Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study.

BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022). INTERPRETATION: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. FUNDING: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.

Exhaled carbon monoxide in asthmatic adults with bronchial reactivity: a prospective study.

HYPOTHESIS: We hypothesized that eCO may permit non-invasive assessment of disease activity in adults with asthma and bronchial reactivity. METHODS: A total of 209 participants 18 to 65 years of age with a diagnosis of asthma and bronchial reactivity provided data for analysis. The association between eCO and bronchial reactivity, forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), peak expiratory flow rate measurements (PEFR), asthma symptoms score, and bronchodilator use cross-sectionally and within-subject change in eCO were analyzed in relation to change in these variables over 6 weeks. RESULTS: There was no difference in eCO in those who were taking inhaled corticosteroids and those who were not (p = 0.33). There was also no cross-sectional or within-in subject association between eCO and bronchial reactivity, FEV(1), FVC, PEFR, symptoms score, or bronchodilator use. CONCLUSIONS: In a population of adults with bronchial reactivity, eCO has no or very limited potential as a biomarker of asthma activity.

An evaluation of the use of bronchoconstriction induced by deep inspiration as a new epidemiological measure for asthma.

RATIONALE: Bronchoconstriction after deep inhalation is associated with increased severity of asthma and is also a predictor of length of hospital stay in individuals admitted with asthma exacerbations. We hypothesized that this effect may represent a new non-invasive method to assess bronchial reactivity and other measures of asthma control. METHODS: We used a cross-sectional study design recruiting participants 18 to 65 years of age with a physician diagnosis of asthma. All participants were asked to provide three serial peak expiratory flow rate (PEFR) measurements in the morning, and bronchial reactivity was measured up to a maximum inhaled dose of 24.5 micromoL methacholine on the same day. Participants also recorded their asthma symptoms score and bronchodilator use during the 7 days before measuring bronchial reactivity. RESULTS: A total of 127 people provided data for analysis. There was no significant relationship between bronchoconstriction after deep inhalation (as measured by three serial PEFR measurements) and either bronchial reactivity to methacholine, asthma symptoms, or bronchodilator use. CONCLUSIONS: Bronchoconstriction induced by deep inspiration does not appear to be a valid marker of airway hyperresponsiveness or asthma severity in adults with mild to moderate asthma.

Does a low sodium diet modify heart rate variability? A randomised placebo-controlled double-blind trial.

BACKGROUND: Increased heart rate variability (HRV) is associated with a low risk of mortality, as is consuming a low sodium diet. As the survival benefits of a low sodium diet may be mediated partly by an increase in HRV, we have tested the hypothesis that adopting a low sodium diet increases HRV. METHODS: We used a randomised double-blind placebo-controlled trial design. Participants were aged 18-65 years old, had a physician diagnosis of asthma. All adopted a low sodium diet and they were randomised to receive either 80 mmol/day of oral sodium supplements (normal sodium intake - NSI) or matched placebo (low sodium intake-LSI) for 6 weeks. The primary outcome was change in SDNN (standard deviation of the N-N intervals); secondary outcomes were changes in other time domain and frequency domain measures of HRV. RESULTS: In those allocated to the LSI, mean daily urinary sodium excretion decreased by 22 mmol; and in those allocated to the NSI mean daily urinary sodium excretion increased by 31 mmol. There were no differences between the two groups for either the primary or secondary outcome measures. The mean difference in change in SDNN between those who received the LSI compared to the NSI was -2.7 ms (95% Confidence Intervals CI; -18.0 to +12.6). CONCLUSIONS: Adopting a low sodium diet does not have an impact on SDNN over a 6 weeks period. Future studies should aim to achieve a larger change in dietary sodium intake for a longer duration than 6 weeks.

Does a low sodium diet improve asthma control? A randomized controlled trial.

RATIONALE: Observational studies and initial randomized trials have indicated that a low sodium diet may improve asthma control. OBJECTIVES: We tested the hypothesis that a low sodium diet would improve asthma control over a 6-week period. METHODS: Participants with a physician diagnosis of asthma and measurable bronchial reactivity to methacholine entered a randomized double-blind placebo-controlled trial. All adopted a low sodium diet and were randomized to receive either 80 mmol/day of oral sodium supplements (normal sodium intake) or matched placebo (low sodium intake) for 6 weeks. The primary outcome was change in bronchial reactivity to methacholine; secondary outcomes were change in lung function, morning and evening peak expiratory flow, asthma symptoms score, daily bronchodilator use, Juniper Standardized Asthma Quality of Life Questionnaire score, and atopy. MEASUREMENTS AND MAIN RESULTS: A total of 220 individuals entered the study, of whom 199 completed the protocol. In the low sodium-intake group, mean daily urinary sodium excretion decreased by 20 mmol (SD, 64 mmol) and in the normal-sodium-intake group increased by 28 mmol (SD, 74 mmol). There were no differences between the two groups in the primary or secondary outcome measures; the mean difference in bronchial reactivity between the low- and normal-intake groups was -0.03 doubling doses of methacholine (95% confidence interval, -0.60 to 0.53). CONCLUSIONS: The use of a low sodium diet as an adjunctive therapy to normal treatment has no additional therapeutic benefit in adults with asthma and bronchial reactivity to methacholine.