Leukotrienes C4 synthase와 cysteinyl leukotriene receptor 1 유전자 다형성과 한국 소아 천식 표현형 및 임상 지표와의 연관성 연구 = Association study of polymorphism in leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes with phenotype of asthma and clinical parameters in Korean children

다국어 초록 (Multilingual Abstract)

Purpose : Cysteinyl leukotrienes are important proinflammatory mediators in asthma. Recently, it was suggested that a promoter polymorphism in the genes encoding for leukotriene C4 synthase (LTC4S), a key enzyme in the leukotriene synthetic pathway, and cysteinyl leukotriene receptor 1 (CysLTR1) might be associated with aspirin-intolerant asthma. We investigated whether polymorphisms in LTC4S and CysLTR1 genes or their interactions were associated with the asthma phenotype, lung function, or bronchial hyperreactivity (BHR) in Korean children.
Methods : A total of 856 asthmatic children and 254 non-asthmatic controls were enrolled; a skin prick test, lung function test and bronchial provocation test were performed. Of those enrolled, 395 children underwent exercise challenge tests. The LTC4S A(-444)C and CysLTR1 T(＋927)C were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis.
Results : Of those enrolled, 699 children were classified as having atopic asthma and 277 children, as having exercise-induced asthma (EIA). LTC4S and CysLTR1 polymorphisms were not associated with atopic asthma, EIA, or asthma per se. Lung function and BHR were not significantly different between the wild type (AA or TT) and the variant (AC＋CC or TC＋CC) genotypes in asthmatics, atopic asthmatics, and EIA (＋) asthmatics, while total eosinophil counts were higher in the variant type of LTC4S than in the wild type in atopic asthmatics. There were no associations between the gene-gene interactions of LTC4S and CysLTR1 genotypes and the asthma phenotypes.
Conclusion : LTC4S A(-444)C and CysLTR1 T(＋927)C polymorphisms and their gene-gene interactions are not associated with asthma phenotype, lung function, or BHR in Korean children.

국문 초록 (Abstract)

목 적 : 류코트리엔은 천식의 병태생리에 중요한 향염증성 매개체이며, 천식이나 운동유발성 천식에서 증가되어 있다. Leukotriene C4 synthase (LTC4S)의 A(-444)C 유전자 다형성과 cysteinyl leukotriene receptor 1 (CysLTR1) T(＋927)C 유전자 다형성이 한국 소아의 천식, 아토피 천식 및 운동유발성 천식과 연관이 있는지 알아보고, 폐기능, 기관지과민성, 총IgE 치에 영향을 미치는지 알아보고자 하였다.
방 법 : 총 856명의 천식 환자와 254명의 천식이 없는 정상아를 대상으로 하여 피부반응검사, 폐기능, 메타콜린 기관지 유발검사, 총 IgE 검사를 실시하였고, 천식 환자를 아토피 천식(699명), 운동유발성 천식(277명)으로 나누어 유전자 다형성과의 연관성을 조사하였다. LTC4S A9-444)C, CysLTR1 T(＋927)C 유전자형은 PCR-restriction fragment length polymorphism 방법으로 분석하였다.
결 과 : LTC4S A(-444)C 및 CysLTR1 T(＋927)C 유전자 다형성은 천식, 아토피 천식, 운동유발성 천식과의 연관성이 없었고, 폐기능, PC20, 총IgE에도 차이를 보이지 않았다. 아토피 천식에서 총 호산구수는 변종형 LTC4S 유전자형에서 야생형 보다 높았다. LTC4S A(-444)C와 CysLTR1 T(＋927)C의 유전자-유전자 상호 작용도 천식, 아토피 천식, 운동유발성 천식과의 연관이 없었다.
결 론 : 한국 소아 천식의 표현형, 폐기능, 기관지과민성, 총IgE 농도는 LTC4S A(-444)C와 CysLTR1 T(＋927)C 유전자 다형성, 혹은 유전자-유전자 상호작용과 연관이 없는 것으로 생각된다.

참고문헌 (Reference)

1 Sampson AP, "Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast" 55 (55): S28-S31, 2000

2 Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma, "This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986" 136 : 225-244, 1987

3 Kim HB, "The leukotriene C4 synthase (A-444C) promoter polymorphism is associated with the severity of exercise-induced asthma in Korean children" 117 : 1191-1192, 2006

4 Hao L, "The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma" 36 : 735-741, 2006

5 Acevedo N, "The A-444C polymorphism of leukotriene C4 synthase gene is associated with IgE antibodies to Dermatophagoides pteronyssinus in a Colombian population" 119 : 505-507, 2007

6 Lee SY, "Responsiveness to montelukast is associated with bronchial hyperresponsiveness and total immunoglobulin E but not polymorphisms in the leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes in Korean children with exercise-induced asthma (EIA)" 37 : 1487-1493, 2007

7 Joseph-Bowen J, "Relationship of asthma, atopy, and bronchial responsiveness to serum eosinophil cationic proteins in early childhood" 114 : 1040-1045, 2004

8 Sayers I, "Promoter polymorphism in the 5-lipoxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population" 33 : 1103-1110, 2003

9 Cowburn AS, "Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma" 101 : 834-846, 1998

10 Bigby TD, "Molecular cloning of the human leukotriene C4 synthase gene and assignment to chromosome 5q35" 2 : 637-646, 1996

11 Choi JH, "Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase" 114 : 337-344, 2004

12 Sanak M, "Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma" 350 : 1599-1600, 1997

13 Asano K, "Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma" 12 : 565-570, 2002

14 Garcia-Martin E, "Interethnic and intraethnic variability of NAT2 single nucleotide polymorphisms" 9 : 487-497, 2008

15 Crapo RO, "Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999" 161 : 309-329, 2000

16 Zhang J, "Determination of structure and transcriptional regulation of CYSLTR1 and an association study with asthma and rhinitis" 17 : 242-249, 2006

17 Crowther SD, "Current treatment of asthma--focus on leukotrienes" 1 : 1021-1040, 2000

18 Kedda MA, "Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma" 113 : 889-895, 2004

19 Lynch KR, "Characterization of the human cysteinyl leukotriene CysLT1 receptor" 399 : 789-793, 1999

20 Sanz C, "Analysis of 927T> C CYSLTRI and -444A > C LTC4S polymorphisms in patients with asthma" 16 : 331-337, 2006

21 Sayers I, "Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma" 58 : 417-424, 2003

22 Arriba-Mendez S, "927T>C polymorphism of the cysteinyl-leukotriene type-1 receptor (CYSLTR1) gene in children with asthma and atopic dermatitis" 17 : 323-328, 2006

23 Van Sambeek R, "5' flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States" 106 : 72-76, 2000