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Published ahead of print on March 12, 2004, doi:10.1164/rccm.200302-281OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 1217-1223, (2004)
© 2004 American Thoracic Society

Original Article

Association of the Interleukin-1 Receptor Antagonist Gene with Asthma

Henning Gohlke, Thomas Illig, Margret Bahnweg, Norman Klopp, Elisabeth André, Janine Altmüller, Nicole Herbon, Monika Werner, Michael Knapp, Lydia Pescollderungg, Attilio Boner, Giovanni Malerba, Pier Franco Pignatti and Matthias Wjst

GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg; Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany; Department of Pediatrics, Bolzano Hospital, Bolzano; and Department of Mother and Child, Biology and Genetics, University of Verona, Verona, Italy

Correspondence and requests for reprints should be addressed to Matthias Wjst, M.D., GSF-National Research Center for Environment and Health, Institute of Epidemiology, Ingolstaedter Landstraße 1, D-85764 Neuherberg, Germany. E-mail: m{at}wjst.de


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The interleukin-1 cluster on human chromosome 2q12-2q14 harbors various promising candidate genes for asthma and other inflammatory diseases. We conducted a systematic association study with single-nucleotide polymorphisms (SNPs) located in candidate genes situated in this cluster. Single-marker, two-locus and three-locus haplotype analysis of SNPs yielded several significant results (p < 0.05–0.0021) for the human IL1RN gene encoding the IL-1 receptor antagonist protein, an antiinflammatory cytokine that plays an important role in maintaining the balance between inflammatory and antiinflammatory cytokines. These findings were replicated and confirmed in an independent Italian family sample in which significant, although weaker, association with asthma was detected. A sequencing approach to the coding region of the human IL1RN gene revealed additional DNA variants, from which a selection was also associated with the disease in German and Italian samples. Calculation of the linkage disequilibrium for the human IL1RN gene showed strong linkage disequilibrium for nearly all analyzed SNPs. Further haplotype analysis indicated that six SNPs are sufficient for tagging all haplotypes with a prevalence of more than 1%. The most frequent haplotype constructed from these SNPs was 1.4-fold overtransmitted in the German family sample.

