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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 323-329

Systematic review and meta-analysis of the association between C-746T and C-703T polymorphisms of the interleukin-5 gene and asthma


1 Department of Immunology, Al-Sader Hospital, AL-Najaf, Iraq
2 Department of Pharmacology, University of Kerbala, Kerbala, Iraq
3 Department of Medical Microbiology, University of Kerbala, Kerbala, Iraq

Date of Submission23-Apr-2020
Date of Acceptance02-May-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Miss. Raghdah Maytham Hameed
Department of Immunology, Al-Sader Hospital, AL-Najaf
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_60_20

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  Abstract 


Background: Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. A number of studies have identified the association between interleukin (IL)-5 C-746T and C-703T polymorphisms and asthma risk, however, the results still remain inconclusive. The objective of the present study was to identify the effect of IL-5 polymorphisms in asthma susceptibility. Methods: PubMed and Google Scholar databases were searched. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the effect and strength of association in the random-effects model or fixed-effects model. Results: A total of 4 case–control and 2 cross-sectional studies were screened out, including 1499 asthma patients and 3766 controls. Two single-nucleotide polymorphisms of the IL-5 gene were identified. Our results detected a no significant association between IL-5 C-746T polymorphisms and asthma risk in the total population (CC genotype showed OR = 0.82, 95% CI = 0.67–1.00, P = 0.05, I2 = 0%; CT genotype showed OR = 0.94, 95% CI = 0.78–1.13, P = 0.50, I2 = 24%; and TT genotype showed OR = 0.85, 95% CI = 0.64–1.13, P = 0.27, I2 = 0%) while a significant association between IL-5 C-703T polymorphisms and asthma in children according to review results. Conclusion: The meta-analysis findings suggest a lack of direct association between the IL-5 C-746T polymorphism and asthma and found that C-703T polymorphisms of the IL-5 gene might contribute to asthma risk. Future well-designed case–control studies with a large population and more ethnicities are still needed to estimate the association.

Keywords: Asthma, interleukin-5, meta-analysis, single-nucleotide polymorphism


How to cite this article:
Hameed RM, Najim Abood HA, Ahmed MM. Systematic review and meta-analysis of the association between C-746T and C-703T polymorphisms of the interleukin-5 gene and asthma. Biomed Biotechnol Res J 2020;4:323-9

How to cite this URL:
Hameed RM, Najim Abood HA, Ahmed MM. Systematic review and meta-analysis of the association between C-746T and C-703T polymorphisms of the interleukin-5 gene and asthma. Biomed Biotechnol Res J [serial online] 2020 [cited 2021 May 17];4:323-9. Available from: https://www.bmbtrj.org/text.asp?2020/4/4/323/305646




  Introduction Top


Asthma is the most common chronic lower respiratory tract and noncommunicable disease in children and adults throughout the world, characterized by inflammation which affects both proximal and distal airways.[1],[2],[3],[4] Asthma typically presents with a history of respiratory symptoms such as wheezing, cough, shortness of breath, and chest tightness and is characterized by underlying chronic airway inflammation.[5] Childhood asthma prevalence doubled from 1980 to 1995 and then increased more slowly from 2001 to 2010.[6] It is a global health problem affecting around 300 million individuals of all ages, ethnic groups, and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma.[7] Asthma is a highly prevalent chronic inflammatory disease of the airways, with differences in etiology, immunologic mechanisms, clinical presentation, pathogenesis, comorbidities, prognosis, and response to treatment, arising from not fully understood heterogenic gene–environment interactions. While environmental factors are important in the development of asthma, genetic factors could have a critical role in the expression of the disease, but the genetic background of bronchial asthma is complex, and it is likely that multiple genes contribute to its development both directly and through gene–gene interactions.[8],[9],[10],[11]

Asthma is primarily an inflammatory disorder of the airways associated with T-helper type 2 (Th2), cell-dependent promotion of immunoglobulin (Ig) E production, and recruitment of mast cells and eosinophils.[12] Allergen exposure results in the activation of numerous cells of the immune system, which include dendritic cells (DCs) and Th2 lymphocytes.[13] DCs in the airway epithelium and submucosa detect inhaled allergens.[14] DCs then migrate to the secondary lymphatic systems where they process and present antigens through major histocompatibility complex Class II to T and B lymphocytes, leading to the proliferation of Th1 or Th2 cell types and B lymphocytes produce IgE, which binds to high affinity FceRI on basophils and mast cells.[15] In response to allergen presentation by airway DCs, T-helper lymphocytes of the adaptive immune system control many aspects of the disease through secretion of interleukin (IL)-4, IL-5, IL-13, IL-17, and IL-22, and these are counterbalanced by cytokines produced by T-regulatory cells.[16]

