Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지

Analysis of the association between bronchial hyperresponsiveness and genetic polymorphism of β2-adrenoceptor in adolescents with long-term asthma remission

장기간 천식 관해 청소년에서 지속되는 기관지 과민성과 β2-아드레날린 수용체 유전자 다형과의 연관성 분석

  • Kang, Hee (Department of Pediatrics, College of Medicine, Seoul National University) ;
  • Koh, Young Yull (Department of Pediatrics, College of Medicine, Seoul National University)
  • 강희 (서울대학교 의과대학 소아과학교실) ;
  • 고영률 (서울대학교 의과대학 소아과학교실)
  • Received : 2007.03.13
  • Accepted : 2007.05.20
  • Published : 2007.06.15
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose : We hypothesized that the persisting bronchial hyperresponsiveness (BHR) of adolescents with asthma remission may be controlled mainly by genetic factors, and the BHR of symptomatic asthma by airway inflammation. ${\beta}_2$-adrenoceptor gene is considered to be a candidate gene in the development of BHR. Thus, ${\beta}_2$-adrenoceptor gene polymorphism may be associated with the BHR of adolescents with asthma remission, but not with the BHR of symptomatic asthma. To evaluate this hypothesis, ${\beta}_2$-adrenoceptor gene polymorphism at 2 sites (Arg16-Gly, Gln27-Glu) were examined. Methods : Two hundred two adolescents with BHR ($PC_{20}<18\;mg/mL$) and long term remission (neither asthma-related symptoms nor medication during the previous 2 years) of their asthma (remission group), 182 adolescents with symptomatic asthma (symptomatic group), and 200 healthy adolescents (control group) were studied. Asthma phenotypes were determined using methacholine bronchial provocation test and skin prick test. Genotypes of ${\beta}_2$-adrenoceptor polymorphism were evaluated by PCR-based methods. Results : Gly/Gly allele and Gly16-Gln27 haplotype were more prevalent in the remission group than in the control group (P=0.01, P=0.02), although there was no difference between the symptomatic group and the control group. In the remission group, there was significant difference in geometric mean of $PC_{20}$ among the 3 groups subdivided by the number of Gly16-Gln27 haplotype, showing that the Gly16-Gln27 haplotype was positively associated with BHR. However, no association was found between Gly16-Gln27 haplotype and BHR in the symptomatic group. Conclusion : This study demonstrates that ${\beta}_2$-adrenoceptor polymorphism at amino acid 16 and 27 was associated with BHR persisting in adolescents with asthma remission.

목 적 : 본 연구에서는 현증 천식 환자의 BHR에는 기도 염증이 중요한 요인으로 작용하기 때문에 ${\beta}_2$-아드레날린 수용체 유전자와의 연관성이 나타나지 않지만, 청소년기 천식 관해 상태에서 지속되는 BHR에는 상대적으로 유전적인 영향이 강하기 때문에 ${\beta}_2$-아드레날린 수용체 유전자와의 연관성이 나타날 것이라는 가설을 세우고, 이를 검증해 보고자 하였다. 방 법 : 장기간 천식 관해 상태(최근 2년간 천식 증상이 없고 치료가 필요 없었던 경우)에서 BHR이 지속되는 청소년 202명(천식 관해군), 현증 천식 청소년 182명(현증 천식군), 정상군 200명을 대상으로, 메타콜린 기관지 유발검사와 피부단자시험을 시행하였으며 혈청 총 IgE를 측정하였다. ${\beta}_2$-아드레날린 수용체 유전자의 일배체형 분석을 위해 아미노산 16번과 27번을 포함하고 있는 ${\beta}_2$-아드레날린 수용체 유전자 부위를 polymerase chain reaction(PCR)으로 증폭한 뒤, 16번 유전형은 allele specific PCR, 27번 유전형은 PCR-restriction fragment length polymorphism (RFLP) 방법으로 분석하였다. 결 과 : Gly 동형접합자(homozygote)의 빈도는 정상군에서 14.5%, 현증 천식군에서 18.1%, 천식 관해군에서 24.2%로 증가하는 경향이 관찰되었으며(P=0.01), 현증 천식군과 정상군 사이에서는 차이가 없었지만 천식 관해군과 정상군 사이에서는 유의한 차이가 관찰되었다(P=0.01). Gly16-Gln27 일배체형 빈도는 정상군에서 36.5%, 현증 천식군에서 40.4%, 천식 관해군에서 44.6%로 증가하는 경향이 관찰되었으며(P=0.02), 현증 천식군과 정상군 사이에서는 차이가 없었지만 천식 관해군과 정상군 사이에서는 유의한 차이가 관찰되었다(P=0.02). 천식 관해군에서 Gly16-Gln27 일배체형의 수가 증가함에 따라 $PC_{20}$ 기하 평균값이 유의한 차이를 보임으로써(P=0.02) Gly16-Gln27 일배체형과 $PC_{20}$ 사이의 연관성이 관찰되었으나 현증 천식군에서는 이러한 연관성이 관찰되지 않았다. 결 론 : ${\beta}_2$-아드레날린 수용체 유전자가 BHR을 유발하는 유전자적 배경을 가지면서 천식 질병을 조절하는 역할을 하고 있음을 시사한다.

