BackgroundThe genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p¼1.03310 (À8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p¼5.59310 (À8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Previous studies showed poor correlation between asthma symptoms and spirometric-based bronchial provocation tests. Use of impulse oscillometry (IOS) in airways resistance measurement may be more sensitive. In 20 individuals with stable asthma, we analysed the relationship between methacholine-induced asthma symptoms scores, IOS and spirometry. Following a screening visit, methacholine challenge testing was performed twice (visits 1 and 2). Dyspnoea, tightness and wheeze were quantified using visual analogue scores. IOS and spirometry were conducted at each incremental dose of methacholine. The Pearson correlation coefficient and linear regression analyses were conducted to explore the relations. A significant correlation was observed between methacholine-induced dyspnoea scores and the change in IOS measures of R((5)) (r=0.62, p=0.004) and X(5) (r=0.51, p=0.022), but not with the spirometric changes in FEV((1)) (r=0.37(,)p=0.11) or MEF(50) (r=0.32, p=0.17). In a multiple linear regression model, R(5) was the only significant variable to explain dyspnoea variability (p=0.003). Results of correlation analyses for chest tightness were similar to those obtained with dyspnoea. However, the symptom of wheeze showed correlation with IOS and spirometry. We conclude that airway resistance measured by IOS during methacholine challenge correlates better with asthma symptoms than traditional spirometric measures implying a higher sensitivity index.

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We conducted a case-control study at three main inner-city hospitals in Birmingham, UK between 2004 and 2006, to determine the risk of adverse perinatal outcomes in pregnant women with tuberculosis (TB) (n = 24), compared with healthy pregnant controls (n = 72). The incidence of TB was 62/100,000 pregnancies, with 54.2% cases having pulmonary TB (41.7% extra-pulmonary; 4.2% both). Infants of mothers with TB had a significantly lower mean birth weight compared with controls (2,735 g vs 3,135 g; p = 0.03). Mean birth weight was lower in pulmonary TB than in the extra-pulmonary TB. Multivariate analysis showed that low birth weight was associated with pre-term delivery (p < 0.001). We conclude that pregnant women with TB are at higher risk of low birth weight due to higher odds of pre-term delivery.