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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 234-240

Three common single-nucleotide variants in the promoter region of thymic stromal lymphopoietin cytokine are not associated with asthma prevalence in a Saudi Arabian population


1 Department of Pediatrics, College of Medicine, Immunology Research Lab; Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Department of Pediatrics, College of Medicine, Immunology Research Lab, King Saud University, Riyadh, Saudi Arabia
3 Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
4 College of Medicine, Imam Mohammed Ibn Saud University, Riyadh, Saudi Arabia
5 Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
6 Department of Plant Production, Faculty of Agriculture and Food Sciences, King Saud University, Riyadh, Saudi Arabia
7 Department of Chemical and Process Engineering Technology, Jubail Industrial College, Jubail Industrial City, Jubail, Saudi Arabia
8 Sharjah Institute of Medical Research, College of Medicine, University of Sharjah; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates

Date of Submission09-May-2020
Date of Decision03-Jun-2020
Date of Acceptance12-Jun-2020
Date of Web Publication02-Oct-2020

Correspondence Address:
Rabih Halwani
College of Medicine, University of Sharjah, Sharjah
United Arab Emirates
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_44_20

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  Abstract 


Background: Thymic stromal lymphopoietin (TSLP) is recognized for its key role in promoting asthma, hence drawing considerable clinical interest as a potential therapeutic target. Population-based studies found association between single nucleotide polymorphisms (SNPs) located in the TSLP promoter region, and asthma; however, discrepancies have been also reported. Aims and Objectives: To determine whether rs1837253, rs2289276, and rs3806933 SNPs of TSLP gene are associated with asthma predisposition in a Saudi population. Materials and Methods: A total of, 272 asthmatic patients and 398 normal controls, all of Saudi citizenship, were recruited. The TSLP target DNA sequences were polymerase chain reaction (PCR) amplified using specific primers and allelic determination was performed by Sanger sequencing and capillary electrophoresis. Results: The relative frequencies for the minor allele, “T,” in all three SNPs, were smaller in asthmatics although not significant. When testing for genotypes, the homozygous T/T of all three SNPs was less frequent in asthmatic patients, but not to statistically significant levels. Both the recessive and dominant genetic models were tested. Homozygous T/T individuals for each SNP had lower odds of being asthmatics, thus suggesting a “protective” effect, although none of the SNPs in either model reached a statistical significance. Conclusion: Three SNPs in TSLP's promoter gene were not significantly associated with asthma in the Saudi population.

Keywords: Allergy, association analysis, atopic asthma, genotyping, risk, rs1837253, rs2289276, rs3806933, Saudi Arabia, thymic stromal lymphopoietin


How to cite this article:
Alenazy MF, Vazquez-Tello A, Kenana R, Sharif-Askari FS, Alkahtani AR, Jamhawi A, Afzal S, Al-Kufiedy R, Temsah MH, Al-Masri A, Alsohaime F, Al-Eyadhy A, Zakri AM, Ratemi E, Al-Muhsen S, Halwani R. Three common single-nucleotide variants in the promoter region of thymic stromal lymphopoietin cytokine are not associated with asthma prevalence in a Saudi Arabian population. J Nat Sci Med 2020;3:234-40

How to cite this URL:
Alenazy MF, Vazquez-Tello A, Kenana R, Sharif-Askari FS, Alkahtani AR, Jamhawi A, Afzal S, Al-Kufiedy R, Temsah MH, Al-Masri A, Alsohaime F, Al-Eyadhy A, Zakri AM, Ratemi E, Al-Muhsen S, Halwani R. Three common single-nucleotide variants in the promoter region of thymic stromal lymphopoietin cytokine are not associated with asthma prevalence in a Saudi Arabian population. J Nat Sci Med [serial online] 2020 [cited 2020 Oct 19];3:234-40. Available from: https://www.jnsmonline.org/text.asp?2020/3/4/234/297116




