|Year : 2020 | Volume
| Issue : 3 | Page : 196-203
Lack of association between interleukin 13, interleukin 4 receptor alpha, andMS4A2 gene polymorphisms and asthma in adult Saudis
Eman A Al Abdulsalam1, Mohamed S Al-Hajjaj2, Mohammad S Alanazi1, Arjumand S Warsy3
1 Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
2 Department of Clinical Science, University of Sharjah, Sharjah, UAE
3 Female Center for Scientific and Medical Studies, Central Laboratory, King Saud University, Riyadh, Saudi Arabia
|Date of Submission||09-Dec-2019|
|Date of Decision||02-Feb-2020|
|Date of Acceptance||15-Apr-2020|
|Date of Web Publication||02-Jul-2020|
Arjumand S Warsy
Department of Biochemistry, Center for Science and Medical Studies for Girls, Central Laboratory, King Saud University, PO Box 22455, Riyadh 11495
Source of Support: None, Conflict of Interest: None
Objectives: Several genes, including interleukin-13 (IL13), MS4A2, and IL 4 receptor alpha (IL4Rα), have been shown to associate with the inflammatory process in asthma. We investigated the possible association between asthma and five single-nucleotide polymorphisms (SNPs) in the IL13, IL4Rα, and MS4A2 gene in comparison with the level of the IL-13 protein in the Saudi asthmatics and controls. Subjects and Methods: The study group included 50 adult asthmatic patients and 50 normal healthy controls. Blood was extracted, and DNA was prepared. Genotyping was performed on DNA using direct sequencing for four SNPs (rs20541, rs1800925, rs1801275, and rs569108), and real-time polymerase chain reaction allelic discrimination to study rs1805010 polymorphism. Levels of IL-13 were measured in plasma using (enzyme-linked immunosorbent. Genotype and allele frequencies were calculated for each SNP. Results: The results showed that GG genotype of rs1801275 in the IL4Rα gene was more common in the asthmatic patients compared to the control group, though the results did not show any statistical significance (P < 0.08). Conclusions: No significant association was observed for any of the other SNPs examined. Of all the SNPs analyzed, only rs1801275, an A > G transition nonsynonymous mutation, resulting in the substitution of glutamine by arginine showed an association, but it was statistically not significant. Interestingly, presence of the mutant allele of both SNPs of IL-13 gene significantly elevated IL-13 level. Comparison of the Saudi results with those of other populations, showed several significant differences. We conclude that further more detailed studies are necessary in Saudis to identify the contribution of SNPs in cytokine genes in asthma development.
Keywords: Association study, asthma, genotyping, interleukin 13, interleukin 4 receptor alpha, MS4A2, Saudi Arabia, single-nucleotide polymorphism
|How to cite this article:|
Al Abdulsalam EA, Al-Hajjaj MS, Alanazi MS, Warsy AS. Lack of association between interleukin 13, interleukin 4 receptor alpha, andMS4A2 gene polymorphisms and asthma in adult Saudis. J Nat Sci Med 2020;3:196-203
|How to cite this URL:|
Al Abdulsalam EA, Al-Hajjaj MS, Alanazi MS, Warsy AS. Lack of association between interleukin 13, interleukin 4 receptor alpha, andMS4A2 gene polymorphisms and asthma in adult Saudis. J Nat Sci Med [serial online] 2020 [cited 2020 Aug 12];3:196-203. Available from: http://www.jnsmonline.org/text.asp?2020/3/3/196/288828
| Introduction|| |
Asthma is a chronic inflammatory disease of the lungs, affecting an estimated 300 million people worldwide., It is a common disease worldwide with significant morbidity and mortality and a prevalence that is on the rise in many developing countries. Studies have been carried out to determine the role of genetic susceptibility in the development of asthma and results have shown that the heritability risk for asthma development is up to 60%. The number of genes that contribute to asthma development may exceed 200 genes. Several genes, have been shown to be associated with the inflammatory process in asthma in some populations but not in others.,, Studies using single-nucleotide polymorphisms (SNPs) have led to the identification of several SNPs which show a close association with asthma development in case–control studies. However, a considerable degree of heterogeneity is apparent, where some SNPs show association with asthma in some populations, while not in others. Ethnic variations are frequently reported and often differences are observed within the same population., It is also apparent that it is not only the presence of a certain SNP that predisposes to asthma development, but also depends on associated environmental factors, such as carpet use in the house, or presence of mold in the environment or others. This confirms the multifactorial nature of asthma. It is also polygenic, with synergistic contributions from a number of genetic loci that lead to asthma development, and modulate its severity and complications. Several genetic loci, associated with asthma and the asthma inflammatory processes have been reported. Polymorphisms in substances contributing to innate immunity have also been investigated for their association with asthma, and novel polymorphisms have been identified in multiple populations. However, extensive population variations have frequently been noted. SNPs in interleukin-13 (IL-13), IL-4 receptor alpha (IL-4Rα), and MS4A2 genes have shown promising results, though differences are reported in different ethnic groups and in different age groups.
