6% variation in ICS effectiveness among the among the pharmacogenetic loci (GLCCI1) was noted. Therefore, identification of pharmacogenetic loci determining the responsiveness of ICS treatment would enhance the personalized approach. References: HAWKINS, G. A., LAZARUS, R., SMITH, R. S., TANTISIRA, K. G., MEYERS, D. A., PETERS, S. P., WEISS, S. T. & BLEECKER, E. R. 2009. The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. J Allergy Clin Immunol, 123, 1376-83.e7. ORTEGA, V. E., MEYERS, D. A. & BLEECKER, E. R. 2015. Asthma pharmacogenetics and the development of genetic profiles for personalized medicine. Pharmacogenomics and personalized medicine, 8, 9. STOCKMANN, C., FASSL, B., GAEDIGK, R., NKOY, F., UCHIDA, D. A., MONSON, S., REILLY, C. A., LEEDER, J. S., YOST, G. S. & WARD, R. M. 2013. Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control. J Pediatr, 162, 1222-7, 1227.e1-2. TANTISIRA, K. G., LAKE, S., SILVERMAN, E. S., PALMER, L. J., LAZARUS, R., SILVERMAN, E. K., LIGGETT, S. B., GELFAND, E. W., ROSENWASSER, L. J., RICHTER, B., ISRAEL, E., WECHSLER, M., GABRIEL, S., ALTSHULER, D., LANDER, E., DRAZEN, J. & WEISS, S. T. 2004. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet, 13, 1353-9. TANTISIRA, K. G., LASKY-SU, J., HARADA, M., MURPHY, A., LITONJUA, A. A., HIMES, B. E., LANGE, C., LAZARUS, R., SYLVIA, J. & KLANDERMAN, B. 2011. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. New England Journal of Medicine, 365, 1173-1183. TANTISIRA, K. G., SMALL, K. M., LITONJUA, A. A., WEISS, S. T. & LIGGETT, S. B. 2005. Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between ?-agonist and corticosteroid pathways. Human molecular genetics, 14, 1671-1677. TSE, S. M., TANTISIRA, K. & WEISS, S. T. 2011. The pharmacogenetics and pharmacogenomics of asthma therapy. The pharmacogenomics journal, 11, 383.

Posted On:26/09/2019




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