  Introduction Top


The human thymic stromal lymphopoietin (TSLP) cytokine gene encodes at least two differentially regulated transcripts; the theoretical molecular weight of their corresponding peptide products are 18.1 and 7 kDa for the long (TSLP-L) and the short (TSLP-S) isoforms, respectively, which have been found recently to exert opposing effects on cells.[1],[2] Even though TSLP-S seems to be constitutively expressed, both isoforms can be up regulated and are secreted by many cell types (e.g., epithelial, keratinocytes, airway smooth muscle cells, fibroblasts, dendritic cells, trophoblasts, and astrocytes) and tissues, including lung parenchyma, skin, intestines, ocular tissues, and spinal cord.[3],[4],[5] Most studies have focused on the pro-inflammatory long isoform, at expense of the much less known anti-inflammatory short isoform. Multiple factors can induce TSLP-L expression;[4] in particular, after stimulation with cytokines, such as Interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, and also by ligands of the toll-like receptor family, including TLR2, TLR3, TLR5, TLR8, and TLR9.[4],[6],[7] On release, TSLP-L binds and activates its heterodimeric receptor, TSLPR (a.k.a. Cytokine Receptor-Like Factor 2, CRLF2)/IL-7R alpha, which results in multiple and varied effects in target cells. Many cells, both of lymphoid and myeloid lineages (e.g., T and B cells; dendritic and mast cells; and eosinophils) are known to express TSLP receptor, but also structural cells do (e.g., lung epithelial; smooth muscle; and fibroblasts) and respond to stimulation.[8],[9] A major signaling pathway is mediated through Janus kinases (JAK1/JAK2) and signal transducers and activators of transcription (STATs) phosphorylation, but other pathways have been uncovered. In contrast, TSLP-S signals through p38alpha kinase and does not activate STAT5 factor, which is congruent with its anti-inflammatory and putative homeostatic role.[1],[2] Hence, TSLP-L/TSLR activation causes changes in phosphorylation status of hundreds of proteins and induces the expression of many target genes, such as the anti-apoptotic factor B-cell lymphoma (Bcl)-2 in T helper-2 (Th2) cells.[10],[11] Not surprisingly, TSLP-L is an essential factor involved in the development and maturation of antigen presenting cells; through myeloid dendritic cell activation, it promotes Th2 cell differentiation and Th2 memory cell proliferation.[12],[13] Furthermore, extensive research has revealed that TSLP-L plays a key regulatory function in the pathogenesis of a long list of allergic inflammatory disorders, not restricted to promoting asthma and skin-specific Th2 inflammatory responses, but to other organ systems and nonallergic diseases, including cancer.[3],[14] Indeed, TSLP has been implicated in promoting vascular endothelial cell growth and angiogenesis, which could be linked with cancer metastasis.[15]

In asthma, it is proposed that TSLP, through STAT5 activation antagonizes the anti-inflammatory effects of T regulatory cells, by inhibiting IL-10 release.[16] Therefore, TSLP and its signaling pathway elements are considered potential therapeutic targets to control asthma inflammation.[14],[17] Of clinical relevance, single-nucleotide polymorphisms (SNPs) in the TSLP gene have been linked with asthma susceptibility and other allergic disorders.[18],[19],[20] However, discrepancies have been also reported [Supplementary Table 1] for list of related studies];[6],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] for instance, rs2289276, which is located in the promoter region, was significantly associated with lower asthma risk in females,[19] or associated with higher risk to childhood atopic asthma,[22] and to increased eosinophilia,[28] yet without significant effect in two other reports;[18],[20] similar contradictory results have been reported for other SNPs and immune disorders. Therefore, evidence that a particular TSLP variant is consistently associated with asthma risk across different ethnic groups remains inconclusive, and more validating studies are needed. In this regard, the present study aims to determine whether rs1837253, rs2289276 and rs3806933 SNPs of TSLP gene are associated with asthma predisposition in a Saudi Arabian population.
Table 1: Allele and genotype frequencies for three thymic stromal lymphopoietin single.nucleotide polymorphism variants: rs2289276, rs1837253, and rs3806933a, in asthmatics and nonasthmatics

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  Methodology Top


Patients and subjects

A total of 670 individuals (43% females and 57% males) were recruited at two major hospitals (King Khalid University Hospital, and King Fahad National Guard Hospital), in Riyadh, Saudi Arabia. All individuals or a parent signed a written consent form; this study was approved by the Ethical Committee of the King Khalid University Hospital, Approval No. E-10-122.

Two hundred and seventy-two asthmatic patients with clinical history of asthma symptoms were eligible based on the following criteria: (a) history of at least 1 year of asthma diagnosed by a physician; (b) of age ≥3–65 years old; and (c) only Saudi nationals were recruited. Atopic asthmatics were identified by total serum IgE levels (>100 IU/ml) and/or by skin prick tests. Patients were excluded if they presented other disorders such as cardiac and renal dysfunction, or uncontrolled hypertension, or acute respiratory tract infections at the time of the interview, or if they were tobacco smokers. The clinical and principal demographic characteristics of the recruited asthmatics have been described in detail previously[32],[33] briefly, a males-to-females ratio of 1:5; of age 15.5 ± 19.7 years old (average ± standard deviation); 15.7% were intermittent, 43.4% mild, 22.3% moderate, and 18.6% severe asthmatics; about two-thirds of patients reported having allergies (67.3% of men and 56.1% of women), of which the most frequent were allergic rhinitis (57.7%), eczema (25.3%), foods (21.4%), antibiotics (2.9%), and aspirin (1.4%).