Keywords

References

  1. Sandford A, Weir T, Pare P. The genetics of asthma. Am J Respir Crit Care Med 1996;153:1749-65 https://doi.org/10.1164/ajrccm.153.6.8665031
  2. Longo G, Strinati R, Poli F, Fumi F. Genetic factors in nonspecific bronchial hyperreactivity. Am J Dis Child 1987; 141:331-4 https://doi.org/10.1001/archpedi.1987.04460030109037
  3. Kim SH, Oh SY, Oh HB, Son SW, Chang YS, Kim YK, et al. Association between $\beta_{2}$-adrenoreceptor polymorphism and asthma phenotypes in the general population. J Asthma Allergy Clin Immunol 2001;21:1152-60
  4. Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the $\beta_{2}$-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993;8:334-9 https://doi.org/10.1165/ajrcmb/8.3.334
  5. Enright PL, Lebowitz MD, Cockroft DW. Physiologic measures: pulmonary function tests. Asthma outcome. Am J Respir Crit Care Med 1994;149(2 Suppl):9S-18S https://doi.org/10.1164/ajrccm/149.2_Pt_2.S9
  6. Fowler SJ, Dempsey OJ, Sims EJ, Lipworth BJ. Screening for bronchial hyperresponsiveness using methacholine and adenosine monophosphate. Relationship to asthma severity and $\beta_{2}$-receptor genotype. Am J Respir Crit Care Med 2000;162:1318-22 https://doi.org/10.1164/ajrccm.162.4.9912103
  7. Hall IP, Wheatley A, Wilding P, Liggett SB. Association of Glu 27 $\beta_{2}$-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995;345:1213-4 https://doi.org/10.1016/S0140-6736(95)91994-5
  8. Ramsay CE, Hayden CM, Tiller KJ, Burton PR, Goldblatt J, Lesouef PN. Polymorphisms in the $\beta_{2}$-adrenoreceptor gene are associated with decreased airway responsiveness. Clin Exp Allergy 1999;29:1195-203 https://doi.org/10.1046/j.1365-2222.1999.00570.x
  9. D'Amato M, Vitiani LR, Petrelli G, Ferrigno L, di Pietro A, Trezza R, et al. Association of persistent bronchial hyperresponsiveness with $\beta_{2}$-adrenoceptor (ADRB2) haplotypes. A population study. Am J Respir Crit Care Med 1998; 158:1968-73 https://doi.org/10.1164/ajrccm.158.6.9804126
  10. Emala CW, McQuitty CK, Eleff SM, Hopkins-Price P, Lawyer C, Hoh J, et al. Asthma, allergy, and airway hyperresponsiveness are not linked to the $\beta_{2}$-adrenoceptor gene. Chest 2002;121:722-31 https://doi.org/10.1378/chest.121.3.722
  11. Summerhill E, Leavitt SA, Gidley H, Parry R, Solway J, Ober C. $\beta_{2}$-adrenergic receptor Arg16/Arg16 genotype is associated with reduced lung function, but not with asthma, in the Hutterites. Am J Respir Crit Care Med 2000;162:599-602 https://doi.org/10.1164/ajrccm.162.2.9910108
  12. von Mutius E. Progression of allergy and asthma through childhood to adolescence. Thorax 1996;51 Suppl 1:3-6 https://doi.org/10.1136/thx.51.1.3
  13. Murray AB, Ferguson AC, Morrison B. Airway responsiveness to histamine as a test for overall severity of asthma in children. J Allergy Clin Immunol 1981;68:119-24 https://doi.org/10.1016/0091-6749(81)90169-X
  14. Boulet LP, Turcotte H, Brochu A. Persistence of airway obstruction and hyperresponsiveness in subjects with asthma remission. Chest 1994;105:1024-31 https://doi.org/10.1378/chest.105.4.1024
  15. Koh YY, Sun YH, Lim HS, Kim CK, Hong SJ. Effect of inhaled budesonide on bronchial hyperresponsiveness in adolescents with clinical remission of asthma. Chest 2001; 120:1140-6 https://doi.org/10.1378/chest.120.4.1140
  16. Peat JK, Salome CM, Woolcock AJ. Factors associated with bronchial hyperresponsiveness in Australian adults and children. Eur Respir J 1992;5:921-9
  17. Koh YY, Kang EK, Kang H, Yoo Y, Park Y, Kim CK. Bronchial hyperresponsiveness in adolescents with longterm asthma remission: importance of a family history of bronchial hyperresponsiveness. Chest 2003;124:819-25 https://doi.org/10.1378/chest.124.3.819
