白三烯C_4合成酶-A_(-444)C基因多态性与支气管哮喘关系的研究

The study on leukotriene C_4 synthase A_(-444)C polymorphism in asthmatics in Chinese Han population in Beijing

目的初步探讨白三烯C4合成酶(LTC4S)-A444C基因多态性在北京地区汉族支气管哮喘患者中的分布及其与哮喘病情严重程度、哮喘患者应用白三烯受体拮抗剂临床反应的关系。方法哮喘患者101例,健康成人对照105例。应用聚合酶链反应-限制性片段长度多态性方法检测LTC4S-A444C基因多态性。从哮喘组中选择规律吸入激素2个月以上的患者18例,在原用药基础上加用孟鲁司特钠治疗2周。结果(1)哮喘组中LTC4S基因-444位点基因型AA、AC及CC频率分别为65.4%、30.5%及3.8%,等位基因A、C频率分别为81.0%、19.0%,与健康对照组的分布比较差异无统计学意义(P>0.05)。(2)哮喘组中,哮喘非急性发作期AC及CC型患者第一秒用力呼气容积占预计值百分比(FEV1%pred)显著低于AA型患者[(58.6±21.6)%比(70.3±22.4)%,P<0.05],AC及CC型患者哮喘病情重于AA型患者(P<0.05)。(3)应用孟鲁司特钠1周后,AA型患者FEV1改善率显著高于AC型患者[(10.8±10.2)%比(-9.8±16.2)%,P<0.01];用药2周后,AA型基因患者FEV1改善率及改善值高于AC型患者,但差异无统计学意义。结论北京地区汉族人群中LTC4S A-444C基因多态性与哮喘非急性发作期病情严重程度及肺功能损害程度相关,并可能与哮喘患者应用白三烯受体拮抗剂的临床反应相关。

Objective To investigate the frequency of LTC4S A-444C polymorphism in Chinese Han population in Beijing and to evaluate its association with susceptibility to asthma, asthma severity and clinical response to leukotriene receptor antagonist. Methods The LTC4S A-444C polymorphism was analyzed in 101 patients with asthma and 105 healthy controls.Then 18 asthmatics were recruited, and a 2-week prospective, open trial of montelukast was performed in addition to the previous medications. Results In the asthma group, the frequencies of A and C allele at -444 locus of LTC4S gene were 81.0% and 19.0% ,respectively,and genotype frequencies of AA,AC and CC were 65.4% ,30.5% and 3.8% ,respectively.There was no significant difference in LTC4S A-444C polymorphism between the asthmatics and healthy controls（ P 〉 0.05）. The asthmatics with the C-444 allele had significantly lower forced expiratory volume in one second（FEV1 ） than wild-type A homozygotes [ （58.6±21.6） % predicted vs （70.3±22.4） % predicted, P 〈 0.05） ]. A correlation was observed between the variant C-444 allele and asthma severity（ P 〈 0.05）. After administered montelukast 1 week, the A-444 allele homozygotes（ n =9） responded better than the C（-444） allele carriers（ n = 7）[ （ 10.8±10.2）% vs （ - 9.8±16.2） % improvement of FEV1, P 〈 0.05]. After 2 weeks, the A-444 allele hemozygotes also responded better, although there was no statistical difference（ P 〉 0.05）. Condusion In Chinese Han population LTC4S A-444C polymorphism is associated with asthma severity and probably contributes to the clinical response to leukotriene receptor antagonists.