Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지

Association of Leukotriene C4 Synthase Gene Polymorphism with Clinical Response to Montelukast in Childhood Asthma

소아 천식환자에서 Leukotriene C4 Synthase 유전자 다형태와 Montelukast의 임상적 효과와의 연관성

  • Shin, Kyung Sue (Department of Pediatrics, Cheju National University College of Medicine) ;
  • Kim, Youn Woo (Department of Pediatrics, Cheju National University College of Medicine)
  • 신경수 (제주대학교 의과대학 소아과학교실) ;
  • 김연우 (제주대학교 의과대학 소아과학교실)
  • Received : 2005.02.18
  • Accepted : 2005.04.08
  • Published : 2005.07.15
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose : Cysteinyl leukotrienes are important inflammatory mediators in the pathogenesis of asthma; therefore interruption of cysteinyl leukotrienes by leukotriene receptor antagonists improves clinical symptoms in the management of patients with mild to moderate asthma. We evaluated whether clinical response to montelukast, a leukotriene receptor antagonist, in childhood asthma was predicted by genotypes of leukotriene $C_4$ synthase($LTC_4S$) promoter gene polymorphism. Methods : An 8-week prospective, open trial of montelukast was carried out in 161 children with mild to moderate asthma. Genotyping of $LTC_4S$ gene polymorphism was determined by restriction fragment length polymorphism. Results : The distribution of the $LTC_4S$ genotypes AA, AC, and CC was 70.8 percent, 23.6 percent, and 5.6 percent, respectively in asthma group and 74.0 percent, 22.6 percent, and 3.4 percent, respectively in control group. A statistically significant difference in the distribution of $LTC_4S$ genotype was not observed between the asthma and the control groups, and there was no significant difference between the $LTC_4S$ genotype and asthma severity. The responders to montelukast were significantly prevalent in the mild asthma group(P<0.05). There was no significant difference in the distribution of the responders compared to non-responders within genotype in the total asthma group or the moderate asthma group. However, the responsiveness for montelukast was significant difference within genotype for both AA and AC/CC in the mild asthma group : The AA genotype was more included in the responder group(P<0.05). Conclusion : In the mild persistent asthma group, the A allele of $LTC_4S$ polymorphism may be regarded as a predictable factor for clinical response to montelukast. However, LTC4S polymorphism was not significantly associated with the clinical response to montelukast in asthmatic children.

목 적 : 류코트리엔 수용체 길항제는 천식의 병리 반응에 관여하는 cysteiny leukotriene의 생성과 작용을 억제하여 급성기 천식 증상의 치료와 천식 증상의 조절 요법에 사용할 수 있다. 본 연구에서는 소아 천식환자에서 cysteinyl leukotriene 생성에 관여하는 $LTC_4S$ 유전자 다형태와 류코트리엔 수용체 길항제인 montelukast의 임상적 효과를 조사하여 약물유전학적 연관성 유무를 알고자 하였다. 방 법 : 환자군은 경증 지속성 천식과 중등증 지속성 천식환자 161명을 대상으로 하였고, montelukast 5 mg을 하루에 한 번씩 총 8주 동안 투여하였다. $LTC_4S$ 유전자 다형태는 restriction fragment length polymorphism을 이용하여 조사하였다. 결 과 : 대조군에서 LTC4S 유전자형의 분포는 A/A, A/C, C/C가 각각 74.0%, 22.6%, 3.4%였고, 환자군에서는 A/A, A/C, C/C가 각각 70.8%, 23.6%, 5.6%였다. 두 군의 유전자형 분포는 통계적으로 유의한 차이를 보이지 않았고, $LTC_4S$ 유전자형 분포와 천식의 중증도 사이에도 유의한 차이가 없었다. 반응군에서는 경증 지속성 천식환자가 반응이 없는 군에서는 중등증 지속성 천식환자가 더 많았다. 전체 소아 천식환자군에서는 montelukast에 대한 반응군과 반응이 없는 군 사이에 $LTC_4S$ 유전자형에 따른 차이는 없었다. 경증 지속성 천식환자의 반응군에서 adenine 대립유전자를 가진 환자가 많았으나, 중등증 지속성 천식환자에서는 유전자형에 따른 반응군과 반응이 없는 군의 유의한 차이가 없었다. 결 론 : 본 연구에서 소아 경증 지속성 천식환자의 경우에는 통계적으로 adenine 대립유전자가 montelukast에 대한 임상적 효과를 예측할 수 있는 인자라고 할 수 있으나 전체 소아 천식환자에서는 $LTC_4S$ 유전자 다형태와 montelukast의 임상적 효과와의 연관성은 통계적으로 없었다.

