Genetic susceptibility to allergic bronchopulmonary aspergillosis in asthma: a genetic association study

Abstract

Background: In patients with asthma, the fungus Aspergillus fumigatus can cause allergic bronchopulmonary aspergillosis (ABPA). Familial ABPA is reported, and some genetic factors have been associated with the disease, however, these are small studies (n ≤ 38) and do not explain all cases of ABPA.

Methods: We analysed SNPs in 95 ABPA patients, comparing frequencies to 152 atopic asthmatic and 279 healthy controls. Twenty two genes were selected from literature, and 195 tagging SNPs were analysed for genetic association with ABPA using logistic regression corrected for multiple testing. We also analysed monocyte-derived macrophage gene expression before and during co-culture with A. fumigatus.

Results: Seventeen ABPA-associated SNPs (ABPA v Atopic asthma) were identified. Three remained significant after correction for multiple testing; IL13 rs20541, IL4R rs3024656, TLR3 rs1879026. We also identified minor differences in macrophage gene expression responses in the ABPA group compared to the control groups.

Conclusions: Multiple SNPs are now associated with ABPA. Some are novel associations. These associations implicate cytokine pathways and receptors in the aberrant response to A. fumigatus and susceptibility to ABPA, providing insights into the pathogenesis of ABPA and/or its complications. We hope these results will lead to increased understanding and improved treatment and diagnostics for ABPA.

Keywords: ABPA; Asthma; Genetic susceptibility; IL13; IL4R; TLR3.

Fig. 1

Genotype frequencies of SNPs associated with ABPA after correction for multiple testing

Fig. 2

Expression of TLRs by MDMs from ABPA, asthmatic and healthy subjects (n = 10, pooled). a–d show expression in the ABPA (black bars) and asthma groups (grey bars) relative to the healthy group (dotted line) at each time point. Stars indicate significant differences between ABPA and asthma, calculated by t-test. e–h show expression in ABPA (open circles), asthmatic (closed squares) and healthy (closed triangles) subjects over time, relative to asthma 0 h. Stars indicate significant changes over time, calculated by repeated measures 1-way ANOVA. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Bars indicate standard deviation of the three replicates

Fig. 3

Expression of TREM1 by MDMs from ABPA, asthmatic and healthy subjects (n = 10, pooled). a shows expression in the ABPA (black bars) and asthma groups (grey bars) relative to the healthy group (dotted line) at each time point. Stars indicate significant differences between ABPA and asthma, calculated by t-test. b shows expression in ABPA (open circles), asthmatic (closed squares) and healthy (closed triangles) subjects over time, relative to asthma 0 h. Stars indicate significant changes over time, calculated by repeated measures 1-way ANOVA. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Bars indicate standard deviation of the three replicates