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Human Molecular Genetics, 2003, Vol. 12, No. 11 1279-1285
DOI: 10.1093/hmg/ddg142
© 2003 Oxford University Press

Association of Eotaxin gene family with asthma and serum total IgE

Hyoung Doo Shin1, Lyoung Hyo Kim1, Byung Lae Park1, Ji Hyun Jung1, Jun Yeon Kim1, Il-Yup Chung2, Jung Sun Kim2, June Hyuk Lee3, Sun Hee Chung3, Yong Hoon Kim3, Hae-Sim Park3, Jeong Hee Choi3, Young Mok Lee3, Sung Woo Park3, Byoung Whui Choi3, Soo-Jong Hong3 and Choon-Sik Park3,*

1Department of Genetic Epidemiology, SNP Genetics Inc., 11th Floor, MaeHun B/D, 13 Chongro 4 Ga, Chongro-Gu, Seoul 110-834, Korea, 2College of Science and Technology, Hanyang University. 1271 Sa-1 dong, Ansan, Kyunggi-do 425-791, Korea and 3Asthma Genome Research Group, Soonchunhyang University Hospital, Ajuo University Hospital, Ulsan University Hospital and Choong-Ang University Hospital, Bucheon, Gyeonggi Do, Korea

Received January 15, 2003; Accepted March 31, 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIAL AND METHODS
 REFERENCES
 
The Eotaxin gene family (Eotaxin1, Eotaxin2 and Eotaxin3) recruits and activates CCR3-bearing cells such as eosinophils, mast cells and Th2 lymphocytes that play a major role in allergic disorders. To date, the effect of polymorphisms of Eotaxin genes on asthma phenotypes has not been thoroughly examined. In our research, we sequenced whole regions of the Eotaxin gene family to identify polymorphisms, which may be involved in the development of asthma and total serum IgE. We have identified 37 SNPs in the Exotaxin gene family (Exotaxin1, 2 and 3), and 17 common polymorphic sites were selected for genotyping in our asthma cohort (n=721). Statistical analysis revealed that the EOT2+1265A>G G* allele showed significantly lower frequency in asthmatics than in normal healthy controls (0.14 versus 0.23, P=0.002), and that distribution of the EOT2+1265A>G G* allele-containing genotypes was also much lower in asthmatics (26.3 versus 40.8%, P=0.003). In addition, a non-synonymous SNP in Eotaxin1, EOT1+123Ala>Thr showed significant association with total serum IgE levels (P=0.002–0.02). The effect of EOT1+123Ala>Thr on total serum IgE appeared in a gene-dose-dependent manner. Our findings suggest that the development of asthma may be associated with EOT2+1265A>G polymorphisms, and the susceptibility to high IgE production may be attributed to the EOT1+123Ala>Thr polymorphism. Eotaxin variation/haplotype information identified in this study might provide valuable insights into strategies for the control of asthma.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIAL AND METHODS
 REFERENCES
 
Asthma is a common and heterogeneous respiratory disease characterized by reversible airway obstruction that is caused by chronic allergic inflammation of the airways. Bronchial hyperresponsiveness is a characteristic feature of asthma, and serum IgE levels are closely associated with asthma development. The development of asthma is determined by the interaction between host susceptibility (genetics) and a variety of environmental exposures (1–4).

The human Eotaxin gene family is located on chromosomes 17 and 7: Eotaxin1 (MIM no. 601156) on 17q21.1–q21 with three exons (~8 kb) (5,6), Eotaxin2 (MIM no. 602495) on 7q11.23 with three exons (~6.5 kb) (7), and Eotaxin3 (MIM no. 604697) on 7q11.23 with three exons (~6 kb) (8), respectively (Fig. 1). The identification of three Eotaxins, each acting via CCR3 receptors, raises the issue of the differential roles of these functionally analogous CC chemokines. The expression of Eotaxin1 mRNA and protein was found to be increased in the bronchial epithelium and submucosal layer of the airways of chronic asthmatics. Furthermore, the elevation of Eotaxin1 levels was proportional to eosinophil infiltration and bronchial hyperreactivity (9,10). The relevance of Eotaxin1 to asthma was evidenced by an association of increased plasma Eotaxin1 levels with impaired lung function of the asthmatics in a large population study (11). In addition, subjects with acutely exacerbated asthma symptoms and airflow obstruction had higher plasma and sputum Eotaxin1 levels than subjects with stable asthma, and higher levels were associated with less airflow reversibility after treatment (12–14), which suggested that Eotaxin1 was induced locally in a certain state of asthma. In addition, Eotaxin1 is important for eosinophilic inflammation in the early phase of the asthmatic response, while Eotaxin3 may account for the eosinophil recruitment to the asthmatic airway in the later stage of asthmatic response (15). Based on the biological properties involved in allergic inflammatory reactions, it is hypothesized that the Eotaxins play an important role in coordinating the recruitment of inflammatory cells to the sites of allergic inflammation that leads to the development of allergic diseases such as asthma.