Keywords

Acknowledgement

Supported by : 한국학술진흥재단

References

  1. Warner JO. The role of leukotriene receptor antagonists in the treatment of chronic asthma in childhood. Allergy 2001; 56 suppl 66:22-9
  2. Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659. Bethesda, MD : National Institutes of Health, 2002
  3. Salvi SS, Krishna MT, Sampson AP, Holgate ST. The anti-inflammatory effects of leukotriene-modifying drugs and their use in asthma. Chest 2001;119:1533-46 https://doi.org/10.1378/chest.119.5.1533
  4. Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997;350:1599-600 https://doi.org/10.1016/S0140-6736(05)64015-9
  5. Asano K, Shiomi T, Hasegawa N, Nakamura H, Kudo H, Matsuzaki T, et al. Leukotriene C4 synthase gene A(-444) C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics 2002;12:565-70 https://doi.org/10.1097/00008571-200210000-00009
  6. Currie GP, Lima JJ, Sylvester JE, Lee DK, Cockburn WJ, Lipworth BJ. Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma. Br J Clin Pharmacol 2003;56:422-6 https://doi.org/10.1046/j.1365-2125.2003.01952.x
  7. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108:E48. Available from : URL : http://www.pediatrics.org/cgi/content/full/108/ 3/e48
  8. Santanello NC, Barber BL, Reiss TF, Friedman BS, Juniper EF, Zhang J. Measurement characteristics of two asthma symptom diary scales for use in clinical trials. Eur Respir J 1997;10:646-51
  9. Ducharme FM. Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment : systematic review of current evidence. BMJ 2003;326:621-5 https://doi.org/10.1136/bmj.326.7390.621
  10. Bigby TD. The leukotriene C4 synthase gene and asthma. Am J Respir Cell Mol Biol 2000;23:273-6 https://doi.org/10.1165/ajrcmb.23.3.f197
  11. Tohda Y, Fujimura M, Taniguchi H, TakagiK, Igarashi T, Yasuhara H, et al. Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients. Clin Exp Allergy 2002;32:1180-6 https://doi.org/10.1046/j.1365-2745.2002.01440.x
  12. Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999;22:168-170. https://doi.org/10.1038/9680
  13. Fowler SJ, Hall IP, Wilson AM, Wheatley AP, Lipworth BJ. 5-Lipoxygenase polymorphism and in-vivo response to leukotriene receptor antagonists. Eur J Clin Pharmacol 2002;58:187-90 https://doi.org/10.1007/s00228-002-0458-1
  14. Sampson AP, Siddiqui S, Buchanan D, Howarth PH, Holgate ST, Holloway JW, et al. Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 2000;55(2 suppl):28S-31S
  15. Sambeek RV, Stevenson DD, Baldasaro M, Lam BK, Zhao J, Yoshida S, et al. 5' Flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States. J Allergy Clin Immunol 2000;106:72-6 https://doi.org/10.1067/mai.2000.107603
  16. Sayers I, Barton S, Rorke S, Beghe B, Hayward B, Van Eerdewegh P, et al. Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene(LTC4S) in asthma. Thorax 2003;58:417-24. https://doi.org/10.1136/thorax.58.5.417
  17. Mastalerz L, Nizankowska E, Sanak M, Mejza F, Pierzchalska M, Bazan-Socha S, et al. Clinical and genetic features underlying the response of patients with bronchial asthma to treatment with a leukotriene receptor antagonist. Eur J Clin Invest 2002;32:949-55 https://doi.org/10.1046/j.1365-2362.2002.01088.x