II-77Posters
PHARMACOGENOMICS OF ASTHMA TREATMENT
Vojko Berce1, Katja Repnik2, 3, Uroš Potočnik2, 3
1 Department for pediatrics, General Hospital Murska Sobota; Slovenia
2 Center for Human Molecular Genetics and Pharmacogenomics, Medical Faculty
3 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical
Engineering, University of Maribor, Slovenia; uros.potocnik@uni-mb.si
POSTERS
POSTERJI
Introduction Asthma is most common chronic disease of childhood. Asthma is inflammatory disease of
unknown etiology. We usually treat asthma with corticosteroids or anti-leukotriene drugs.
As symptom relieving drugs asthmatics use bronchodilators – usually beta2 receptor ago-
nists. There are substantial differences in the effect of antiasthmatic therapy between indi-
viduals which are related to different genetic code. Single nucleotide polymorphisms (SNPs)
in α2 adrenergic receptor gene (α2AR)1 and corticotropine releasing hormone receptor 1
(CRHR1)2 have been recently associated with treatment outcome in asthma. In our study
we corellated polymorphisms in α2AR, ALOX5, CRHR1 and MDR1/ABCB1 genes with clin-
ical features and treatment outcome in Slovenian childhood asthma patients.
Methods We enrolled 100 Slovenian patients with childhood asthma and their parents for disease
association and pharmacogenomic studies. Patients were children aged from 6 to 18 years
with mild persistent asthma, which were diagnosed according to American Thoracic Soci-
ety criteria.3 They also had no other chronic disease. We obtained informed consent from
above 15 years old patients and from parents for younger patients. We first examined
allergic status with skin prick test. In all children we measured spirometry, PD20 with
metacholine bronchoprovocation test and nitric oxide in exhaled air. We also measured
FEV1 before and after inhalation of bronchodilator – albuterol (3 puffs with MDI). Asth-
matic children measured PEF at home for at least two weeks and wrote values in diary.
From same venepuncture we also used blood for analysis of total IgE, specific IgE and
number of eosinophils in peripheral blood. In addition to 100 patients with previous anti-
asthmatic treatment we enrolled 20 children without previous antiasthmatic treatment in
the prospective study. According to NAEEP guidelines we started to treat all children with
fluticasone propionate.4 They took medication for at least 4–6 months. First outpatient
visit was after 4–6 weeks, then after 12–14 weeks and finally at the end of the study 4–6
months after start of therapy. DNA, RNA and proteins were isolated from peripheral blood
leucocytes using Tri reagent (Sigma). We used RFLP and Taqman methods for SNP geno-
typing. We used t-test and χ2 statistics and SPSS program for statistical analysis.
Results Before therapy overall variation of PEF was 39.2 % (95 % CI, 34.2–44.2), PD20 was 0.21
mg of metacholine (95 % CI, 0.16–0.26), eNO 46.2 ppb (95 CI, 38.0–54.4), blood total IgE
885 IU/ml (95 % CI, 443–1327) and number of eosinophils in mm3 of blood 701 (95 % CI,
617–785). We found Arg16Gly SNP in α2AR associated with treatment outcome, patients
with genotype Arg/Arg had worse outcome and decrease in PEF values of 20.8±10.5 L/min
after regular beta2 receptor agonists treatment. In patients with Arg/Arg genotype FEV1
increased for only 6.9 ± 5.5 % after application of albuterol which is significantly less than
13.2±8.4 % in patients with Gly/Gly genotype (p = 0.01). We also found SNP rs242941 in
CRHR1 gene is associated with response to corticosteroid treatment. In patients with wild
type genotype G/G, FEV1 increased for 16.4±9.1 % what is significantly better than in-
crease of FEV1 for 7.7±7.9 in patients with genotype T/T (p = 0.02).
Conclusions We have confirmed genetic variation in α2AR and CRHR1 genes associatied with treat-
ment outcome in Slovenian childhood asthma patients. Identification of additional genes
II-78 Zdrav Vestn 2007; 76: SUPPL II
associatied with treatment outcome will enable to contruct genetic profiles which should
improve the clinical relevance of using pharmacogenetic data for prediction of treatment
outcome in asthma patients.
References
1. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Asso-
ciation between genetic polymorphisms of the beta(2)-adreno-
ceptor and response to albuterol in children with and without a
history of wheezing. J Clin Invest 1997; 100: 3184–8.
2. Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silver-
man EK, et al. Corticosteroid pharmacogenetics: association of
sequence variants in CRHR1 with improved lung function in asth-
matics treated with inhaled corticosteroids. Hum Mol Genet 2004;
13: 1353–9.
3. American Thoracic Society. Standards for the diagnosis and care
of patients with chronic obstructive pulmonary disease (COPD)
and asthma. Am Rev Respir Dis 1987; 136: 225–44.
4. Liu AH, Spahn JD, Leung DYM. Childhood asthma. In: Behrman
RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics.
17th ed. Philadelphia: Saunders; 2004. p. 760–74.