  18. Koh YY, Kang H, Nah KM, Kim CK. Absence of asso-ciation of peripheral blood eosinophilia or increased eosinophil cationic protein with bronchial hyperresponsiveness during asthma remission. Ann Allergy Asthma Immunol 2003;91:297-302 https://doi.org/10.1016/S1081-1206(10)63533-8
  19. Yoon KA, Lim HS, Koh YY, Kim H. Normal predicted values of pulmonary function tests in Korean school aged children. J Korean Pediatr Soc 1993;36:25-37
  20. Prieto L, Berto JM, Gutierrez V. Airway responsiveness to methacholine and risk of asthma in patients with allergic rhinitis. Ann Allergy 1994;72:534-9
  21. Chai H, Farr RS, Froehlich LA, Mathison DA, Rosenthal RR, Sheffer AL, et al. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975; 56:323-7 https://doi.org/10.1016/0091-6749(75)90107-4
  22. Hong SJ, Kim BS, Kim JH, Oh HB, Lee MS, Choi SO, et al. $\beta_{2}$-adrenoceptor polymorphisms between asthmatic and normal children in Korea. Pediatr Allergy Respir Dis (Korea) 2002;12:253-62
  23. Weir TD, Mallek N, Sandford AJ, Bai TR, Awadh N, Fitzgerald JM, et al. $\beta_{2}$-adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma. Am J Respir Crit Care Med 1998;158:787-91 https://doi.org/10.1164/ajrccm.158.3.9801035
  24. Ulbrecht M, Hergeth MT, Wjst M, Heinrich J, Bickeboller H, Wichmann HE, et al. Association of $\beta_{2}$-adrenoreceptor variants with bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;161:469-74 https://doi.org/10.1164/ajrccm.161.2.9902072
  25. Choudhry S, Ung N, Avila PC, Ziv E, Nazario S, Casal J, et al. Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. Am J Respir Crit Care Med 2005;171:563-70 https://doi.org/10.1164/rccm.200409-1286OC
  26. Gao JM, Lin YG, Qiu CC, Liu YW, Ma Y, Liu Y. $\beta_{2}$- adrenergic receptor gene polymorphism in Chinese Northern asthmatics. Chin Med Sci J 2004;19:164-9
  27. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the $\beta_{2}$- adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997;100:3184- 8 https://doi.org/10.1172/JCI119874
  28. Martinez FD. Complexities of the genetics of asthma. Am J Respir Crit Care Med 1997;156(4 Suppl):117S-22S https://doi.org/10.1164/ajrccm.156.4.12tac-8
  29. Rigoli L, Salpietro DC, Lavalle R, Cafiero G, Zuccarello D, Barberi I. Allelic association of gene markers on chromosome 11q in Italian families with atopy. Acta Paediatr 2000; 89:1056-61 https://doi.org/10.1080/713794577
  30. Green SA, Turki J, Bejarano P, Hall IP, Liggette SB. Influence of $\beta_{2}$-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995;13:25-33 https://doi.org/10.1165/ajrcmb.13.1.7598936
  31. Oostendorp J, Postma DS, Volders H, Jongepier H, Kauffman HF, Boezen HM, et al. Differential desensitization of homozygous haplotypes of the $\beta_{2}$-adrenergic receptor in lymphocytes. Am J Respir Crit Care Med 2005;172:322-8 https://doi.org/10.1164/rccm.200409-1162OC
  32. Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic polymorphisms of the $\beta_{2}$-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995;95:1635-41 https://doi.org/10.1172/JCI117838
  33. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human $\beta_{2}$-adrenergic receptor impart distinct agonist promoted regulatory properties. Biochemistry 1994;33:9414-9 https://doi.org/10.1021/bi00198a006
  34. Dewar JC, Wilkinson J, Wheatley A, Thomas NS, Doull I, Morton N, et al. The glutamine 27 $\beta_{2}$-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J Allergy Clin Immunol 1997;100:261-5 https://doi.org/10.1016/S0091-6749(97)70234-3
  35. Deichmann KA, Schmidt A, Heinzmann A, Kruse S, Forster J, Kuehr J. Association studies on $\beta_{2}$-adrenoceptor polymorphisms and enhanced IgE responsiveness in an atopic population. Clin Exp Allergy 1999;29:794-9 https://doi.org/10.1046/j.1365-2222.1999.00571.x