Key Words: association • asthma • IL1RN • single-nucleotide polymorphisms

Asthma, a chronic inflammatory disease of the airways, is currently the most common chronic childhood disease in industrialized countries (1, 2). Although environmental factors are known to contribute to development of the disease, epidemiologic studies point toward a strong genetic influence (3, 4). To localize genetic components that add to the occurrence of asthma, several genome scans have been performed and have identified more than a dozen genomic regions linked to asthma and associated phenotypes (5). After a genome-wide scan (6) and a subsequent fine mapping approach (7) we were able to identify a candidate gene locus on human Chromosome 2q12-2q14 that is in accordance with other genome scans (8–15). Further evidence for this locus was provided by two studies in mice that describe linkage to the human syntenic region: an A/J x C3H backcross for ovalbumin-induced airway hyperresponsiveness and an A/J x C57BL/6J backcross for methacholine-induced airway responsiveness (16). Most recently another gene, DPP10, encoding a homolog of dipeptidyl peptidases, has been identified as a novel gene influencing asthma. This gene is also located on Chromosome 2q14, about 800 kb distal to the IL-1 cluster (17), which harbors various promising candidate genes involved in the mediation of inflammatory responses (18–21). Members of the interleukin (IL)-1 receptor family reside between 101.5 and 102.0 Mb, and the corresponding ligands are clustered between 114.6 and 115.2 Mb. The cytokines and their respective receptors participate in two well-investigated signal transduction cascades (22–24). The IL-1 receptor Type I pathway (gene, IL1R1) consists of the receptor itself, the proinflammatory cytokines IL-1{alpha} gene (IL1A) and IL-1ß gene (IL1B), the antiinflammatory cytokine IL-1 receptor antagonist IL-1ra gene (IL1RN), and the IL-1 Type II receptor IL-1RII gene (IL1R2) that appears to act as a decoy inhibitor (25). The immediate production and secretion of proinflammatory cytokines, especially IL-1ß, and to a minor degree tumor necrosis factor-{alpha}, contribute to the changes in airway responses that are characteristic features of asthma (22, 26, 27). IL-1ra has antiinflammatory activity and thereby reduces airway responsiveness (22, 26). These results have been confirmed by experiments showing that bronchial hyperreactivity to histamine or substance P, as well as accompanying airway inflammation with effector cells, decreased after IL-1ra treatment of antigen-sensitized animals (22, 27). We decided to test a dense map of nucleotide polymorphisms derived from the genes of the IL1 cluster for association with asthma and associated traits. We selected 219 candidate gene-based single-nucleotide polymorphisms (SNPs) from public databases and tested their prevalence in pools of genomic DNA via matrix-assisted laser desorption/ionization time of flight mass spectrometry (28). Subsequently, all SNPs with a minor allele frequency of greater than 10% were genotyped in the German study.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Probands
We investigated two independent collections of father–mother–affected child trios, where either one or neither of the parents had confirmed clinical asthma. For the first panel, 127 trio families with 381 individuals were randomly selected from a larger sample recruited in Germany and Sweden (6). The second panel included 127 trio families with 381 individuals randomly derived from a family-based study that was performed in Italy. German asthma sib pair families have been examined since 1994, mainly in pediatric university clinical centers in Germany and Sweden as described previously (6). Asthma was the primary trait examined; however, all participants were also examined for associated phenotypes such as positive skin prick tests with frequent allergens, serologic IgE measurement, and eosinophil count. Blood was taken from a cubital vein with a closed EDTA-coated system (Sarstedt, Nümbrecht, Germany). Subsequently, DNA was isolated or serologic analysis was performed. Italian families were enrolled over a period of 3 years (1995–1998) (29). The Pediatrics Clinic of the University of Verona and the Hospital of Bolzano performed the study. Only families with one child with allergic asthma, showing positive skin prick tests and asthma, were included. The mean age of the probands was 9 years, comparable to that of the German sample. Asthma was defined through a physician diagnosis according to American Thoracic Society criteria, including positive response to a validated respiratory questionnaire. Data regarding bronchial hyperresponsiveness to methacholine, total serum IgE levels, and skin prick test reactivity against common aeroallergens were collected as in the German family collection.

SNP Genotyping
Genotyping for all SNPs was achieved by primer extension of multiplex polymerase chain reaction products with detection of the allele-specific products by matrix-assisted laser desorption/ionization time of flight mass spectroscopy (30–32).

Mutation Screening
To discover new mutations we performed sequence analysis of polymerase chain reaction products of all eight exons of the IL1RN gene. Sequencing of a panel composed of 37 affected and 10 healthy individuals was performed as described elsewhere (33).