The cytokine IL-13 is considered as one of the candidate genes involved in asthma development. The IL-13 gene encodes the cytokine IL-13 that is involved in hypersensitivity reactions as it stimulates the B-lymphocytes to synthesize IgE. Animal models show that IL-13 knockout mice failed to produce mucus and even to replenish basic IgE levels after stimulation with IL-4. This suggests that IL-13 is a cytokine involved in the pathogenesis of asthma. In the IL-13 gene, association studies have reported several polymorphisms that are associated with asthma development.,, In Saudi patients, Halwani et al., investigated four SNPs within the IL-13 gene or near, in a cohort of asthmatic patients with ages from >3 years to almost 70 years. They showed an association of rs20541/R130Q and rs1295686/+1923C/T with asthma development, while, rs1800925/−1112C/T and rs762534/C/T did not associate.
The IL4Rα gene encodes for IL-4 receptor α chain. This receptor is a heterodimer of two subunit α chains that have high affinity for binding to IL-4 and shares with IL-13R and γ chain that is common in cytokine receptors. The IL4R gene has been linked to atopy and asthma in different populations ,,, due to the important role played by binding to the IL-4 or IL-13 cytokines. This binding activates the signaling pathways to induce the inflammatory process. Several polymorphisms in this gene are shown to associate with asthma development in different populations. Al-Muhsen et al. studied the association between SNPs in IL4-Rα is Saudi asthmatics, 11–70 years old, and showed that rs1805010 and rs1801275 associated significantly with asthma development.
The MS4A2 gene, also termed as FcεRIβ, encodes β subunit of the high affinity IgE receptor (FcєRI). The FcєRI is a multimeric receptor that binds to the Fc region of IgE. Crosslink of FcєRI receptor by IgE and antigen on mast cells leads to a signaling cascade within minutes resulting in the release of preformed mediators such as histamine, rapid synthesis of arachidonic acid metabolites, such as prostaglandins and leukotrienes and the expression of cytokines (e.g., IL-3, IL-4, IL-5, IL-6, IL-13 and TNFα) and chemokines. Cookson et al. reported the first genetic linkage for allergy in 1989 on chromosome 11q13 where a strong linkage was observed with a gene that is in close proximity to the MS4A2 gene., Several polymorphisms have been identified in the MS4A2 gene ,,, and a meta-analysis published in 2014 showed the association of several SNPs in MS4A2 gene and asthma risk. To the best of our knowledge, no studies have been conducted on MS4A2 gene polymorphism in Saudi population.
In addition, studies including meta-analysis have shown heterogeneity in the extent of association of a SNP to asthma development in different age groups, and we observed that many international studies have been conducted either in the adult or children and adolescent population. Hence, we designed this study on adult Saudi asthmatic population and aged-matched normal controls with the aim to determine if any association existed between five SNPs in IL13,IL4Rα, and MS4A2 genes and asthma development, and to compare these results with those reported earlier. The five SNPs included in this study were: Two in IL13 (Arg144Gln G > A [rs20541] and C1111T C > T [rs1800925]), two in IL4Rα, (Ile50Val A > G [rs1805010] and Gln551Arg A > G [rs1801275]), and one in MS4A2 gene, (Glu237Gly A > G [rs569108]).
| Subjects and Methods|| |
The Local Ethics Committee at the College of Medicine and King Khalid University Hospital (KKUH), King Saud University, Riyadh, Saudi Arabia, approved this case–control study and an IRB was obtained. The study group included 50 adult patients (age range: (Mean ± standard error of mean [SEM]) 50.0 ± 1.97 year) attending the outpatients clinics of Dr. Al-Hajjaj and 50 controls (age range (Mean ± SEM):29.4 ± 1.02 year), who were attending the blood bank at KKUH for blood donations. Informed consent was obtained from all study population. The patients had an established diagnosis of bronchial asthma made by the routine clinical and physiological parameters, and were visiting the pulmonary clinics at the KKUH for follow-up. A physician (Dr. Al-Hajjaj) interviewed all patients and a questionnaire was filled. Blood samples (5 ml) were drawn by venipuncture in EDTA tubes.
