Abstract
Different genes are associated with categorical classifications of asthma severity. However, continuous outcomes should be used to catch the heterogeneity of asthma phenotypes and to increase the power in association studies. Accordingly, the aim of this study was to evaluate the association between single nucleotide polymorphisms (SNPs) in candidate gene regions and continuous measures of asthma severity, in adult patients from the general population. In the Gene Environment Interactions in Respiratory Diseases (GEIRD) study (www.geird.org), 326 subjects (aged 20–64) with ever asthma were identified from the general population in Verona (Italy) between 2007 and 2010. A panel of 236 SNPs tagging 51 candidate gene regions (including one or more genes) was analysed. A symptom and treatment score (STS) and pre-bronchodilator FEV1% predicted were used as continuous measures of asthma severity. The association of each SNP with STS and FEV1% predicted was tested by fitting quasi-gamma and linear regression models, respectively, with gender, body mass index and smoking habits as potential confounders. The Simes multiple-test procedure was used for controlling the false discovery rate (FDR). SNP rs848 in the IL13 gene region (IL5/RAD50/IL13/IL4) was associated with STS (TG/GG vs TT genotype: uncorrected p-value = 0.00006, FDR-corrected p-value = 0.04), whereas rs20541 in the same gene region, in linkage disequilibrium with rs848 (r2 = 0.94) in our sample, did not reach the statistical significance after adjusting for multiple testing (TC/CC vs TT: uncorrected p-value = 0.0003, FDR-corrected p-value = 0.09). Polymorphisms in other gene regions showed a non-significant moderate association with STS (IL12B, TNS1) or lung function (SERPINE2, GATA3, IL5, NPNT, FAM13A) only. After adjusting for multiple testing and potential confounders, SNP rs848 in the IL13 gene region is significantly associated with a continuous measure of symptom severity in adult subjects with ever asthma.
Highlights
Asthma is a complex chronic disease that involves the interaction among multiple genetic, environmental and life-style factors
The present study is aimed at assessing the association between candidate gene polymorphisms and continuous measures of disease severity in adult subjects with ever asthma, who were identified from the general population in Italy
Single nucleotide polymorphism (SNP) rs848 in the IL13 gene region is significantly associated with a continuous measure of symptom severity in adult subjects with ever asthma, who were identified from the general population in Italy; Fig 4
Summary
Asthma is a complex chronic disease that involves the interaction among multiple genetic, environmental and life-style factors. The genetic of asthma has been investigated in many association studies, which have shown that different genes are likely to play a role in disease severity. Polymorphisms in ADRB2 [1], ARG1 and ARG2 [2], CTLA4 [3], IL4 [4], IL4R [5], IL18 [6], TGFB1 [7] and TLR4 [8] genes are associated with asthma severity in several populations. Polymorphisms in ADAM33 are associated with adult-onset asthma and disease severity [9], and this gene and ADAM8 may contribute to the remodelling process that occurs with asthma progression [10]. The expression of IL33 increases in patients with a severe form of the disease [15]
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