Statistical Analysis
All genotypes were tested for Hardy–Weinberg equilibrium and correct Mendelian inheritance, using SIB-PAIR version 0.99.9 (David Duffy, Queensland, Australia), before being analyzed with SAS version 8.1 (SAS Institute, Cary, NC). Frequencies of the variants of each SNP were estimated on the basis of pseudocontrol genotypes obtained by combining parental alleles not transmitted to the affected child. A {chi}2 test was used to test the distribution of genotypes in pseudocontrol subjects for deviations from Hardy–Weinberg equilibrium. The significance of the observed transmission disequilibrium for alleles at a single marker locus and for haplotypes consisting of alleles at two or three adjacent SNPs was assessed by the transmission/disequilibrium test (34) and an extension of the transmission/disequilibrium test (35), respectively. Pairwise linkage disequilibrium (LD) was measured with the standardized LD, denoted as D' (36), and was calculated from the maximum-likelihood haplotype frequency estimates obtained from the parental genotypes. The locus-iterative mode of the program FAMHAP (http://www.uni-bonn.de/~umt70e/becker.html) was used to obtain frequency estimates for long-range haplotypes in the human IL1RN gene. Next, the minimal subset of SNPs (haplotype-tagging SNPs) allowing discrimination among all haplotypes with estimated frequency exceeding 1% was determined. With this set of SNPs, FAMHAP was run again to compare, for each haplotype, the estimated frequency of this haplotype in transmitted and nontransmitted haplotypes by means of a likelihood ratio test with 1 degree of freedom (37).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
SNP Validation and Genotyping
To resolve the genomic region, we selected 219 tightly spaced SNPs for this study. All SNPs were derived from public databases (dbSNP [http://www.ncbi.nlm.nih.gov/SNP/] and Ensembl [http://www.ensembl.org]) and validated by primer extension of polymerase chain reaction products with detection by matrix-assisted laser desorption/ionization time of flight mass spectrometry in pools of genomic DNA. Pools were generated with overrepresented samples from asthma patients. Of the initial 219 SNPs selected, 144 SNPs were polymorphic in our validation screen, showing more than 10% allele frequency of the minor variant. All SNPs were subsequently genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry in 127 German trio families consisting of father, mother, and one child with asthma. Ninety-nine percent of all genotypes passed a paternity check and most of them were in Hardy–Weinberg equilibrium. Genotype acquisition was generally larger than 90%.

Association Results
We analyzed each SNP by transmission disequilibrium test and obtained the most significant result (p < 0.05; Figure 1C and Table 1) in the IL1RN gene, where 11 SNPs showed p values < 0.05. Outside the human IL1RN gene, two other SNPs showed positive associations (rs1609682, p = 0.03; rs1143623, p = 0.02; Figure 1C). An 86-bp tandem repeat in Intron 2 (A2 allele) was only weakly associated with asthma (p = 0.06; Table 1). Two locus haplotype analyses for adjacent SNPs yielded even stronger association results (minimal p = 0.002; Table 2) , whereas the minimal p value for haplotypes consisting of alleles at three adjacent SNPs was 0.002 (Table 2).



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  		Figure 1. (A) Metaanalysis of 214 linkage studies (13 genome scans) with 18.972 marker available September 2002 in the Asthma Gene Database. Markers are given for Chromosome 2, using the Decode linkage map (50) relocated on the UCSC physical map, August 2001. (B) Gene positions in the IL1 cluster between 101 x 106 and 115 x 106 bp. A gap between 102 x 106 and 114 x 106 bp is marked with diagonal axis breaks. (C) All significant association results for asthma with p < 0.10 in a 150-SNP single-point analysis of 127 German trio families.

 

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  		TABLE 1. Single-nucleotide polymorphisms in the human IL1rn gene

 

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  		TABLE 2. Overview of significant two- and

three-locus haplotypes in the human IL1rn gene

 
These results were confirmed by genotyping 12 SNPs in the IL1RN gene in 121 asthma trio families of Italian origin (Table 1). Two of the 12 SNPs were likewise significantly associated with asthma in single-marker analysis (rs3087271, p = 0.02; rs447713, p = 0.04; Table 1).

Resequencing of the IL1RN Coding Region
We sequenced all exons of the human IL1RN gene with adjacent intronic sequences in 47 probands. By this approach we found 28 additional DNA variants (Table 1), of which 16 were entered into the public SNP database during the study. From these additional SNPs we selected eight for genotyping in both study populations. Of these, three SNPs were associated with asthma in the German sample (rs2234678, p = 0.01; rs878972, p = 0.05; rs454078, p = 0.006; Table 1), and two of them also in the Italian sample (rs2234678, p = 0.03; rs878972, p = 0.04; Table 1).