IL-5 is an interdigitating homodimeric glycoprotein.[17] IL-5 produced by both hematopoietic and nonhematopoietic cells including T-cells, granulocytes, and natural helper cells.[18] It is a T-cell-derived cytokine involved in the pathogenesis of atopic diseases and plays important roles in the pathogenesis of asthma, hypereosinophilic syndromes, and eosinophil-dependent inflammatory diseases,[17],[19],[20] it is believed to regulate the growth, differentiation, and activation of eosinophils.[21] Further, acts on mature eosinophils to prolong maturation and survival and increased circulating eosinophil progenitors, suggesting a key role for systemic IL-5 in eosinophil mobilization. Moreover, IL-5 causes terminal maturation of the eosinophil by increasing CCR3 expression, potentially affecting CCR3-dependent chemotaxis by eosinophils and lymphocytes.[22],[23] In addition, overexpression of IL-5 significantly increases antibody levels in vivo and reported to act as a B-cell differentiation factor by stimulating activated B-cells to secrete antibody.[20],[24]

IL-5 gene is located on chromosome 5.[25] It is a potential candidate gene in the pathogenesis of asthma, which may play a role in blood eosinophilia associated with atopic dermatitis.[26],[27] Locus overexpression of IL-5 significantly increases eosinophil numbers and antibody levels in vivo. Conversely, mice lacking a functional gene for IL-5 or the IL-5 receptor-alpha chain (IL-5Rα) display a number of developmental and functional impairments in B-cell and eosinophil lineages.[18],[20] In addition, polymorphisms in the IL-5 genes may contribute to the susceptibility to atopic bronchial asthma and could determine the clinical course of the disease.

IL-5 gene is located on chromosome 5 within a cytokine gene cluster IL-4 and IL-13.[28] Further, IL-5 gene, IL4, and IL13 may be regulated coordinately by long-range regulatory elements spread over 120 kilobases on chromosome 5q31.1. This gene encodes a cytokine that acts as a growth and differentiation factor for both B-cells and eosinophils.[29] The association between the IL-5-746C/T and IL-5C703T polymorphisms and susceptibility of pediatric asthma has been investigated in previous study,[26],[27],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39] but the results are conflicting and inconclusive. In addition, there was no previous meta-analysis that assesses the association between IL-5-746C/T and IL-5C703T polymorphisms and risk of asthma. Further, this association has not been comprehensively reviewed, as previous review studies mainly focused on the association of other gene polymorphisms with the development of asthma. Therefore, we performed this study to precisely estimate the association between the IL-5-746C/T and IL-5C703T polymorphisms and susceptibility to asthma.


  Methods Top


Search strategy

This is an integrative review of the literature, of a descriptive and exploratory character, based on the results of previous studies on the subject of IL-5-746C/T and IL-5C703T polymorphisms into asthma.

A comprehensive literature search was conducted using the electronic databases (PubMed and Google Scholar) using the keywords “Interleukin-5 polymorphism” and “Asthma” to search relevant articles published. The electronic searches were conducted during August 2019, and the search strategies were defined after the selection of the databases.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) a case–control study, a cross-sectional study, and a cohort study; (2) the study must be evaluating the association between IL-5-746C/T and IL-5C703T polymorphisms and asthma susceptibility; and (3) the sample is composed of individuals of any age, of both sexes, with a diagnosis of asthma and independent of the time of diagnosis of the disease. The exclusion criteria were as follows: (1) conference papers, reports, comments, or review articles; (2) with duplicated data; (3) data cannot be extracted; (4) IL-5 polymorphisms in site other than 746C/T and IL-5C703T; and (5) the study evaluating the association between IL-5 polymorphisms and other diseases.

Quality assessment

The quality of the studies was assessed using our inclusion and exclusion criteria [Figure 1]. Study quality was assessed by all the authors. The following data were retrieved: the name of the first author, publication year, ethnicity, country, mean age, genotyping methods and single-nucleotide polymorphisms, and a number of cases and controls.
Figure 1: Flowchart depicting the literature search process