DNA extraction and genotyping
DNA was extracted from the buffy coat using the Illustra blood GenomicPrep Mini Spin Kit from GE Healthcare Amersham, UK, according to the manufacturer's instructions. In addition, all subjects were genotyped for each polymorphism by polymerase chain reaction (PCR) amplification of the region containing the polymorphic site, followed by sequencing or real-time PCR for allelic discrimination. PCRs were carried out in a total volume of 25 μl containing approximately 50 ng of genomic DNA, 2.5 μl of 10x PCR buffer (Qiagen), 2 μl of 2.5 mM dNTPs (promega), 1 μl from each of primer F and R (5 pmole), 1 μl of DNA (50 ng/μl), and 0.2 μl of hot start enzyme (Qiagen). The reaction was activated at 95°C for 15 min, followed by 35 cycles of DNA denaturation at 95°C for 1 min, annealing at 60°C for 1 min, and elongation at 72°C for 1 min, followed by final elongation step at 72°C for 10 min. The PCR product was subjected to agarose gel electrophoresis to confirm that the amplification had taken place and the fragment produced was of the correct size. Sequencing was conducted using the “big-dye system v3” (Applied Biosystems, USA) and forward primer for all mentioned SNPs, and the image was visualized in the commercial POP-7 gel using an automated sequencer (ABI 3130xl Genetic Analyzer). Real-time PCR was carried out for allelic discrimination using Fast 7500 ABI thermal cycler and Custom Taqman SNP genotyping assay, ready designed for the customer (ABI, USA).
Enzyme-linked immunosorbent assay
Plasma IL-13 levels were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit supplied by Invitrogen and Biosource.
Genotype and allele frequencies were obtained by genotype and allele counting and errors were assigned. For all comparative analysis, 2 × 2 tables were generated between populations and between asthmatics and nonasthmatics using Chi-square test or Fischer's exact test, 95% confidence intervals and odds ratio. Statistical Package for the Social Science, version 18 (SPSS; Inc., Chicago, IL, USA) was used for the comparative studies between asthmatic and nonasthmatic. For ELISA calculations, student un-paired t-test was used. All analysis were calculated by computerized methods using excel sheet and statistical software GraphPadInStat version 2.04 (Ralf Stahlman, Purdue Univ. 931897s). A P = 0.05 was considered statistically significant for all analysis.
| Results|| |
[Table 1] shows the demographic details and clinical findings in the study population of asthmatics. All individuals included in this study were adults. The age of asthma diagnosis was 44.0 ± 2.15 years. Shortness of breath and wheezing was the major symptoms. About 89% of the patients were suffering from allergic reactions.
|Table 1: Demographic data and major clinical characteristics of the asthmatic patients included in this study|
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Genotype and allele frequencies of the five studied SNPs are presented in [Table 2]. The rs20541 polymorphism in the IL13 gene was studied in the asthmatic patients and controls and the sequencing results showed that the majority of samples were homozygous for the wild type G allele. Genotype and allele frequencies were calculated and the results in patients and controls are presented in [Table 2]. No significant differences were observed in the genotype or allele frequencies in the asthma patients and controls. The investigation of rs1800925 polymorphism in the IL13 gene, in the patients and control groups, showed that the majority of samples (both patients and controls) were heterozygous for this SNP. No statistically significant differences were obtained in the genotype and allele frequency in asthmatic patients and controls [Table 2]. The investigation of rs1805010 polymorphism in the IL4Rα gene showed that the majority of samples, from both asthmatics and controls, were heterozygous for this SNP. No statistically significant differences were obtained in the genotype and allele frequency in asthmatic patients and controls [Table 2]. The results of rs1801275 polymorphism in the IL4Rα gene showed that majority of samples were homozygous for the wild type A allele. No statistically significant differences were obtained in the genotype and allele frequency in asthmatic patients and controls [Table 2]. The IL-13 levels in asthmatics and nonasthmatics are presented in [Table 3]. The results were grouped according to the IL13 genotypes and the level of the IL-13 was obtained for each genotype separately in the patients and control groups. Between the patients and controls, there was no significant difference, but within each group, the IL-13 level was significantly higher in the heterozygous genotype compared to the wild type of both SNPs.
|Table 2: Genotype and allele frequencies of the studied single nucleotide polymorphisms in the asthmatics and control groups|
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|Table 3: Association between the interleukin 13 genotype and interleukin-13 plasma levels in asthmatic patients and control|
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The screening of the rs569108 polymorphism in the MS4A2 gene showed that the majority of samples were homozygous for the wild-type A allele. No statistically significant differences were obtained in the genotype and allele frequency in asthmatic patients and controls [Table 2].