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  		Figure 1. Gene maps and haplotypes of the Eotaxin gene family (Eotaxin1, 2 and 3). Coding exons are marked by shaded blocks and 5'- and 3'-UTR by white blocks. Asterisks indicate SNPs which were genotyped in larger population. The frequencies of SNPs without large-scale genotyping were based on sequencing data (n=24). First base of the transcription start site (Eotaxin1) or first base of the translation start site (Eotaxin2 and Eotaxin3) was denoted as nucleotide +1. Dots in A2, B2 and C2 represent the alleles that are found on the most common haplotype. (A1) Polymorphisms identified in Eotaxin1 on 7q21.1–q21.2 (reference sequence Z92709). (A2) Haplotypes of Eotaxin1. (B1) Polymorphisms identified in Eotaxin2 on 7q11.23 (reference sequence of Eotaxin2 mRNA: NM_002991). (B2) Haplotypes of Eotaxin2. Haplotypes with frequency >0.02 are presented. Others (1) contain rare haplotypes: GATAC, GATGA, GACGC, AACGC, GCTAC, GACGA, GATGC and ACTAA. (C1) Polymorphisms identified in Eotaxin3 on 7q11.2 (reference sequence of Eotaxin3 mRNA: AB010447). (C2) Haplotypes of Eotaxin3.

 
The known biological effects of Eotaxins in allergic inflammation and the positive signals from genome-wide studies for atopy and/or total IgE on the region of chromosome 17q (16,17), on which Eotaxin genes are located, facilitated systemic study of this gene family. Here we describe genetic polymorphisms in the Eotaxin gene family (Eotaxin1, 2 and 3) and their relationship with the development of asthma and serum total IgE.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIAL AND METHODS
 REFERENCES
 
By direct DNA sequencing, 37 single-nucleotide polymorphisms (SNPs) in the Eotaxin gene family (Exotaxin1, 2 and 3) were identified: 14 in Eotaxin1 [eight in the 5' flanking region, one in the coding region (exon1; Ala>Thr) and five in the intron region, including three known polymorphisms], 16 in Eotaxin2 [one in the coding region (exon1; Leu>Ile), 13 in the intron region and two in 3' end], and seven in Eotaxin3 (one in 5'-UTR, five in the intron region and one in 3'-UTR), respectively. Among the SNPs identified, 17 common polymorphic sites were selected for genotyping in our asthma cohort, in consideration of the location, linkage disequilibrium (LD) with other sites and frequency: nine from Eotaxin1, five from Eotaxin2 and three from Eotaxin3, respectively. The frequencies of SNPs are shown in Table 1. The distributions of all 17 SNPs were in Hardy–Weinberg equilibrium (HWE: P>0.05, data not shown). Several absolute LDs (|D'|=1 and d2=1) and complete LDs (|D'|=1 and d2!=1) were observed in each gene. Haplotypes of each gene were constructed by EM algorism with genotyped SNPs (Fig. 1). Although complete and/or absolute LDs were observed between all SNPs in Eotaxin1 (chr. 17q21.1–21.2), significant breakdowns of LDs were apparent in Eotaxin2 (chr. 7q11.23) and Eotaxin3 (chr. 7q11.2 Fig. 1).


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  		Table 1. Rare allele frequencies of SNPs in the Eotaxin gene family (Eotaxin1, Eotaxin2 and Eotaxin3), and distributions in asthmatics (n=550) and normal subjects (n=171) in the Korean population
 
Allele frequencies of each SNP and common haplotypes (frequency>0.1) were compared between the patients and the normal controls using logistic regression models (Table 1). The EOT2+1265A>G G* allele showed a significantly lower frequency in the asthma patients than in the normal controls (0.14 versus 0.23, P=0.002), and the distribution of EOT2+1265A>G G* allele-containing genotypes was also much lower in asthma patients than in the normal controls (26.3 versus 40.8%, P=0.002; Table 2). The protective effect of the EOT2+1265A>G G* allele was clearer in the atopic population (0.0007–0.04, Table 2). The P-values of this EOT2+1265A>G (P=0.002 by co-dominant model; see Table 1) retained significance after the strict correction of multiple comparisons. A significant difference in allele frequency of neighboring EOT2+1916A>C (P=0.05) could be the result of linkage with EOT2+1265A>G.