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Statistical analysis

Review Manager version 5.3 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Sweden) was used to conduct the meta-analysis, sequential analysis, and publication bias assessment. The odds ratio (OR) with 95% confidence interval (CI) was employed to calculate the association between IL-5 C-764T polymorphisms and asthma risk. The pooled OR was determined using the Z-test, which considered as significant with P < 0.05. A test for heterogeneity was performed separately for three ORs, that is, homozygous dominant model (CC), heterozygous model (CT), and homozygous recessive model (TT). A test for heterogeneity was performed separately for three ORs, that is, homozygous dominant model (CC), heterozygous model (CT),and homozygous recessive model (TT) for the IL-5 C-764T gene. The between-study heterogeneity was assessed by the I2 test. The fixed-effects model was used when the P value of the I2 test was <25%. To estimate whether our results were substantially influenced by the presence of any individual study, a sensitivity analysis was performed by systematically omitting each included case–control study and recalculating the significance of the result. Checking Hardy–Weinberg equilibrium (HWE), HWE was checked in the patient and control groups using the Chi-square test. The funnel plot was used to examine the publication bias. In the absence of publication bias, it assumes that studies with high precision (large study effects) will be plotted near the average, and studies with low precision (small study effects) will be spread evenly on both sides of the average, creating a roughly funnel-shaped distribution. Deviation from this shape can indicate publication bias.


  Results Top


Six studies were selected for the review and meta-analysis. All of them were conducted with the general objective of investigating relationships between IL-5-746C/T and IL-5C703T gene polymorphisms and asthma.

After filtering by availability and reading, consisting of reading the title, abstract, and keywords of each study, six articles were selected[30],[31],[32],,[34],[35],[38] [Table 1]. The remainder were excluded from the analysis because they were not aligned with the subject of the review or with the inclusion criteria.

With relation to the types of study, all publications were the result of case–control, cross-sectional, and cohort study. Four of these were case–control studies. The samples used in the studies varied in terms of age group: one with adults, four with children, and one with mixed-age groups (children and adults). Half of the studies were conducted in the Caucasian and another half in the Asian. All studies used unique samples: a total of 1499 genotyped asthma cases and 3766 genotyped nonasthmatic controls were included in the meta-analysis. The characteristics and the genotype in each study are presented in [Table 1]. Deviation from HWE was detected to the asthmatic patients and controls in three studies[30],[31],[32],[38] and only to the patients in one study,[34] while the HWE result of Zhang et al.[35] was taken from their original article. All studies suggested that the distribution of genotypes in the controls was consistent with HWE, as shown in [Table 2].
Table 1: Characteristics of the studies

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Table 2: Distribution of interleukin.5 genotype among asthmatic patients and controls

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Funnel plot of IL-5 C-746T CC, CT, and TT genotypes for all studies included in the meta-analysis were presented in [Figure 2],[Figure 3], and [Figure 4] respectively. Standard error of the logarithm of the OR (SE(log[OR])) was plotted against the OR for each study. The symmetric, inverted funnel shape implies an absence of publication bias.
Figure 2: Funnel plot of interleukin-5 C-746T polymorphism and asthma risk under the homozygous dominant model CC

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Figure 3: Funnel plot of interleukin-5 C-746T polymorphism and asthma risk under the heterozygous model CT

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Figure 4: Funnel plot of interleukin-5 C-746T polymorphism and asthma risk under the homozygous recessive model TT

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The result found that no significant difference was noted between the asthmatic patient and control groups in the genetic IL-5 c-764T polymorphism (CC genotype showed OR = 0.82, 95% CI = 0.67–1.00, P = 0.05; CT genotype showed OR = 0.94, 95% CI = 0.78–1.13, P = 0.50; and TT genotype showed OR = 0.85, 95% CI = 0.64–1.13, P = 0.27). As with the overall analysis, overt between-study heterogeneity (I2 = 0% and 24%) and publication bias were not detected, as presented in [Figure 5].
Figure 5: Forest plots of the association between interleukin-5 C-746T polymorphism and asthma risk in the total population under the allelic model, (a) for homozygous dominant model (CC), (b) for heterozygous model (CT), and (c) for homozygous recessive model (TT)

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Guideline for interpretation of the I2 statistic results at figure 5: I2 = 0% – no heterogeneity, I2 = 25% – low heterogeneity, I2 = 50% – moderate heterogeneity, and I2 = 75% – high heterogeneity.[40]

Review

The foci of identification of the studies selected were investigations of associations between IL-5-746C/T and IL-5C703T polymorphisms involved in the asthmatic patients.

