From expression pattern to genetic association in asthma and asthma-related phenotypes
© Vaillancourt et al.; licensee BioMed Central Ltd. 2012
Received: 21 May 2012
Accepted: 6 November 2012
Published: 13 November 2012
Asthma is a complex disease characterized by hyperresponsiveness, obstruction and inflammation of the airways. To date, several studies using different approaches as candidate genes approach, genome wide association studies, linkage analysis and genomic expression leaded to the identification of over 300 genes involved in asthma pathophysiology. Combining results from two studies of genomic expression, this study aims to perform an association analysis between genes differently expressed in bronchial biopsies of asthmatics compared to controls and asthma-related phenotypes using the same French-Canadian Caucasian population.
Before correction, 31 of the 85 genes selected were associated with at least one asthma-related phenotype. We found four genes that survived the correction for multiple testing. The rs11630178 in aggrecan gene (AGC1) is associated with atopy (p=0.0003) and atopic asthma (p=0.0001), the rs1247653 in the interferon alpha-inducible protein 6 (IFI6), the rs1119529 in adrenergic, alpha-2A-, receptor (ADRA2A) and the rs13103321 in the alcohol dehydrogenase 1B (class I), beta polypeptide (ADH1B), are associated with asthma (p=0.019; 0.01 and 0.002 respectively).
To our knowledge, this is the first time those genes are associated with asthma and related traits. Consequently, our study confirms that genetic and expression studies are complementary to identify new candidate genes and to investigate their role to improve the comprehension of the complexity of asthma pathophysiology.
Asthma is a complex disease which is characterized by hyperresponsiveness, obstruction and inflammation of the airways and is modulated by the interaction of genetic and environmental factors. The appearance of an immune response and of a remodeling process, which implicates structural and inflammatory cells, dictates the development, the severity and the chronicity of asthma. Atopy, which also shows a genetic component, is characterized by the excessive production of immunoglobulin E in response to environmental allergens and is an important risk factor of asthma. Using candidate genes approach, genome wide association studies, linkage analysis or genomic expression, studies of the last decades revealed that the pathophysiology of asthma is related with more than 300 genes[4, 5]. Indeed, several studies showed that microarrays are a relevant tool to highlight genes that are implicated in the different processes occurring during asthma.[6, 7] This study aims firstly to demonstrate that expression and genetic association studies complement each other and secondly to test the hypothesis that differences in the expression of several genes identified in the studies of Laprise et al. and Chamberland et al. could be caused by genetic variants. To achieve this, we combined the results of Laprise et al. and Chamberland et al. and performed association analysis between the differently expressed genes and asthma-related phenotypes in the family sample of Saguenay–Lac-St-Jean (SLSJ). The present study identified four significantly associated genes, which are the aggrecan gene (AGC1) the interferon alpha-inducible protein 6 (IFI6), the adrenergic, alpha-2A-, receptor (ADRA2A) and the alcohol dehydrogenase 1B (class I), beta polypeptide (ADH1B).
Selection of genes
Differently expressed genes in two microarrays studies using bronchial tissues of asthmatic and control subjects
Immune signaling molecules
CX3CR1* † , IL7R † , CD14* † , SFRP1 † , SCYA21, SDF1, TNFRSF7, TRA@, CD19, ALOX15* † , NOS2A † , SCYA5, IL2RB † , IL1R2* †
COL11A1, FMOD, MUC5AC £ , MUC2 £ , COL2A1, AGC1, FBLN1, GPC3, MUC4 £ , SFRP4
IGKC, HLA-DPB1*, HLA-DQA1*, HLA-DQB1*, HLA-DRB4, TRBA £ , MS4A1, IGHM, IGLJ3, CEACAM5, ERAP2, IGHG1*, IGJ, IGLA, IGKV1D-13
PTPRC,IFI6, ARHGEF16, PSPHL, GNB2, SYK £ , PPP1R3C, PHLDA1, TYROBP, FKBP8, PIM2, FLRT3
CPA3*, GZMA, CTSC, CTSG £ , PSMA6, TPSB1 £ , SERPINB2, SERPINB4*, SPINK5
TM4SF3, KLRC3, LGALS7, NKG7, ARHGAP4, ADRA2A, CLCA2, CLDN10, KCNJ16
Free radical metabolism
GPX3, GSTA2, CYBA*, CYBB, NQO1* †
TCF21, ZNF38, LDB1, MAF, STAT5A
Cell growth and proliferation
GAS1, IGFBP6, CORO1A, TRIM16, EMP3, OGN, S100A14, S100P, SFN
Cell adhesion molecules
C1QB, C7 £ , CFD
RBP4, ALDH3A1, FA2H, ADH1B, PIK3R1
KRT23, TNC £
For the present study, some of the 100 genes were not considered for the following reasons: 1) in the first functional group named immune signaling molecules (Table1), 9 genes (CX3CR1, IL7R, CD14, SFRP1, ALOX15, NOS2A, IL2RB, NQO1 and IL1R2) were already included in previous studies and consequently removed for the present study[10–12]; 2) no SNP for the SDF1, COROA1 and SFN genes were available in the Illumina 610KQuad array (genome wide data used for the present study); 3) the TRA@ and TRB@ regions were not included in the present study as they identify loci and contained several genes and 4) no reference sequence was available for the IGHM gene. Consequently, a total of 85 genes were included in this genetic association study.