Nonasthmatic controls (n = 398) were also recruited if fulfilling the following criteria: (a) of age ≥3–65 years old; (b) must be nonsmokers; (c) must not have any asthma symptoms and no history of allergies; (d) not taking any medications at the time of recruitment; (e) be of Saudi ethnicity/nationality. Individuals were excluded if they presented any respiratory illness, or cardiac (e.g., hypertension) and renal dysfunction, or acute respiratory infections at the time of recruitment.

Genotyping

DNA samples were obtained from whole peripheral blood, using a QIAamp DNA Blood Midi Kit (QIAGEN), following the manufacturer's instructions. Genotyping for TSLP rs2289276, rs1837253, and rs3806933a SNPs was performed by polymerase chain reaction (PCR) amplification of the DNA segments (about 150–250 bp) encompassing each variant, using Taq Polymerase (Quick-Load Taq 2X Master Mix; New England BioLabs) and specific primers; primers for rs2289276: 5'-AGT TAA CAC CAG CCC TAC AAG T-3' (reverse) and 5'-AGG CAA CAG CAT GGG TGA AT-3' (forward); for rs1837253: 5'-CAG GAA ACC GTG GCT CTT AAT G-3' (reverse) and 5'-CTG AGA AGA GTG GGA CTC ACA A-3' (forward); for rs3806933a: 5'-CAT CTC GAT GCT TCT CCT GTC-3' (reverse) and 5'-ATT AAA TGT GCA ACC GTG ACC-3' (forward). The conditions for polymerase chain reaction (PCR) were the following: 10 min at 95°C for initial denaturation, followed by 35 cycles of 30 s at 95°C for denaturation, 30 s at 60°C for annealing, 1 min at 72°C for extension, and 7 min at 72°C for the final extension. The purified PCR segments were then Sanger sequenced using the BigDye Terminator kit, and separated by capillary electrophoresis (Sequencer model 3730XL; Applied Biosystems; Sequence analysis was performed using the SeqMan 6.1 module of the Lasergene (DNA Star Inc. WI, USA) software package). The conditions for the sequencing reaction were the following: 1 min at 96°C for initial incubation, followed by 25 cycles of 10 s at 96°C for denaturation, 5 s at 50°C for annealing, and 4 min at 60°C for the extension. Genotyping analysis was performed with the Sequencing Analysis software version 5.2 (Applied Biosystems).

Statistical analysis

Statistical analysis of both allele and genotype frequencies was performed as described previously.[32],[33] Yates corrected Chi-square tests and Yates P values were calculated. Two-tailed P < 0.05 was considered statistically significant. Hardy–Weinberg equilibrium (HWE) test was done using SNPStats computer program.[34] Logistic regressions for each SNP were performed to test the interaction of genotypes with asthma by testing the dominant and recessive genetic models; a Bonferroni correction for significance was applied. Calculations of odds ratios (ORs) and confidence intervals (CIs) were done with an interactive calculation tool.[35] To calculate haplotype frequency, the Expectation Maximization-based haplotype frequency estimation methods was used.[36]


  Results Top


Hardy–Weinberg equilibrium and linkage disequilibrium

For all SNPs, rs3806933, rs2289276, and rs1837253, the genetic distributions were in HWE among the control group (P > 0.05); this was also the case when the genotype frequencies from both asthma and control groups were taken together, except for rs1837253, which was not in equilibrium (P < 0.05). Rs2289276 variant was in moderate linkage disequilibrium (LD) with the other two variants, rs3806933 and rs1837253 (D′ = 0.40 and 0.42, respectively), whereas rs3806933 and rs1837253 were in low LD (D' = 0.12).

Frequencies of alleles and genotypes and asthma susceptibility in a Saudi Arabian population

Alleles and genotype frequencies of the three SNPs are shown in [Table 1]. The relative frequencies for the minor allele, 'T', in all three SNPs, were smaller in asthmatics, comparatively to the control group, although these differences were not significant (Yates' corrected Chi-squared tests, P > 0.05). Considering genotype frequencies, the homozygous T/T of the three SNPs was most frequent in healthy controls, relative to asthmatics, but no statistically significant differences were found (Yates' corrected Chi-squared tests, P > 0.05).

