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Effect of CYP3A5*3 on asthma control among children treated with inhaled beclomethasone

2015; Elsevier BV; Volume: 136; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2015.02.009

1097-6825

Chris Stockmann, Christopher A. Reilly, Bernhard Fassl, Roger Gaedigk, Flory L. Nkoy, Bryan L. Stone, Jessica K. Roberts, Derek A. Uchida, J. Steven Leeder, Catherine M.T. Sherwin, Michael G. Spigarelli, Garold S. Yost, Robert M. Ward,

Pharmaceutical studies and practices

Inhaled glucocorticoids are a primary therapy for controlling persistent asthma symptoms.1Tantisira K.G. Lasky-Su J. Harada M. Murphy A. Litonjua A.A. Himes B.E. et al.Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma.N Engl J Med. 2011; 365: 1173-1183Crossref PubMed Scopus (299) Google Scholar However, approximately 30% of patients continue to experience poor symptom control.2Szefler S.J. Phillips B.R. Martinez F.D. Chinchilli V.M. Lemanske R.F. Strunk R.C. et al.Characterization of within-subject responses to fluticasone and montelukast in childhood asthma.J Allergy Clin Immunol. 2005; 115: 233-242Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar Criteria to identify patients who might respond more favorably to a specific inhaled glucocorticoid could be beneficial.3Drazen J.M. A step toward personalized asthma treatment.N Engl J Med. 2011; 365: 1245-1246Crossref PubMed Scopus (14) Google Scholar We previously identified a genetic variant in the cytochrome P450 3A4 enzyme (CYP3A4*22) that was associated with improved asthma control among children treated with inhaled fluticasone.4Stockmann C. Fassl B. Gaedigk R. Nkoy F. Uchida D.A. Monson S. et al.Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.J Pediatr. 2013; 162 (1227.e1-2): 1222-1227Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Patients with the CYP3A4*22 allele have been reported to feature 1.6- to 6.3-fold lower CYP3A4 mRNA expression and enzyme activity in the liver.5Wang D. Guo Y. Wrighton S.A. Cooke G.E. Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs.Pharmacogenomics J. 2011; 11: 274-286Crossref PubMed Scopus (381) Google Scholar Fluticasone is efficiently metabolized by CYP3A4 and is a potent mechanism-based inhibitor of CYP3A5 and to a lesser extent CYP3A4.4Stockmann C. Fassl B. Gaedigk R. Nkoy F. Uchida D.A. Monson S. et al.Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.J Pediatr. 2013; 162 (1227.e1-2): 1222-1227Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar It was hypothesized that decreased levels of CYP3A4 combined with inhibition of CYP3A5 by fluticasone may extend the half-life of fluticasone within lung cells and in the systemic circulation, thereby increasing its therapeutic effectiveness. We speculated that similar processes may occur for other inhaled glucocorticoids.4Stockmann C. Fassl B. Gaedigk R. Nkoy F. Uchida D.A. Monson S. et al.Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.J Pediatr. 2013; 162 (1227.e1-2): 1222-1227Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Beclomethasone is a commonly prescribed inhaled glucocorticoid that features potent anti-inflammatory effects and effectively reduces bronchial hyperresponsiveness.6Roberts J.K. Moore C.D. Ward R.M. Yost G.S. Reilly C.A. Metabolism of beclomethasone dipropionate by cytochrome P450 3A enzymes.J Pharmacol Exp Ther. 2013; 345: 308-316Crossref PubMed Scopus (29) Google Scholar In this study, a convenience sample of beclomethasone-treated children aged 2 to 17 years with a physician-confirmed diagnosis of asthma were recruited at Primary Children's Hospital (Salt Lake City, Utah). Details of the study design and genotyping have been described previously.4Stockmann C. Fassl B. Gaedigk R. Nkoy F. Uchida D.A. Monson S. et al.Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.J Pediatr. 2013; 162 (1227.e1-2): 1222-1227Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Briefly, saliva samples were collected and tested for 9 single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and CYP3A7. Demographic and clinical data were obtained through patient and/or parent survey and medical record abstraction. Asthma control was assessed using a questionnaire modified from the National Heart, Lung, and Blood Institute.4Stockmann C. Fassl B. Gaedigk R. Nkoy F. Uchida D.A. Monson S. et al.Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.J Pediatr. 