Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients.

One of the major asthma susceptibility loci is 17q12-17q21.1, but the relationship between this locus and adult asthma is unclear. Association analysis of 13 single nucleotide polymorphisms (SNPs) and haplotypes from 17q12-17q21.1 was performed in 418 adult patients with asthma and 288 controls from Slovenia. Single SNP analysis revealed only marginal associations with adult asthma for SNPs located in GSDMA, GSDMB, ORMDL3 and ZPBP2 genes, and rs7219080 was the most highly associated. Analyses of asthma phenotypes found no association with atopy or lung function, but rs2305480 and rs8066582 were associated with childhood asthma and rs9916279 was associated with asthma in smokers. Notably, haplotypes consisting of rs9916279, rs8066582, rs1042658, and rs2302777 harbouring PSMD3, CSF3 and MED24 genes were highly associated with asthma. The four most common haplotypes, TCCG, TTTA, CCCA and TTCA, were more frequent in patients with asthma, whereas TTCG, TCCA, TCTA and TTTG were more frequent in controls. Only 3% of asthma patients belonged to haplotypes TTCG, TCCA, TCTA and TTTG compared with nearly one-third (31%) of controls. Associations confirmed that the 17q12-17q21.1 locus harbours a genetic determinant for asthma risk in adults and suggest that in addition to the previously known ORMDL3-GSDM locus, CSF3-PSMD3-MED24 also plays a role in asthma pathogenesis.

Let-7a is differentially expressed in bronchial biopsies of patients with severe asthma.

Asthma is a chronic inflammatory disease. Around 5 to 10% of patients classified as having severe asthma can-not be adequately controlled despite the use of all currently available therapeutic approaches. Previous studies have revealed the potential important role of miRNAs in the regulation of a variety of inflammatory processes, including asthma. Expression of selected miRNAs, specifically let-7a, miR-21 and miR-223, that were shown to have important roles in asthma pathogenesis, were analyzed in bronchial biopsies of 24 patients with asthma, 12 mild and 12 severe, and 10 controls with no chronic disease. We found significantly reduced expression of let-7a in bronchial biopsies from patients with severe asthma in comparison to patients with mild asthma as well as in comparison to the non-asthmatic controls. On the other hand, no significant differences in miR-21 and miR-223 expression were found between the different groups analyzed. Reduced let-7a levels in bronchial biopsies of patients with severe therapy-resistant asthma could not only be used as a potential biomarker to discriminate between different asthma phenotypes, but also might be a target for modulation of treatment at the inflammatory site for a group of patients that are most affected and still lack effective treatment.

Asthma treatment outcome in adults is associated with rs9910408 in TBX21 gene.

Inhaled corticosteroids (ICS) are one of the most commonly used asthma therapies and have highly variable treatment success. Polymorphisms in TBX21, a gene important for the biological action of corticosteroids, could be associated with treatment response in asthmatics. We genotyped for rs9910408 in TBX21 in 208 adult asthmatic patients, treated at least 3 years with ICS. Polymorphism rs9910408 was associated with response to ICS treatment. When treatment success was assessed by a decrease in bronchial hyperresponsiveness (BHR), the frequency of AA genotype was significantly higher in good responders (P = 0.049). This genotype related response was even more evident in the subgroups of non-smokers (P = 0.008) and in non-atopic patients (P = 0.009). AA genotype was overrepresented among good responders according to changes in FEV1 in the subgroups of non-smokers (P = 0.013) and in non-atopic patients (P = 0.048). Our results showed that treatment response to ICS, assessed as changes in BHR and FEV1, is associated with TBX21.