Linkage Disequilibrium and Further Haplotype Reconstruction
Calculation of the LD in the gene showed an almost perfect LD for nearly all DNA markers in the IL1RN gene (Figure 2) . For construction of long-range haplotypes in the human IL1RN gene, we dropped rs794066 and rs380092, because neither of those markers was in Hardy–Weinberg equilibrium nor gave consistent results during an initial attempt at haplotype reconstruction. For the remaining 26 SNPs we obtained 57 haplotypes, of which only 9 haplotypes showed a population frequency exceeding 1% (Table 3) . To discriminate among those 9 haplotypes, at least 6 SNPs out of the initial set of 26 SNPs (8-9-11-19-23-24 or rs315934-rs392503-rs1794067-rs598859-rs973635-rs440286) were necessary. These haplotype-tagging SNPs were then used to build a condensed haplotype, describing the major variation in the human IL1RN gene (Table 4) . Of these, two haplotypes possessed different frequencies in transmitted and nontransmitted haplotypes (Table 4).



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  		Figure 2. One hundred forty-nine pairwise comparisons of R2 values, with R2 = 1 set to black and R2 = 0 set to white.

 

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  		TABLE 3. Overview of the nine most common haplotypes in the human IL1rn gene

 

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  		TABLE 4. Tagging haplotypes in the human

IL1rn gene

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Because the interleukin-1 cluster on human Chromosome 2q12-2q14 consists of various candidate genes possibly involved in the development of asthma, we investigated the association between 219 tightly spaced SNPs derived from these genes and asthma or related traits.

This investigation showed that SNPs and haplotypes in the IL1RN gene encoding the IL-1 receptor antagonist (IL-1ra) are associated with the disease (Tables 1 and 2). In this regard it is unlikely that a gene flanking the IL1RN gene is responsible for the association results, because all significantly associated SNPs or haplotypes are located in, or close to, IL1RN (Figure 3) . To strengthen the hypothesis that IL1RN is an important risk factor, not only in the German population, we also analyzed 12 SNPs in an Italian study. We detected a significant although weaker association in this sample (Table 1).



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  		Figure 3. Genomic structure of the IL1RN gene. Exons are denoted by icI, icII, IcIII, 1, 2, 3, and 4, whereas splice products sIL-1ra, icIL-1ra, icIL-IIra, and icIL-IIIra are shown below the gene. Depicted are only the 28 genotyped SNPs from Table 1. s = secretory; ic = intracellular.

 
Although we performed in total 429 statistical tests (single-marker analyses, two-locus haplotypes, three-locus haplotypes) we hypothesize that multiple testing is not a major issue, given the independent replication in a second sample. The haplotypes tagging SNPs identified here should also allow rapid replication in other studies.

In addition, our results are supported by a previous study of the A2 allele of the DNA repeat in Intron 2 of IL1RN that has been associated with asthma in a smaller Japanese study (22) and a larger Finnish study (38–40). In contrast to this, Joos and coworkers (41) reported a protective effect of the A2 allele on the decline of lung function whereas Ishii and coworkers found no association for this repeat with chronic obstructive pulmonary disease (42). In the German population we could detect weak association with the A2 allele, whereas no significant association was found in the Italian population. These somehow contradictory results show that there are marked differences not only between different ethnic groups but also within one ethnic group, emphasizing the genetic heterogeneity of complex diseases such as asthma.

Even though we resequenced the entire coding region of IL1RN, we have not been able to identify a single causative mutation that could account for the development of asthma. Nevertheless, we have been able to identify SNPs that reside in miscellaneous DNA motifs, whose specific function regarding the development of asthma is currently under investigation (Table 1).