The frequencies for the different alleles of the studied SNPs in Saudis were compared with the results reported in different populations and the results are presented in [Table 4].
|Table 4: Allele frequencies for the study single nucleotide polymorphisms and allele frequency comparison between asthmatic Saudis and other populations|
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| Discussion and Conclusions|| |
Asthma constitutes a major health problem in Saudi population. A recent meta-analysis of 31 studies from different regions of the country and on adult and children, reported a pooled asthma prevalence of 14.3%, with the range from 3.2% in Qaseem to 33.7% in Al-Hafouf. A study on adults showed that asthma occurred at a prevalence of 11.3%. Environmental and genetic factors were implicated as the causative factors. Several well-conducted studies have explored the association between different polymorphism in several genes, including IL-10,IL-13,STAT-6,IL-4Ra,CD-14, glucocorticoid-inducible 1, and interferon γ genes and asthma development in Saudis and several associations have been reported.,,,,,,,,,
In this study on Saudis patients, three different genes reported to be associated with asthma inflammatory processes were studied in adult asthmatics, and the results were compared with the results in their control counterparts. In addition, the allele frequencies in Saudi asthmatics were compared with those in other populations to assess ethnic variations.
Several polymorphisms have been reported in the IL13 gene, and though there are population variations, a significant association has been demonstrated between some of the SNPs in the IL13 gene and asthma. [15,,, It has been suggested that this association may be due to an effect of the allele on the amount of IL-13 synthesized, since, any mutation that may increase the IL-13 level or signaling pathway is expected to increase hypersensitivity or viceversa.
In the IL13 gene, the Arg144Gln G > A (rs20541) polymorphism was identified in the Saudi asthmatic and normal individuals. The results in the asthmatic and nonasthmatic were not statistically different indicating that the rs20541 is not linked to asthma development in the adult Saudi population. Although the study of Halwani et al., showed a significant association in a mixed population of Saudi adults and children. Several other studies have also reported the association between rs20541 and asthma, while, some others have failed to do so. Furthermore, population differences are obvious, and differences are also reported in children and adult populations. When the results of this study were compared with frequency in three different populations, i.e., the UK and Italian, Dutch and African Americans [Table 4], significant differences were identified (P < 0.001), where Saudi results were similar to those reported for African Americans  but significantly different from Danish, UK, and Italian populations.,
Some studies have reported that the rs20541 polymorphism affects IL-13 level in the plasma due to amino acid substitution that increases the IL-13 binding capacity to its receptor, thus enhancing IL-13 signaling and may affect IL-13 concentrations in the presence of the homozygous mutant allele (AA). Interestingly, our results showed that the presence of the mutant allele significantly increased the Il-13 level for both SNPs in IL-13 gene. There were no homozygous cases for both SNPs in the studied groups.
In the IL13 gene another SNP, C1111T C > T (rs1800925) has also been investigated in several studies, and it was reported to be associated with asthma development.,,, This polymorphism occurs in the promoter region and may influence the gene expression of the IL13 gene. The homozygous state of the mutant allele (TT) existed at a higher prevalence in the asthmatic groups compared to the control group. Results of this investigation showed no significant difference in the genotype and allele frequency between the asthmatic patients and controls. Thus, indicating that the polymorphic site plays no part in asthma development in Saudis. These results are in agreement with the results obtained in the study reported by Halwani et al.
The allele frequencies obtained for rs1800925 in the Saudi asthmatics were compared with the allele frequencies reported in four different populations (African American, Dutch, UK and Italy, and Amsterdam),,, and the results showed a significant difference as compared to all populations [Table 4] except the African American. In the UK and Italian population, the T allele (mutant allele) occurred at higher frequency, while in populations from Amsterdam and the Dutch, the C allele (wild type allele) was significantly higher.
