Leukotrienes play a central pathophysiological role in both pediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. To test the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late onset and 1,080 early onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12 month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta analysis. While no significant association was found with European late-onset subjects, a meta analysis of 523 early onset individuals from European ancestry demonstrated the risk of experiencing asthma exacerbations in the G allele carriers group (AG or GG), despite montelukast treatment, was increased (odds-ratio=3.27, 95%confidence interval: 0.98 to 10.93, I2=69%, p=0.05) compared to those in the AA group. When meta analyzing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR=1.69, 95% CI: 0.56 to 5.09, I2=84.81%, p=0.35). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. Europeans individuals with early-onset (less than 18 years old) carrying the rs2660845 G allele have increased risk of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.

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LTA4H与孟鲁司特反应在早发和晚发哮喘中的关联

白三烯在小儿和成人哮喘中均起着重要的病理生理作用。但是，35％至78％的哮喘患者对白三烯抑制剂无反应。测试LTA4H调节型变体rs2660845的作用，以及在不同种族的人群中响应孟鲁司特的哮喘发作年龄。我们从7个队列（UKBiobank，GoSHARE，BREATHE，Tayside RCT，PAGES，GALA II和SAGE）中鉴定了3594例接受孟鲁司特治疗的哮喘患者（2,514例晚期发作和1,080例早期发作）。使用每个队列的逻辑回归和荟萃分析，比较接受孟鲁司特治疗的患者在12个月内至少发作一次的情况与未发作的情况进行比较。虽然没有发现与欧洲晚期发病受试者有显着关联，对来自欧洲血统的523名早期发病个体进行的荟萃分析表明，尽管采用孟鲁司特治疗，G等位基因携带者组（AG或GG）发生哮喘急性发作的风险有所增加（比值比= 3.27，95％置信区间：0.98至与AA组相比，差异为10.93，I2 = 69％，p = 0.05）。当与其他种族进行荟萃分析时，未发现哮喘急性发作的风险显着增加（OR = 1.69，95％CI：0.56至5.09，I2 = 84.81％，p = 0.35）。我们的研究表明，LTA4H的遗传变异以及哮喘发作的时机可能会导致孟鲁司特反应的变异性。在孟鲁司特治疗下，携带rs2660845 G等位基因的早期发作（不到18岁）的欧洲人患急性发作的风险增加，可能是由于LTA4H活性上调所致。