2013; 162 (1227.e1-2): 1222-1227Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 7National Asthma Education and Prevention ProgramExpert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007.J Allergy Clin Immunol. 2007; 120: S94-S138Abstract Full Text Full Text PDF PubMed Google Scholar Asthma control scores were analyzed as a numeric variable that ranged from 0 (well controlled) to 15 (poorly controlled). Logistic regression models were developed in R 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria) to assess the effect of CYP3A polymorphisms on asthma control with inhaled beclomethasone. The Bonferroni correction was applied to adjust for 3 pairwise group comparisons (3 SNPs) for each CYP3A enzyme. The daily dose of beclomethasone dipropionate (μg/d) was evaluated as a covariate in the regression analyses; however, the dose did not significantly alter the β coefficient in any of the models tested (P > .5) and was not retained in final analyses. A total of 64 beclomethasone-treated children with asthma were recruited. The median age was 8 years (interquartile range, 5.5-11 years) and 42 (66%) were boys. The median asthma control score was 5.5 (interquartile range, 4-8). Saliva was collected from all participants, and CYP3A genotyping results are presented in Table I. Allelic variants in CYP3A4 and CYP3A7 were not significantly associated with asthma control scores, following adjustment for multiple comparisons. Two SNPs in CYP3A5 were associated with improved asthma control. The CYP3A5*3/*3 genotype was associated with a 2.7-point (95% CI, 0.9-4.6) improvement in the asthma control score when compared with patients with CYP3A5*1/*1 or CYP3A5*1/*3 genotypes (Fig 1). As previously reported, the CYP3A5*1D SNP (rs15524) was found in the same patients carrying the CYP3A5*3 SNP (rs776746), presumably explaining the concurrent association with asthma control.8Kuehl P. Zhang J. Lin Y. Lamba J. Assem M. Schuetz J. et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet. 2001; 27: 383-391Crossref PubMed Scopus (1932) Google Scholar, 9Quaranta S. Chevalier D. Allorge D. Lo-Guidice J.M. Migot-Nabias F. Kenani A. et al.Ethnic differences in the distribution of CYP3A5 gene polymorphisms.Xenobiotica. 2006; 36: 1191-1200Crossref PubMed Scopus (31) Google Scholar The CYP3A5*3 SNP was found to be in complete linkage disequilibrium with the CYP3A5*1D SNP (Hedrick's multiallelic D' = 1.0).10Hedrick P.W. Gametic disequilibrium measures: proceed with caution.Genetics. 1987; 117: 331-341PubMed Google ScholarTable IAssociation of CYP3A genetic polymorphisms and asthma control scores among 64 children receiving daily inhaled beclomethasone dipropionatePolymorphismReference SNP (rs no.)Association with asthma control scores (P value)∗Bonferroni adjustment for multiple comparisons.Reference allele frequencyVariant allele frequencyCYP3A4 CYP3A4∗22rs35599367NA1.000.00 CYP3A4 int 7rs2246709.390.600.40 CYP3A4 int 7rs4646437.100.700.30CYP3A5 CYP3A5∗3rs776746.010.660.34 CYP3A5∗6rs10264272.570.980.02 CYP3A5∗1Drs15524.010.660.34CYP3A7 CYP3A7rs2687133.130.840.16 CYP3A7∗2rs2257401.140.810.19 CYP3A7 6 nt 5′ of ex 14rs2740565.070.770.23No patients identified with the variant allele (NA). All SNPs were in Hardy-Weinberg equilibrium.∗ Bonferroni adjustment for multiple comparisons. Open table in a new tab No patients identified with the variant allele (NA). All SNPs were in Hardy-Weinberg equilibrium. Using recombinant CYP3A enzymes, we have previously shown that beclomethasone is efficiently inactivated by CYP3A5.6Roberts J.K. Moore C.D. Ward R.M. Yost G.S. Reilly C.A. Metabolism of beclomethasone dipropionate by cytochrome P450 3A enzymes.J Pharmacol Exp Ther. 2013; 345: 308-316Crossref PubMed Scopus (29) Google Scholar Several CYP3A5 genetic polymorphisms have been shown to alter mRNA expression and enzyme function, with the most common being CYP3A5*3, which codes for an inactive form of CYP3A5.8Kuehl P. Zhang J. Lin Y. Lamba J. Assem M. Schuetz J. et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet. 2001; 27: 383-391Crossref PubMed Scopus (1932) Google Scholar A majority of whites are homozygous for CYP3A5*3 and therefore do not express active CYP3A5, whereas other racial and ethnic groups commonly express the CYP3A5*1 allele, which codes for an active form of CYP3A5.9Quaranta S. Chevalier D. Allorge D. Lo-Guidice J.M. Migot-Nabias F. Kenani A. et al.Ethnic differences in the distribution of CYP3A5 gene polymorphisms.Xenobiotica. 