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LTA4H rs2660845 association with montelukast response in early and late-onset asthma.

ABSTRACT: 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.

SUBMITTER: Maroteau C

PROVIDER: S-EPMC8457475 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLimited information exists about the nature of late-onset asthma (LOA) without medication intervention when compared to early-onset asthma (EOA). Our goal was to understand how EOA and LOA affect clinical and pathophysiological features.MethodsA population-based cross-sectional study was carried out in Zhongshan Hospital (Shanghai, China). EOA and LOA were based on age of diagnosis (before and after age 40 years, respectively). Clinical variables were collected with an emphasis on allergic features, analyzed, related, and compared using one-way ANOVA or Kruskal-Wallis test. Correlations between blood basophils and clinical data were evaluated by Spearman's rank test. Statistical analyses were conducted with SPSS v24.0.ResultsOf a total of 12,760 adults with cough, sputum, or chest tightness, 90 subjects with EOA (mean age ± standard deviation (SD):28.73 ± 5.89), 111 with LOA (mean age ± SD: 60.25 ± 9.85), and 106 with chronic obstructive pulmonary disease (COPD) (mean age ± SD: 61.58 ± 10.95) were selected. FEV1/FVC (%), FEV1% predicted, and FVC% predicted were all significantly lower in LOA compared to EOA (p < 0.01). The values of post-bronchodilator FEV1 in bronchodilator reversibility testing were higher in the LOA and EOA groups compared to subjects with COPD (p < 0.01). Among allergic features, mite sensitization was most common in EOA patients, followed by LOA and COPD, whereas mold sensitization was more prevalent in LOA than EOA. Moreover, blood eosinophils were a typical feature of asthma in both EOA and LOA compared to COPD and controls (p < 0.01), and there were no differences in blood neutrophils in LOA compared to controls. Interestingly, blood basophils were increased in both EOA (p < 0.01) and LOA (p < 0.05) compared to COPD and controls. This variable correlated with eosinophils in EOA (r = 0.549, p=0.002) but not in LOA.ConclusionLOA is a distinct clinical entity from EOA. In LOA, atopy was less frequent and spirometry values were lower when compared to EOA. In EOA, blood basophils and eosinophils were significantly correlated owing to pathophysiological differences between the two forms of the disease.

Project description:Studies of asthma phenotypes have identified obesity as a component of a group characterized by a high proportion of subjects with adult-onset asthma. However, whether age of asthma onset modifies the association between obesity and asthma is unknown.We sought to compare the associations between body mass index (BMI) categories with physiological, inflammatory, and clinical parameters across age of asthma onset phenotypes; and to compare the rate of BMI change in relation to asthma duration, by age of onset asthma phenotypes.From the Severe Asthma Research Program, we defined age of asthma onset as early (<12 years of age) and late (?12 years of age). Comparisons of BMI categories were done within age-of-onset groups, and obesity was also compared across these groups. Multivariable logistic regression analysis was done to evaluate the association between BMI categories with health care use and respiratory symptoms and multivariable linear regression for the association between duration of asthma and weight gain (BMI change per year). An interaction between obesity and age of asthma onset was included in the multivariable analyses.The study population consisted of 1049 subjects, and the median age for asthma onset was 10 years (interquartile range, 4-25 years); 48% had late-onset asthma (?12 years of age), and 52% had early-onset asthma (<12 years of age). Compared with obese subjects with late-onset asthma, obese subjects with early-onset asthma had more airway obstruction, bronchial hyperresponsiveness, and higher odds ratios of ever having 3 or more previous oral steroid tapers per year or intensive care unit admissions for asthma per preceding year (interactions between obesity and age of asthma onset were P = .055 and P = .02, respectively). In subjects with early-onset asthma but not in subjects with late-onset asthma, there was a significant association between increasing BMI and duration of asthma after adjusting for confounders. The interaction between asthma duration and age of asthma onset was a P value of less than .01.Asthmatic subjects are differentially affected by obesity based on whether they had asthma early (<12 years of age) or later in life. These results highlight the need to understand obesity as a comorbidity that affects specific clinical phenotypes and not all asthma subjects alike.

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LTA4H rs2660845 association with montelukast response in early and late-onset asthma.

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