LTA4H rs2660845 association with montelukast response in early and late-onset asthma.
LTA4H rs2660845 association with montelukast response in early and late-onset asthma.
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DOI：
10.1371/journal.pone.0257396
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
PiCA Consortium
中科院分区：
文献类型：
--
作者：
Maroteau C;Espuela-Ortiz A;Herrera-Luis E;Srinivasan S;Carr F;Tavendale R;Wilson K;Hernandez-Pacheco N;Chalmers JD;Turner S;Mukhopadhyay S;Maitland-van der Zee AH;Burchard EG;Pino-Yanes M;Young S;Lassi G;Platt A;Palmer CNA;PiCA Consortium
白三烯在儿童和成人哮喘中起着重要的病理生理作用。然而，35%到78%的哮喘患者对白三烯抑制剂没有反应。在这项研究中，我们测试了LTA4H调节变异体rs2660845在不同种族人群中对孟鲁司特的反应与哮喘发病年龄的关系。我们从7个队列(UKBiobank，GoSHARE，Breath，Tayside RCT，PAGE，Gala II和SAGE)中鉴定了3594名接受孟鲁司特治疗的哮喘患者(2514名晚发和1080名早发)，并对其进行了基因分型。接受孟鲁司特治疗的患者在12个月内至少有一次恶化，并与没有恶化的患者进行比较，每个队列的Logistic回归和荟萃分析。虽然没有发现与欧洲晚发性受试者有显著关联，但对523名来自欧洲血统的早发性受试者的荟萃分析表明，与AA组相比，携带至少一个G等位基因的人经历哮喘恶化的几率增加(优势比=2.92，95%可信区间：1.0-8.18，I2=62%，p=0.0412)。当与其他民族进行Meta分析时，未发现哮喘加重的风险显著增加(OR=1.6，95%CI：0.61-4.19，I2=85%，P=0.342)。我们的研究表明，LTA4H的遗传变异，以及哮喘发作的时间，可能有助于孟鲁司特反应的变异性。至少携带一份rs2660845拷贝的欧洲早发性(≤18y)患者在接受孟鲁司特治疗后，病情恶化的奇数增加，可能是由于LTA4H活性上调所致。这些发现支持使用孟鲁司特治疗哮喘的精确医学方法。
Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested 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 odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04–8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61–4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd 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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影响因子：
4
作者：
Turner SW;Ayres JG;Macfarlane TV;Mehta A;Mehta G;Palmer CN;Cunningham S;Adams T;Aniruddhan K;Bell C;Corrigan D;Cunningham J;Duncan A;Hunt G;Leece R;MacFadyen U;McCormick J;McLeish S;Mitra A;Miller D;Waxman E;Webb A;Wojcik S;Mukhopadhyay S;Macgregor D
通讯作者：
Macgregor D
影响因子：
2.1
作者：
Farzan, Niloufar;Vijverberg, Susanne J.;Maitland-van der Zee, Anke H.
通讯作者：
Maitland-van der Zee, Anke H.
影响因子：
158.5
作者：
Bouzigon, Emmanuelle;Corda, Eve;Demenais, Florence
通讯作者：
Demenais, Florence
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
3.7
作者：
Almomani B;Hawwa AF;Millership JS;Heaney L;Douglas I;McElnay JC;Shields MD
通讯作者：
Shields MD