LTA4H association with montelukast response in early and late-onset asthma

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: 0.98–10.93, 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: 0.56-5.09, 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 (≤18y) 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement BREATHE was funded by Scottish Enterprise Tayside, the Gannochy trust, the Perth and Kinross City Council and Brighton and Sussex Medical School. Tayside RCT is supported by Merck, Sharpe and Dohme, United Kingdom. PAGES was funded by the Chief Scientist Officer for Scotland. The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. The GoDARTS study was funded by The Wellcome Trust (Award 072960 and 084726) and the UK Medical Research Council (Award G0601261). Genotyping of PAGES was funded by grant AC15/00015 by Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Programmed framework, and by the SysPharmPedia grant. The SysPharmPediA consortium is supported by ZonMW [project number: 9003035001], the Ministry of Education, Science and Sport of the Republic of Slovenia [contract number C330-16-500106], the German Ministry of Education and Research (BMBF) [project number FKZ 031L0088], Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Programme framework [award numbers AC15/00015 and AC15/00058] under the frame of the ERACoSysMed JTC-1 Call. Genotyping service was carried out at CEGEN-PRB3-ISCIII; supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and European Regional Development Fund (ERDF). GALA II and SAGE were supported by the NHLBI of the United States National Institutes of Health (NIH) through grants R01HL117004 and X01HL134589. Additional study enrolment was supported by the Sandler Family Foundation, the American Asthma Foundation, the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, and the National Institute of Environmental Health Sciences (NIEHS) grant R01ES015794. The generation, cleaning, quality control, and analysis of GALA II and SAGE data was funded by the NHLBI grants R01HL128439, R01HL135156, R01HL141992, and R01HL141845; the NIEHS grant R21ES24844; the National Institute on Minority Healthand Health Disparities (NIMHD) P60MD006902, R01MD010443, and R56MD013312; the National Institute of General Medical Sciences (NIGMS) grant RL5GM118984; the Tobacco-Related Disease Research Program under Award Numbers 24RT-0025 and 27IR-0030; and the National Human Genome Research Institute (NHGRI) U01HG009080 to EGB. CM is supported by an AstraZeneca postdoctoral fellowship. EH-L is supported by a fellowship (PRE2018-083837) from the Spanish Ministry of Science, Innovation and Universities. MP-Y is funded by the Ramon y Cajal Program by the Spanish Ministry of Economy, Industry and Competitiveness (RYC- 2015-17205). N.H-P was supported by a fellowship (FI16/00136) from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Social Funds from the European Union (ESF) ESF invests in your future. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The studies included in this article comply with the Declaration of Helsinki, and locally appointed ethics committee have approved respective research protocols and informed consent has been obtained from the subjects. PAGES was approved by the Cornwall and Plymouth Research Ethics Committee (Plymouth, United Kingdom). GoSHARE, BREATHE and Tayside RCT was approved by the Tayside Committee on Medical Research Ethics (Dundee, United Kingdom). The UKBiobank was approved by the National Research Ethics Committee. 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