Clinical characteristics of the French-Canadian family study
n = 253
n = 1031
Male: Female ratio
1 : 1.1
1 : 1.2
Mean age, yr (range)
Smoking status, n (%)
FEV1, % predicted (SD) b
PC20, mg/ml (SD) c
Serum IgE in μg/l (SD) d
Number of persons with subphenotypes (%)
Atopic asthma (Asthma + Atopy)
The sample used in the present study was genotyped using Illumina 610KQuad array (Illumina, San Diego, USA) at the Centre National de Génotypage (CNG, Evry, France). A total of 1217 SNPs that are located in a ± 10 kb area from the 85 selected genes and fulfilling the following quality control criteria were considered in the analyses: call rate ≥ 95%, minor allele frequency ≥ 5%, Hardy-Weinberg equilibrium p value ≥ 5% and Mendelian errors ≤ 1%. Genotypes were extracted from the genome wide association study (GWAS) data using PLINK software (http://pngu.mgh.harvard.edu/∼purcell/plink/, version 1.07).
To identify associations between SNPs and asthma-related phenotypes, transmission disequilibrium was analyzed using the Family-Based Association Tests software (FBAT) (version 2.0.3,http://www.biostat.harvard.edu/∼fbat/default.thml). SNP associations were investigated under an additive genetic model and with the empirical variance estimator “-e” to account for the inclusion of multiple affected family members. All the associations of SNPs obtained had to survive a multiple test correction for the number of independent tagSNPs and the number of independent phenotypes, which was identified as two using a matrix spectral decomposition (matSpD) (http://gump.qimr.edu.au/general/daleN/matSpD/).
For the analyses, a total of 1217 SNPs located in the 85 studied genes were tested individually for association with asthma, atopy, and atopic asthma. Before correction, 95 SNPs located in 30 genes (CD19COL11A1, MUC2, COL2A1, AGC1, FBLN, HLA-DPB1, MS4A1, CEACAM5, IGHG1, IGLA, PTPRC, IFI6, SYK, CTSC, PSMA6, SPINK5, KLRC3, ADRA2A, CLCA2, KCNJ16, CYBA, ZNF38, ITGB2, C7, ALDH3A1, FA2H, ADH1B, PIK3R1 and TNC) were associated with asthma-related phenotypes (data not shown, see Additional file1).
Associated SNPs after correction with asthma-related phenotypes
Gene/ Corr. thresholda
This study aimed to demonstrate that gene expression studies may lead to the identification of genetic determinants. Indeed, although all expression differences cannot be explained by a genetic variant, it is possible that differential expression is related to a SNP in a regulatory region or in the promoter. As the genotypes for the SLSJ family study were available from the GWAS data, we investigated the association of SNPs located in genes that are differently expressed in bronchial biopsies of atopic asthmatics compared to controls from two previous publications and asthma-related phenotypes[8, 9]. We showed that four genes are genetically associated with asthma or asthma-related phenotypes (the AGC1 gene associated with atopy and atopic asthma, the IFI6, ADRA2A and ADH1B genes associated with asthma).