2006; 36: 1191-1200Crossref PubMed Scopus (31) Google Scholar However, it is important to note that in this study, 88% of the individuals with the CYP3A5*1/*1 or *1/*3 genotype self-reported their race as white, demonstrating the importance of genetic testing when variations in CYP3A genotypes are considered as a potential basis for personalizing therapy. CYP3A5*1D is found in the 3′-untranslated region (UTR) of the CYP3A5 gene, although its effect on CYP3A5 function has not been established. It is possible that this SNP may influence the efficacy of beclomethasone treatment; however, previous studies have found that the CYP3A5*1D allele was identified only in those patients who had the CYP3A5*3 allele.8Kuehl P. Zhang J. Lin Y. Lamba J. Assem M. Schuetz J. et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet. 2001; 27: 383-391Crossref PubMed Scopus (1932) Google Scholar, 9Quaranta S. Chevalier D. Allorge D. Lo-Guidice J.M. Migot-Nabias F. Kenani A. et al.Ethnic differences in the distribution of CYP3A5 gene polymorphisms.Xenobiotica. 2006; 36: 1191-1200Crossref PubMed Scopus (31) Google Scholar In this study, all patients who were homozygous for the CYP3A5*1D SNP (rs15524) were also homozygous for the CYP3A5*3 SNP (rs776746). Therefore, the relative contributions of these SNPs to the clinical effects we observed could not be differentiated, although it is well known that CYP3A5*3 causes an alternative splicing event that results in nonfunctional CYP3A5 protein. Additional studies are needed to clarify the role of CYP3A5*1D and its effect(s), if any, on the expression and function of CYP3A5. Based on the current state of the field, the current data support the hypothesis that the relationship between improved asthma control scores among beclomethasone-treated children with the CYP3A5*1D/*1D genotype is ultimately due to the inactivation of CYP3A5 caused by the CYP3A5*3 SNP. The physiological basis for the association between improved asthma control with beclomethasone and CYP3A5*3 is not completely understood. This inactivating SNP abolishes CYP3A5 activity both in the lung and in the liver.8Kuehl P. Zhang J. Lin Y. Lamba J. Assem M. Schuetz J. et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet. 2001; 27: 383-391Crossref PubMed Scopus (1932) Google Scholar Reduced pulmonary and hepatic enzyme activity is likely to prolong the presence of active beclomethasone within the airway, thereby increasing the duration of its anti-inflammatory effects. In addition, further investigation is warranted to determine whether diminished CYP3A5 activity may be associated with higher systemic concentrations of beclomethasone, which has the potential to increase the risk of adverse effects, including suppression of the hypothalamic-pituitary-adrenal axis. Interpretation of our findings should be considered in light of several limitations. First, the precision of our effect estimates is limited by our sample size (n = 64). Second, it was not possible to directly measure CYP3A5 expression or tissue-specific activity; however, these studies are ongoing. Last, we did not obtain pulmonary function tests because standard spirometry measurements require a degree of patient cooperation that is difficult to achieve in the youngest of children. The clinical relevance of this observed association requires further mechanistic explanation and additional study with larger sample sizes. Nevertheless, these data support an association between improved asthma control with inhaled beclomethasone and the loss of function CYP3A5*3 allele and are consistent with our earlier work in which asthma control was found to be improved among children treated with fluticasone who had a genotype consistent with reduced CYP3A4 activity.4Stockmann C. Fassl B. Gaedigk R. Nkoy F. Uchida D.A. Monson S. et al.Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.J Pediatr. 2013; 162 (1227.e1-2): 1222-1227Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar When genetic testing is clinically available, these findings may be useful in selecting an appropriate therapeutic agent for patients who do not achieve optimal control with their currently prescribed inhaled glucocorticoid. We thank Bradley W. Thomas and Amber Bagherian for their technical support.