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  		Table 2. Logistic analysis of EOT2+1265A>G in asthmatic and normal subjects
 
All single SNPs and common haplotypes (frequency >0.1) were also analyzed for their association with serum total IgE among asthma patients, using multiple regression models. The serum levels of total IgE were highly associated with age, sex and atopy among asthma patients (P<0.0001). Male, atopic and younger patients showed higher levels of total IgE, as expected (data not shown). Among the 21 loci analyzed, EOT1+123Ala>Thr showed significant association with log-transformed total IgE level in the asthma patients (P=0.002, Table 3). The effect of EOT1+123Ala>Thr on total serum IgE was apparent in a gene-dose-dependent manner, i.e. highest in homozygotes (Thr–Thr 2.63), intermediate in heterozygotes (Ala–Thr 2.35), and lowest in wild-type homozygotes (Ala–Ala 2.19; Tables 3 and 4). In further analyses with subgroups of patients, EOT1+123Ala>Thr revealed a similar association with total serum IgE in atopic asthmatic patients (P=0.02–0.05, Table 4). Although it was not statistically significant in non-atopic patients, the levels of total serum IgE showed the same trend of increasing in proportion to the number of Thr allele of EOT1+123Ala>Thr (Table 4).


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  		Table 3. Regression analyses for age, sex, smoking and atopy adjusted log(total IgE) with 17 SNPs and haplotypes among bronchial asthma patients
 

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  		Table 4. Regression analyses of log(total IgE) as functions of EOT1+123G>A (Ala>Thr) among bronchial asthma patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIAL AND METHODS
 REFERENCES
 
Eotaxins are a family of CC chemokines that coordinate the recruitment of inflammatory cells bearing the CCR3 receptor to the sites of allergic inflammation (18). During the last decade there has been intensive investigation into the biological effects of Eotaxins. To date, three members of this family: Eotaxin1 [CC chemokine ligand (CCL)3 11], Eotaxin2 (CCL24) and Eotaxin3 (CCL26) have been identified. Although there is low sequence homology between the Eotaxins, all the Eotaxins have been shown to signal via the chemokine receptor, CCR3 (6,19–23). CCR3 is highly expressed on eosinophils (6,24,25), and all three Eotaxins have been known to activate eosinophils with the same potentials (6,19,21,22,26,27). CCR3 has also been detected on other cell types, including basophils, mast cells and a subpopulation of Th2 cells (27–29).

In this study, we demonstrated that one of the SNPs of the Eotaxin2 gene, EOT2+1265A>G, was associated with asthma development, and that Eotaxin1+123G>A (Ala>Thr) was related to total serum IgE in asthmatics. To our knowledge, an association study has not been performed to examine the relationship between Eotaxin2 and Eotaxin3 and asthma development. Our result concerning the association of the SNP of the Eotaxin2 gene (EOT2+1265A>G) with asthma development is a novel finding. A non-synonymous SNP of Eotaxin1 [+123G>A (Ala>Thr)] has been reported to reduce the secretion of Eotaxin protein (30). This non-synonymous SNP alters the predicted Eotaxin1 amino acid sequence by substituting a polar threonine residue for the hydrophobic alanine residue. As a secreted protein, Eotaxin1 contains an amino-terminal sequence of hydrophobic amino acids that are a substrate for signal peptidases, which process proteins for transport to the cell surface and secretion (31,32). The substitution of threonine for alanine substantially reduced the predicted signal peptidase activity for the threonine variant of EOT+123Ala>Thr, and subsequently secreted significantly less than did the alanine form. This was confirmed in an in vivo study. Asthmatic subjects who were homozygous for the threonine form of Eotaxin1 had significantly lower plasma Eotaxin1 levels than asthmatic individuals with the alanine form (30). Although biological action of Eotaxin1 in IgE production has not been well studied, we found the expression of Eotaxin1 to be decreased markedly in peripheral blood mononuclear cells of the patients with hyper-IgE syndrome (33). Two other single nucleotide substitutions of Eotaxin1, i.e. C to T at position -426 (-426C>T, -371C>T in this study calculated from the transcriptional start site) and A to G at position -384 (-329 A>G in this study) from the translation start site, were associated with serum IgE levels in patients with atopic dermatitis (34), but not with susceptibility to asthma (35). Our study showed a positive association of Eotaxin1 (+123G>A) SNP with serum IgE levels in asthma patients, and a result of no association with asthma development by the Eotaxin1+123G>A (Ala>Thr), which is concordant with that shown in the previous study (31).