The immediate production and secretion of the proinflammatory cytokine IL-1ß contributes to the changes in airway responses (26). On the other hand, IL-1ra has antiinflammatory activity that reduces airway responsiveness. This was confirmed by experiments showing that bronchial hyperreactivity decreases after treatment of antigen-sensitized animals with IL-1ra (22, 27). IL-1ra resembles IL-1{alpha} and IL-1ß in its amino acid sequence as well as in the three-dimensional folding pattern (25). It binds to the Type I IL-1 receptor-like antagonist without transducing signals and therefore has antiinflammatory cytokine effects. In rabbits IL-1ra prevents death from LPS-mediated septic shock (24), whereas in humans LPS response is blocked—a mechanism that turned out to be a protective factor for asthma (43–45). In addition, it has been claimed that airway epithelial cells stimulated with IL-1ß increase the production of mucins (46), which are produced by the majority of secretory epithelial cells. Inflammatory diseases of the airways, such as asthma and chronic bronchitis, are accompanied by mucus hypersecretion, which can lead to the obstruction of small and even large airways. It was shown that IL-1ß activates MUC2 and MUC5AC mucin production by activating either the ERK or the p38-PGE2 pathway (47). Finally, the results of another study raise the possibility that one of these newly identified SNPs or haplotypes in the IL1RN gene may also confer a risk for other inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, or Alzheimer's disease, which have all been found to be associated with this gene or its gene product (48). It might also be possible that gene variants in IL1RN are responsible for a general susceptibility to inflammation (49), where other risk genes and environmental factors may be decisive as to which organ will be affected.

We conclude that variants in the IL1RN gene are likely to contribute to the pathology of asthma. Functional tests must be performed to find the molecular mechanism that drives the phenotype via IL-1ra.


   Acknowledgments
 
The authors thank all participating families and members of the clinical centers for their work: M. Hoeltzenbein (Greifswald), R. Nickel, K. Beyer, R. Kehrt, U. Wahn (Berlin), K. Richter, H. Janiki, R. Joerres, H. Magnussen (Grosshansdorf), I. M. Sandberg, L. Lindell, N. I. M. Kjellman (Linkoeping), C. Frye, G. Woelke, I. Meyer, O. Manuwald (Erfurt), A. Demirsoy, M. Griese, D. Reinhardt (München), G. Oepen, A. Martin, A. von Berg, D. Berdel (Wesel), Y. Guesewell, M. Gappa, H. von der Hardt (Hannover), J. Tuecke, F. Riedel (Bochum), M. Boehle, G. Kusenbach, H. Jellouschek, M. Barker, G. Heimann (Aachen), S. van Koningsbruggen, E. Rietschel (Koeln), P. Schoberth (Koeln), G. Damm, R. Szczepanski, T. Lob-Corzilius (Osnabrueck), L. Schmid, W. Dorsch (Muenchen), M. Skiba, C. Seidel, M. Silbermann (Berlin), A. Schuster (Duesseldorf), J. Seidenberg (Oldenburg), W. Leupold, J. Kelber (Dresden), W. Wahlen (Homburg), F. Friedrichs, K. Zima (Aachen), P. Wolff (Pfullendorf), D. Bulle (Ravensburg), W. Rebien, A. Keller (Hamburg), and M. Tiedgen (Hamburg). The Italian families have been examined by A. Boner (Verona) and L. Pescollderungg (Bolzano). The authors thank G. Schlenvoigt and L. Jaeger for IgE determination, G. Fischer for data handling, L. Thaller for secretarial assistance, C. Braig, and B. Wunderlich for excellent laboratory work, A. Jendretzke for technical support, and M. Emfinger for proofreading of the manuscript.


   FOOTNOTES
 
Supported by Deutsche Forschungsgemeinschaft DFG WI621/5-1, DFG Kn378/1, and GSF FE 73922; German National Genome Network UW S15T01; the Italian Ministry of University and Research; and the Italian National Research Council Project Biotechnology.

M.W., H.G., and T.I. contributed equally to this article.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: H.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; G.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.F.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.W. served as a speaker at scientific meetings of GlaxoSmithKline, Wyeth, Boehringer, and Roche and has been doing joint research projects with Sequenom and Illumina.

Received in original form February 26, 2003; accepted in final form March 11, 2004


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