Like the majority of asthma associated SNPs, the variants associated in the present study are located in introns. Although, mutations located in an intron may lead to the suppression of critical steps (such as the binding of splicing factors or DNA polymerase) and to the abolition or creation of a binding site causing alteration in gene expression.
The AGC1 gene, located in the chromosomal region 15q26, is coding for the aggrecan, a major component of the extracellular matrix of the cartilage that binds with tenascins. More specifically, it binds to the type C tenascins that are upregulated in acute and chronic inflammatory diseases. In asthmatic subjects, there is an abnormal deposition of tenascin C on the basal membrane, which leads to a decrease of the airway lumen. Tenascin C is implicated in allergies and increases during seasonal atopic asthma. Three SNPs in the tenascin C gene, including a coding SNP (GLN/1978/ARG), were associated with atopy in our study before correction (data not shown). The implication of the tenascin C in the atopic mechanisms supports its association with atopy and atopic asthma phenotypes in our study, but this gene was also associated with asthma in other studies. In the literature, the AGC1 gene was mostly associated with skeleton and spinal cord diseases[27, 28].
The IFI6 gene is located on the chromosome 1 and codes for an interferon-induced protein that regulates the apoptosis process. This gene is involved in the treatment of myeloma and other malignancy diseases by its antiapoptotic activity. There is no function established for this gene in respiratory disorder except for its implication in tract infection caused by the respiratory syncytial virus (RSV). As RSV leads to the inflammation of the epithelium in affected patients and as a previous GWAS demonstrated that genes implicated in the epithelial function are strongly associated with asthma, the IFI6 gene could play a role in asthma through the modulation of the epithelium structure.
The ADRA2A gene, mapped on the 10q23 chromosomal region, codes for the A subtype of the adrenergic g protein-coupled receptors family. This family plays a role in the regulation of neurotransmitters, the production of normal neurons, and is implicated in the cardiovascular and the central nervous systems. The B subtype of the receptor is known to be a biomarker in asthma and its agonists are used as therapeutic molecules as bronchoconstriction regulators[32, 33]. Several studies associated SNPs in the ADRA2B gene with asthma and atopic diseases[34–37]. In the respiratory system, the activation of the adrenergic alpha-2A-receptor regulates the recovery of the cholinergic outflow to the airways in response to repeated allergen exposition and also leads to the release of proinflammatory cytokines[32, 38]. This gene is also involved in the regulation of mood, response to stress, anxiety and autonomic function[39, 40]. Consequently, interactions between physiological factors and emotions may modulate the severity and the symptoms of asthma at least partially through the ADRA2A gene.
The ADH1B gene is located on the long arm of the chromosome 4 and codes for the beta unit of class I alcohol dehydrogenase. This enzyme catalyzes the oxidation of alcohol to acetaldehyde. SNPs in the alcohol dehydrogenase and the acetaldehyde dehydrogenase genes are involved in alcohol-induced hypersensitivity[42, 43]. Moreover, the inhalation of acetaldehyde (alcohol) and a fast metabolism of ethanol can lead to a bronchoconstriction in asthmatic subjects. Therefore, the ADH1B gene seems to be involved in an increase of airway obstruction in asthma by its effects on the alcohol metabolism.
The association analysis on genes differently expressed in microarray studies of bronchial biopsies obtained from asthmatic and control subjects allowed confirming the association of four new genes to asthma and/or allergy. The known functions of these genes suggest that they could play a significant role in the pathogenesis of asthma. On the 100 genes identified as differently expressed in the Laprise et al. and Chamberland et al. studies, the combination of the four association studies performed by our team associated 9 genes after correction for multiple testing (9%). This study illustrates the potential of combining studies of expression and association in order to increase our understanding of the biology of complex traits, and more specifically to identify gene and biological pathways relevant to asthma.
The authors thank all the families for their valuable participation to this study. Catherine Laprise is the chair holder of the Canada Research Chair for genetic determinants in asthma and is responsible for the Inflammation and remodeling strategic group of the Respiratory Health Network of the Fonds de la recherche du Québec en santé (FRQS), and member of AllerGen NCE Inc. (the Allergy, Genes and Environment Network), a national multidisciplinary research network. This work was supported by the European Commission as part of GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community) contract number 018996 under the Integrated Program LSH-2004-1.2.5-1 Post genomic approaches to understand the molecular basis of asthma aiming at a preventive or therapeutic control.
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