In addition, some studies showed an elevation in the level of IL-13 in individuals who are homozygous to the mutant allele (TT), possibly due to the effect of rs1800925 promoter polymorphism in increasing transcription factor binding to the IL13 gene in T cells and hence IL-13 production. However, our findings failed to show any relationship between this polymorphism and IL-13 plasma level.
IL-4 receptor α (IL-4Rα) is an important candidate gene for asthma development. The presence of the polymorphic forms induces functional changes in the receptor. Two polymorphisms were investigated during this study. rs1801275 is a A > G transition which leads to a Gln to Arg substitution at amino acid 551 located in the cytoplasmic domain and influences the signaling pathway while the rs1805010 polymorphism, also an A > G transition, results in Ile substitution by Val at amino acid 50, located in the exon 5, which constitute the extracellular domain of the IL-4Rα and affects the binding between the cytokine and the receptor. Several studies report an association between these polymorphisms and asthma development.,
When the allele frequency of rs1805010 polymorphism in the IL4Rα gene obtained in the Saudi asthmatics were compared with the frequencies reported in six different populations (Danish, Italian, Japanese, UK, Swedish, and African Americans),,,,, the results [Table 4] were in agreement with all populations except the Danish population, who showed a significant association between this polymorphism and asthma development.
Similarly, the rs1801275 polymorphism in IL4Rα gene is an A > G transition, which results in the substitution of glutamine by arginine at position 576, and has been reported to be associated positively with asthma development in different populations [Table 4]. In this study on Saudis, the results did not show any significant association with asthma development in the asthmatic Saudi adult, though, 14 of the 50 asthmatics were homozygous for the mutated allele (GG) compared to only 4/50 in the control group. This suggests that homozygous to the mutant allele may have a higher susceptibility to develop asthma. However, in this study, the difference in genotype and allele frequencies was not statistically significant, possibly due to small sample size. The study by Al-Muhsen et al., on Saudi the population in Riyadh showed significant association between both these SNPs and asthma development. The difference in our results and those of Al-Muhsen et al., could be due to difference in the age groups studied. Al-Muhsen et al. screened 11–70 years old group, whereas in the present study, the study group were adults. Differences in the extent of association in different age groups have been reported in previous studies. It is shown in a meta-analysis, that some SNPs that associate with asthma in children do not do so to the same extent in adults.
Comparing the rs1801275 allele frequencies in the Saudi asthmatics with the results reported for the UK and Italy, UK, Japan, the USA, Australia, and Swedish  populations, showed significant differences when compared to the population from Australia and Japan but not others [Table 4].
Finally, the rs569108 polymorphism in the MS4A2 gene, an A > G transition, results in substitution at position 237, which is located in the exon 7 of the gene and falls in the domain which constitutes the cytoplasmic domain of the FceRβ. It results in the substitution of an acidic amino acid (glutamic acid) by a nonpolar amino acid (glycine), hence altering the mechanism of intercellular signaling. Several studies have reported that this polymorphism is linked to asthma development,,,, though other studies have failed to show any association. Results of our investigation agree with the finding of the studies that show no significant differences between asthmatics and controls. When the results of rs569108 polymorphism in the MS4A2 gene in the Saudi asthmatics were compared to results reported in the literature for the Australians, Europeans, and Asian, significant differences were observed in the gene frequencies. Saudi results were similar to results reported for the Sub-Saharan Africans [Table 4].
In conclusion, this study reports the frequency of five polymorphic sites in three genes (IL-13,IL4RaandMS4A2) and shows that these SNPs do not associate with asthma in adult Saudi patients, though earlier studies on Saudi patients with ages ranging from >3 to over 70 years, have shown an association between some of the studied SNPs (rs20541, rs1801275, rs1805010), but not with others (rs1800925). No studies have been conducted on rs569108 in Saudis. Our findings of no association with this SNP, are in line with some earlier reports, but contradict other reports.
We also show that Saudi genotype and allele frequencies of the studied SNPs are significantly different from some populations, when compared to results reported in the literature, highlighting the heterogeneity in different ethnic groups. We want to stress a limitation of this study, and that is the small sample size used for the investigation. We would like to suggest that this study be considered a pilot investigation, with future more detailed studies on a larger adult population size to clarify the association between the different SNPs and asthma, a condition frequently encountered in this population.
Financial support and sponsorship
This work was funded by a grant from the Deanship of Scientific Research at King Saud University.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]