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Background: Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes. Objective: Linkage and association analyses using 587 United Kingdom and Dutch asthma families (n = 2819 subjects) were used to investigate this region. Methods: A 3-phase procedure was used: (1) linkage and association analyses using 15 microsatellite markers spanning 14.4 mega base pairs (Mbps) on 19q13, (2) fine mapping of the refined region using 26 haplotype tagging single nucleotide polymorphisms (SNPs), and (3) dense gene analyses using 18 SNPs evaluated for association with asthma, bronchial hyperresponsiveness (BHR), FEV1, plasma urokinase plasminogen activator receptor (PLAUR), and rate of annual FEV1 decline in subjects with asthma. Results: The microsatellite analyses provided tentative support for an asthma/lung function susceptibility locus (48.9-49.1Mbps), and fine mapping localized modest association to the PLAUR gene. PLAUR SNPs in the 5′ region, intron 3, and 3′ region are associated with asthma and BHR susceptibility and predict FEV1 and plasma PLAUR levels. SNPs in the 5′ region showed association for asthma (2 populations), FEV1 (2 populations), and BHR (2 populations) phenotypes. SNPs in intron 3 showed association with asthma (2 populations) and BHR (3 populations). Importantly, the same 5′ region and intron 3 SNPs were associated with plasma PLAUR levels. The same 5′ region and 3′ region SNPs were found to be determinants of FEV1 decline in subjects with asthma. Conclusion: This study represents the first report to identify PLAUR as a potential asthma susceptibility gene and determine PLAUR regions underlying this association, including a role in influencing plasma PLAUR levels. Finally, the association of PLAUR with lung function decline supports a role for PLAUR in airway remodeling in asthma. [Copyright &y& Elsevier]

Rationale: Guidelines advocate adding long-acting β-agonist (LABA) to inhaled corticosteroid as the preferred step-up therapy to increasing inhaled corticosteroid dose for patients with uncontrolled asthma on inhaled corticosteroid monotherapy. However, less than 5% of patients with asthma qualify for the randomized controlled trials on which guidelines are based. Thus, real-world data are needed to complement the results of randomized trials with narrow entry criteria., Objectives: To compare the effectiveness of stepping up asthma therapy with an increased dose of various types of inhaled corticosteroid as compared with add-on LABA., Methods: We performed a historical matched cohort study using large primary care databases to compare asthma step-up therapy with small- and standard size-particle inhaled corticosteroid versus added LABA for patients 12-80 years old. As outcomes, we examined a composite of asthma control and rates of severe exacerbations., Measurements and Main Results: The odds of asthma control and rates of severe exacerbations over one outcome year were comparable with increased inhaled corticosteroid dose versus added LABA. The adjusted odds ratios (95% confidence interval) for achieving asthma control with increased inhaled corticosteroid dose versus inhaled corticosteroid/LABA were 0.99 (0.88-1.12) for small-particle inhaled corticosteroid (n = 3,036 per cohort) and 0.85 (0.67-1.07) for standard size-particle inhaled corticosteroid (n = 809 per cohort). The adjusted rate ratios (95% confidence interval) for severe exacerbations, compared with inhaled corticosteroid/LABA combination inhaler, were 1.04 (0.91-1.20) and 1.18 (0.92-1.54), respectively. The results were not affected by smoking status., Conclusions: When applied to a broad primary care population, antiinflammatory therapy using increased doses of small- or standard size-particle inhaled corticosteroid is as effective as adding LABA, as measured by outcomes important to both patients and providers. Real-world populations and outcomes need to be taken into consideration when formulating treatment recommendations.

Background: Real-life studies are needed to determine the cost-effectiveness of asthma therapies in clinical practice., Aim: To compare the cost-effectiveness of extrafine-particle inhaled corticosteroid (ICS) with standard size-particle ICS in the United Kingdom (UK) and United States (US)., Methods: These retrospective matched cohort analyses used large electronic databases to study asthma-related outcomes for patients in the UK (12-60 years old; n=1730) and US (12-80 years; n=10,312) prescribed extrafine beclomethasone or fluticasone as their first ICS therapy for asthma. Patients were matched on demographic characteristics and asthma severity during 1 baseline year, and asthma control and asthma-related costs were compared during 1 outcome year., Results: In both the UK and US, adjusted odds of risk-domain asthma control were similar, whereas the odds of overall control (no hospitalisation or oral steroids for asthma, no antibiotics for lower respiratory infection, limited reliever use) were greater for extrafine ICS in both countries (UK odds ratio, 1.23; 95% confidence interval (CI), 1.01-1.50). Asthma-related annual costs, adjusted for baseline, were significantly lower for extrafine-particle ICS cohorts in both countries (UK difference, -£66 (95% CI,-93 to -37)). Cost-effectiveness analyses using the two measures of asthma control found 92 and 98% probabilities of extrafine-particle ICS being the preferred treatment strategy (less costly and more effective than standard size-particle ICS) in the UK, and 84 and 100% probabilities in the US., Conclusions: Initiating ICS therapy for asthma as extrafine-particle ICS seems the dominant treatment option (less costly and more effective) compared with standard size-particle ICS in both the UK and the US.