Background: Many genes are associated with asthma severity1. However, studies on the association of genes with a measure of asthma severity enabling to catch the heterogeneity of the phenotypes are needed. Aims: To assess the single nucleotide polymorphisms (SNPs) associated with an overall severity score in adult subjects with active or non-active asthma. Methods: We evaluated 334 asthmatic subjects (aged 20-64) from the general population in Verona, who were identified in the clinical stage of an Italian multi-centre (multi)casecontrol study (GEIRD; 2008-2010)2. A panel of 384 Tag-SNPs (representative of 69 candidate genes) was genotyped by a custom GoldenGate Genotyping Assay. A symptom score [range: from 0 (non-active asthma and no respiratory symptoms in the past 12 months) to 8.5 (active asthma and maximum frequency of respiratory symptoms in the past 12 months)] was computed by a nonlinear principal component analysis (NLPC). The overall severity score was computed as a function of the symptom score, treatment (0=no treatment, 1=relievers only, 2=inhaled corticosteroids), and lung function (LF) [0=normal, 1=borderline, 2=airflow obstruction (AO) with FEV1 ≥80% predicted, 3=AO with FEV1 <80% predicted] by a second NLPC. For each SNP, the association with the overall severity score and the symptom score was tested by quasi-gamma models, whereas the association with treatment and LF was tested by ordered logistic models, adjusting for gender, BMI, and smoking habits. Simes multiple testing procedure was used for controlling the false discovery rate (FDR)3. Results: A SNP in the IL13 gene region was associated with the overall severity score (uncorrected p=0.0001; FDR-corrected p=0.036), whereas a second SNP in linkage disequilibrium (LD; r2=0.94) did not reach the statistical significance after the correction for multiple comparisons (uncorrected p=0.0006; FDR-corrected p=0.09). Both the SNPs were strongly associated with the symptom score (uncorrected p≤0.00004; FDR-corrected p≤0.006), but they were not associated with treatment and LF. A SNP in the SMAD3 gene region was associated with LF only (uncorrected p=0.00007; FDRcorrected p=0.021). Conclusions: Our results suggest that IL13 and SMAD3 gene regions (or genes in LD) play a role in asthma severity in adults.

ASSOCIATION ANALYSIS OF CANDIDATE GENE POLYMORPHISMS WITH ASTHMA SEVERITY: RESULTS FROM THE GEIRD STUDY

ACCORDINI, Simone;Calciano, Lucia;BOMBIERI, Cristina;MALERBA, Giovanni;BALDAN, Alessandro;BELPINATI, Francesca;FERRARI, Marcello;LO PRESTI, Anna Rita;PERBELLINI, Luigi;PIGNATTI, Pierfranco;DE MARCO, Roberto
2013

Abstract

Background: Many genes are associated with asthma severity1. However, studies on the association of genes with a measure of asthma severity enabling to catch the heterogeneity of the phenotypes are needed. Aims: To assess the single nucleotide polymorphisms (SNPs) associated with an overall severity score in adult subjects with active or non-active asthma. Methods: We evaluated 334 asthmatic subjects (aged 20-64) from the general population in Verona, who were identified in the clinical stage of an Italian multi-centre (multi)casecontrol study (GEIRD; 2008-2010)2. A panel of 384 Tag-SNPs (representative of 69 candidate genes) was genotyped by a custom GoldenGate Genotyping Assay. A symptom score [range: from 0 (non-active asthma and no respiratory symptoms in the past 12 months) to 8.5 (active asthma and maximum frequency of respiratory symptoms in the past 12 months)] was computed by a nonlinear principal component analysis (NLPC). The overall severity score was computed as a function of the symptom score, treatment (0=no treatment, 1=relievers only, 2=inhaled corticosteroids), and lung function (LF) [0=normal, 1=borderline, 2=airflow obstruction (AO) with FEV1 ≥80% predicted, 3=AO with FEV1 <80% predicted] by a second NLPC. For each SNP, the association with the overall severity score and the symptom score was tested by quasi-gamma models, whereas the association with treatment and LF was tested by ordered logistic models, adjusting for gender, BMI, and smoking habits. Simes multiple testing procedure was used for controlling the false discovery rate (FDR)3. Results: A SNP in the IL13 gene region was associated with the overall severity score (uncorrected p=0.0001; FDR-corrected p=0.036), whereas a second SNP in linkage disequilibrium (LD; r2=0.94) did not reach the statistical significance after the correction for multiple comparisons (uncorrected p=0.0006; FDR-corrected p=0.09). Both the SNPs were strongly associated with the symptom score (uncorrected p≤0.00004; FDR-corrected p≤0.006), but they were not associated with treatment and LF. A SNP in the SMAD3 gene region was associated with LF only (uncorrected p=0.00007; FDRcorrected p=0.021). Conclusions: Our results suggest that IL13 and SMAD3 gene regions (or genes in LD) play a role in asthma severity in adults.
Genetics; Asthma - mechanism; Epidemiology
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/871590
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