The relationship between IL-5-746C/T polymorphism and asthma was analyzed in four studies with samples of adults and children with different population profiles. One of them[31] found that the association between asthma and IL-5-746C/T polymorphisms was not significant by comparing the occurrence of polymorphisms in asthmatic children and healthy children. The frequencies of the IL-5 CC homozygote 11.2% and CT heterozygote 41.7% in children with atopic asthma were not significantly different from the frequencies in healthy children (13.2% and 36.8%, respectively), whereas the study indicates that IL-5-746C/T polymorphisms may play a role in the pathogenesis of asthma, which found that the log serum total IgE concentration was significantly higher in asthmatic children with homozygous CC and heterozygous CT IL-5 mutant alleles (2.58–60.45 IU/mL) compared with those with wild-type TT alleles (2.45–60.44 IU/mL), P = 0.022. Further, atopic children with asthma with CC homozygote and CT heterozygote had lower forced expiratory flow at 25%–75% of forced vital capacity than those with the TT homozygote (74.2% ± 21.6% vs. 85.3% ± 24.5%) P = 0.002. A study by Kabesch et al.[30] showed that the T allele at position-746 in the IL-5 gene was significantly protective for atopy in the International Study of Asthma and Allergies in Childhood-II population (P = 0.006). Furthermore, the risk for atopic asthma was decreased in carriers of the T allele (P = 0.036). Moreover, Zhang et al.[35] failed to observe any association between polymorphisms of IL-5 at position-746C/T and susceptibility to asthma. Finally, another study demonstrated an association between the IL5 C-746T polymorphism and a decreased risk of developing asthma.[32]

The other two studies with a different site of polymorphism (C-703T) analyzed links between asthma and IL-5 gene polymorphism. A study by Freidin et al.[34] is the first evidence of an association between the IL-5 C-703T gene polymorphism and bronchial asthma, which found that analysis of the asthmatic patients and their relatives from Tomsk by the use of transmission/disequilibrium test revealed the presence of a statistically significant association between the C-703 IL5 allele and asthma (P = 0.005). In addition, this finding characterizes the polymorphisms examined as race specific. It can be hypothesized that the C-703T substitutions in the IL5 genes appeared long before the subdivision of humankind into the main races. Later processes of racial divergence resulted in the accumulation of different gene variants in the Caucasoids and Mongoloids. High heterozygosity observed for the C-703T polymorphism in all populations examined, which was close to the maximum for a biallelic marker, confirmed the possible ancient origin of these gene variants. Another study tested suggest that asthma in children is associated with TT genotype of IL-5 C-703T polymorphism. The frequency of genotype TT recorded OR = 2.026 with CI between 0.947 and 4.335 under 95%; it showed a statistically significant difference (P = 0.045) according to Fisher's exact test.[38]


  Discussion Top


We believe this is the first meta-analysis to investigate the association between IL-5 C-746T and C-703T polymorphisms and susceptibility to asthma. On the basis of three case–control studies and one cross-sectional and cohort study involving 1198 asthma cases and 3681 controls, the present meta-analysis did not find a significant association between the IL-5 C-746T polymorphism and asthma. In spite of between-study heterogeneity was not significant. On the other hand, the review of two other studies[34],[38] has revealed the presence of a statistically significant association between the C-703T IL-5 polymorphism and developing asthma in children.

Certain limitations to this review and meta-analysis need to be taken into consideration when interpreting the findings. First, there was only one case–control study that investigated the association of IL-5 C-703T polymorphisms with pediatric asthma risk in the Asian. Further, there was no case–control study that investigated the association of IL-5 C-703T polymorphisms with pediatric asthma risk in the Caucasian. Therefore, more studies with larger sample sizes are needed to investigate the association of IL-5 C-703T among asthmatic children at the Asian and Caucasian. Second, because the number of included studies was insufficient and small studies with negative results are less likely to publish, hence the possibility of publication bias cannot be completely ruled out, even though the Egger's test and funnel plots did not show evidence of publication bias in this meta-analysis. Third, the control group for one study included in this meta-analysis was not in HWE.[34] Fourth, the asthma phenotype was often not fully specified, details of asthma diagnoses were often scanty, and lack of evaluation of the effects of gene to gene and gene to environment interactions during pediatric asthma development. Without sufficient information in individual studies, the condition labeled as asthma in this meta-analysis is likely to be heterogeneous and may be contributing to the inconsistency of results.


  Conclusions Top


This may be the first systematic and comprehensive meta-analysis of C-764T and C-703T polymorphisms in IL-5 and asthma. The results in this meta-analysis suggest that IL-5 C-746T polymorphisms are not associated with increased asthma risk, whereas IL-5 C-703T polymorphisms are associated with asthma in children. Further studies with large sample sizes were needed to confirm our findings.

Acknowledgment

The authors are grateful to the staff of the Karbala Teaching Hospital for children, Karbala University, Iraq, for their great help throughout this work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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