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Background Combination treatments, targeting multiple disease processes, benefit subjects with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, predicting treatment response and exacerbation risk remain challenging. Objective To identify genetic associations with AECOPD risk and response to combination therapy (fluticasone furoate, umeclidinium bromide and vilanterol). Methods The genetic basis of AECOPD disease was investigated in 19,841 subjects from 23 clinical studies and 2 disease cohorts to identify exacerbation disease targets. AECOPD pharmacogenetic effects were examined in 8,439 moderate to severe COPD patients with exacerbation rate, lung function and quality of life endpoints; results were followed up in an additional 2,201 subjects. Results We did not identify significant associations in the AECOPD disease analysis. In the AECOPD pharmacogenetics analysis, rs56195836 (MAPK8) was significantly associated with moderate to severe exacerbation rate in subjects on fluticasone furoate with baseline blood eosinophils ≥150 cells/μl (P = 1.8 x 10-8). Post-hoc, one variant was associated with on-treatment moderate to severe exacerbation rate stratifying by exacerbation history. AZU1 rs1962343 was significantly associated in subjects with frequent moderate exacerbation history when treated with fluticasone furoate/vilanterol (P = 1.1 x 10-8). Neither of these signals was supported in independent follow-up. Conclusion Common genetic variants do not play major roles in AECOPD disease nor predict response to triple therapy or its components in moderate to very severe COPD.

To The Editor: Inhaled corticosteroids (ICS) are the primary anti-inflammatory therapy for the control and management of asthma, but their effects are characterised by some inter-individual variability that may have a genetic basis1–4. Identification of genetic markers that predict ICS treatment response will facilitate individualised treatment for asthma patients in the future, particularly in those with more severe disease. An association between genetic variation in GLCCI1 and response to ICS therapy in non-Hispanic white asthma subjects was observed by Tantisira et al.5 Genome wide association analysis of 118 trios (one asthmatic child and two parents) from the NHLBI Childhood Asthma Management Program (CAMP) identified 13 single nucleotide polymorphisms (SNPs) with evidence for association with the level of ICS treatment response. These 13 SNPs which included the GLCCI1 promoter polymorphism rs37972, were genotyped and evaluated in four additional independent collections: adult studies SOCS (Salmeterol Or CorticosteroidS) and SLIC (SalmeteroL ± Inhaled CorticosteroidS) (n=264); a second adult study (n=385); LOCCS (Leukotriene modifier Or Corticosteroid or Corticosteroid-Salmeterol) (n=185) and CARE (Childhood Asthma Research and Education) (n=101). In three of the four replicate populations GLCCI1 rs37973, a functional promoter polymorphism5 in complete linkage disequilibrium with rs37972 in white populations, was associated (P

Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism.The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network).A significant association of the coding polymorphism, 601AG, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601AG were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601AG compared to wild-type CYSLTR2.Since 601AG alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.

Background Inhaled corticosteroids (ICSs) are considered the most effective anti-inflammatory therapy for asthma control and management; however, there is substantial treatment response variability. Objective We sought to identify genetic markers of ICS response by conducting the largest pharmacogenetic investigation to date in 2672 ICS-treated patients with asthma. Methods Genotyping and imputation was performed in fluticasone furoate (FF) or fluticasone propionate–treated patients with asthma from 3 phase IIB and 4 phase IIIA randomized, double-blind, placebo-controlled, parallel group, multicenter studies. The primary end point analyzed was change in trough FEV 1 (ΔFEV 1 ) from baseline to 8 to 12 weeks of treatment. Results More than 9.8 million common genetic variants (minor allele frequency ≥ 1%) were analyzed to test for association with ΔFEV 1 . No genetic variant met the prespecified threshold for statistical significance. Conclusions This study provides no evidence to confirm previously reported associations between candidate genetic variants and ICS response (ΔFEV 1 ) in patients with asthma. In addition, no variant satisfied the criterion for genome-wide significance in our study. Common genetic variants are therefore unlikely to prove useful as predictive biomarkers of ICS response in patients with asthma.

Background The efficacy of inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD) varies between patients, which may be partially due to genetic differences. A single-nucleotide polymorphism, rs37972, in the glucocorticoid-induced transcript 1 gene (GLCCI1) has been associated with variations in response (forced expiratory volume in 1 s [FEV1] and residual volume) to fluticasone propionate (Groningen and Leiden Universities Study of Corticosteroids in Obstructive Lung Disease [GLUCOLD] study). The aim of this study was to determine whether variation in the GLCCI1 gene at rs37973 is associated with ICS response in patients with COPD.