LTA4H rs2660845 association with montelukast response in early and late-onset asthma.
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 ethnic...
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Public Library of Science (PLoS)
2021-01-01
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| author | Cyrielle Maroteau Antonio Espuela-Ortiz Esther Herrera-Luis Sundararajan Srinivasan Fiona Carr Roger Tavendale Karen Wilson Natalia Hernandez-Pacheco James D Chalmers Steve Turner Somnath Mukhopadhyay Anke-Hilse Maitland-van der Zee Esteban G Burchard Maria Pino-Yanes Simon Young Glenda Lassi Adam Platt Colin N A Palmer PiCA Consortium |
| author_facet | Cyrielle Maroteau Antonio Espuela-Ortiz Esther Herrera-Luis Sundararajan Srinivasan Fiona Carr Roger Tavendale Karen Wilson Natalia Hernandez-Pacheco James D Chalmers Steve Turner Somnath Mukhopadhyay Anke-Hilse Maitland-van der Zee Esteban G Burchard Maria Pino-Yanes Simon Young Glenda Lassi Adam Platt Colin N A Palmer PiCA Consortium |
| author_sort | Cyrielle Maroteau |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-336ae4e495164e158dd79d9dc9b0ed2d |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-336ae4e495164e158dd79d9dc9b0ed2d2025-01-17T05:32:03ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01169e025739610.1371/journal.pone.0257396LTA4H rs2660845 association with montelukast response in early and late-onset asthma.Cyrielle MaroteauAntonio Espuela-OrtizEsther Herrera-LuisSundararajan SrinivasanFiona CarrRoger TavendaleKaren WilsonNatalia Hernandez-PachecoJames D ChalmersSteve TurnerSomnath MukhopadhyayAnke-Hilse Maitland-van der ZeeEsteban G BurchardMaria Pino-YanesSimon YoungGlenda LassiAdam PlattColin N A PalmerPiCA ConsortiumLeukotrienes 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0257396&type=printable |
| spellingShingle | Cyrielle Maroteau Antonio Espuela-Ortiz Esther Herrera-Luis Sundararajan Srinivasan Fiona Carr Roger Tavendale Karen Wilson Natalia Hernandez-Pacheco James D Chalmers Steve Turner Somnath Mukhopadhyay Anke-Hilse Maitland-van der Zee Esteban G Burchard Maria Pino-Yanes Simon Young Glenda Lassi Adam Platt Colin N A Palmer PiCA Consortium LTA4H rs2660845 association with montelukast response in early and late-onset asthma. PLoS ONE |
| title | LTA4H rs2660845 association with montelukast response in early and late-onset asthma. |
| title_full | LTA4H rs2660845 association with montelukast response in early and late-onset asthma. |
| title_fullStr | LTA4H rs2660845 association with montelukast response in early and late-onset asthma. |
| title_full_unstemmed | LTA4H rs2660845 association with montelukast response in early and late-onset asthma. |
| title_short | LTA4H rs2660845 association with montelukast response in early and late-onset asthma. |
| title_sort | lta4h rs2660845 association with montelukast response in early and late onset asthma |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0257396&type=printable |
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