The presence of an association between asthma development and the Eotaxin2 polymorphism, and between IgE production and the Eotaxin1 polymorphism, could raise questions regarding the differential roles of Eotaxin1 and Eotaxin2, which are functionally analogous chemokines, by acting via CCR3 receptors. The plausible explanations for this are the differential expression of Eotaxins and the differential modulation of them. Eotaxin1 is induced mainly by inflammatory cytokines, while Eotaxin2 and Eotaxin3 are up-regulated by Th2 cytokine such as IL4 and IL13 (23,36). Although Eotaxin1 is important for eosinophilic inflammation in the early phase of the asthmatic response, it does not account for ongoing late asthmatic response (37). A comparative study regarding the different roles among Eotaxins showed that Eotaxin3 rather than Eotaxin1 or Eotaxin2 may account for the eosinophil recruitment to the asthmatic airway in the later stage of asthmatic response (15). However, the specific relation of Eotaxin2 and Eotaxin3 with a Th2 environment remains unproven. The role of Eotaxins in IgE production still lacks supporting biological data. However, the expression of the CCR3 receptor on human dendritic cells (38) and Th2 cells (17) raises a possibility that Eotaxins may promote or down-regulate IgE production by acting on these two main cells in the immune response of allergic inflammation.

In summary, we have identified 37 SNPs in the Exotaxin gene family (Exotaxin1, 2 and 3), and 17 common polymorphic sites were selected for genotyping in our asthma cohort. The EOT2+1265A>G G* allele showed decreased risk of asthma. In addition, EOT1+123Ala>Thr showed significant association with total IgE level in a gene-dose dependent manner. Further studies would be needed to elucidate the functions of the variants, which showed significant association with asthmatic phenotypes.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIAL AND METHODS
REFERENCES
 
Subjects
Subjects were recruited from the Asthma Genome Research Center that consists of four tertiary hospitals located around Seoul, Korea (Soonchunhyang University Hospital, Ajuo University Hospital, Choong-Ang University Hospital and Ulsan University Hospital). Ethical approvals were obtained from the institutional review board of each hospital. All subjects in this study were ethnically Korean. All patients with asthma had currently the one or more asthma symptoms and the physical examination compatible with asthma definition by the American Thoracic Society (39). Normal subjects were recruited from spouses of the patients and the general population who answered negatively to a screening questionnaire for respiratory symptoms and had FEV1 greater than 75% predicted, PC20 methacholine greater than 10 mg/ml, and normal findings on a simple chest radiogram. Total IgE and specific IgE to Dermatophagoides farinae (Df) and D. pteronyssinus (Dp) were measured using CAP system (Pharmacia Diagnostics, Sweden). Twenty-four common inhalant allergens were used for the skin prick test. Atopy was defined as having wheal reaction equal to or greater than a histamine of 3 mm in diameter and/or positive response of specific IgE to Dp and Df. The clinical parameters are summarized in Table 5.


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  		Table 5. Clinical profile of the study subjects
 
Sequencing analysis of the human Eotaxin gene family
Genomic DNAs for sequencing were isolated from 24 healthy volunteers. We sequenced the whole gene, including the 5' flanking region (~1.5 kb), to discover single nucleotide polymorphisms (SNPs) using the ABI PRISM 3700 DNA analyzer (Applied Biosystems, Foster City, CA).

Genotyping by single-base extension (SBE) and electrophoresis
Primer extension reactions were performed with the SNaPshot ddNTP Primer Extension Kit (Applied Biosystems, Foster City, CA, USA). To clean up the primer extension reaction, one unit of SAP was added to the reaction mixture, and the mixture was incubated at 37°C for 1 h, followed by 15 min at 72°C for enzyme inactivation. The DNA samples, containing extension products, and Genescan 120 Liz size standard solution were added to Hi-Di formamide (Applied Biosystems, Foster City, CA, USA) at the recommendation of the manufacturer. The mixture was incubated at 95°C for 5 min, followed by 5 min on ice, and then electrophoresis was performed by using the ABI Prism 3100 Genetic Analyzer. The results were analyzed using the program ABI Prism GeneScan and Genotyper (Applied Biosystems, Foster City, CA, USA).

Statistics
We examined widely used measures of linkage disequilibrium between all pairs of biallelic loci, Lewontin's D' (|D'|) (40). Haplotypes and their frequencies were inferred using the algorithm developed by Stephens et al. (41). Logistic regression models were used for calculating odds ratios (95% confidential interval) and corresponding P-values for SNP sites and haplotypes controlling age and sex as co-variables (Table 1). Means and standard deviations (SD) of log(total IgE) and P-values for regression analyses of three alternative models (co-dominant, dominant and recessive models) were calculated using multiple regression analyses controlling age, sex and atopy as co-variables. The values of total serum IgE were log transformed.


   ACKNOWLEDGEMENTS
 
This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (01-PJ3-PG6-01GN04-003).


   FOOTNOTES
 
* To whom correspondence should be addressed at: Division of Allergy and Respiratory Medicine, Department of Internal Medicine Soonchunhyang University Bucheon Hospital, 1174, Jung Dong, Wonmi Ku, Bucheon, Gyeonggi Do 420-021, Korea. Tel: +82 326215105; Fax: +82 326215016; Email: mdcspark{at}unitel.co.kr Back


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 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIAL AND METHODS
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