[Table 2] shows a single-variant logistic regression analysis of the association of genotypes with asthma. Two genetic models of inheritance were tested, the dominant and recessive models, with frequencies adjusted for covariate gender. Although homozygous T/T individuals for each SNP had lower odds of being asthmatics (OR <1), thus suggesting a “protective” effect, none of the SNPs in either model tested reached a statistically significant association with asthma (P > 0.05).
Table 2: Logistic regression analysis of the association of three TSLP SNP variants, rs2289276, rs1837253, and rs3806933, with asthma, by testing two inheritance models

Click here to view


[Table 3] shows an analysis of interaction of asthma and genotypes, testing both the dominant and recessive models, with covariate gender as the stratifying variable. In the case of rs2289276 and rs1837253 variants, homozygous T/T male individuals (recessive model) had lower odds (OR <1) of being asthmatics, whereas in the case of rs3806933, only homozygous T/T women had lower odds (OR <1) of being asthmatics; however, these differences failed to become significantly associated with asthma.
Table 3: Analysis of interaction between gender and genotypes with asthma

Click here to view


Finally, an analysis of haplotypes in association with asthma was performed. The rare individuals (3.4%) whose haplotype was triple-homozygous for the minor alleles, TTT (rs2289276, rs1837253, and rs3806933, in that order), had greater odds (OR = 1.68, 95% CI = 0.67–4.22) of being asthmatics, in relation to the very common haplotype (31.1%), being triple-homozygous for the major alleles, CCC; however, this difference was not significant (P = 0.27). Other common haplotypes were also not significantly different to the CCC reference haplotype, nor were they linked with asthma risk.


  Discussion Top


The key role of TSLP cytokine in the pathogenesis of allergic inflammation and in promoting pro-allergic Th2 responses has been extensively and convincingly documented.[3],[4],[12],[14],[37] This study reports the analysis of three common SNPs located in the promoter region of the TSLP gene, which have been previously found in association with asthma.[18],[19],[22],[28] Specifically, rs1837253, of which the minor T allele was associated with reduced risk (e.g., “protective” effect) of asthma, atopic asthma, and airway hyperresponsiveness in various populations of varied ethnic composition/origin;[18],[19] rs2289276, which was associated with increased eosinophilia, and higher risk of childhood atopic asthma,[22],[28] but contradictorily, also associated with lower risk of asthma in women;[19] and rs3806933, for which the minor T allele was associated with increased TSLP promoter activity,[6],[21] and risk of both childhood atopic asthma and adult asthma.[22] However, nonsignificant results have been reported too: indeed, several studies failed to find an association of these variants with asthma, in distinct ethnic backgrounds.[18],[20],[27],[28] Our present case–control analysis on a Saudi Arabian population showed non-significant associations between the three TSLP SNPs tested and asthma predisposition, which goes in agreement with the reported non-significant results. Therefore, these contrasting results may indicate that the potential genetic effects of TSLP variants on asthma risk/protection rely on a much more complex mechanism not fully understood, and very likely involve other genes or epigenetic/environmental factors and their interactions.[38],[39],[40]

A previous functional analysis revealed that in the case of rs3806933, the C→T substitution seemingly creates a putative binding site for the transcriptional initiation factor AP-1 (c-jun and c-fos), therefore, enhancing expression of TSLP-L transcript in response to poly(I:C), a synthetic double-stranded RNA (dsRNA) analog that mimics (inin vitro experiments) thein vivo effects of common cold rhinoviral infection.[6] This mechanism seems congruent with its association with increased risk to childhood atopic asthma and adult asthma;[22] however, an association with lower risk to generalized vitiligo was reported too.[21] Given the reportedly functional relevance of this SNP in TSLP promoter activation, it remains unclear how this mutation could be of relevance in the context of asthma and absence of rhinovirus infection (e.g., no Toll-receptor-like-3 activation by dsRNA); this question is relevant to our case, since one of the selective criteria, we applied to recruit asthmatic patients and healthy controls was that they should be free of respiratory tract infections. Asthmatics are known for their increased susceptibility to airway infections, and it could be argued that by restricting recruited patients with this selective criterion may have introduced bias and influenced our results toward lack of significant association of asthma with TSLP variants. Similar questions could be raised for the other two promoter-located SNPs: the substitution C→T in rs2289276 seemingly disrupts a cis-element that decreases binding of AP-2alpha, a transcriptional repressor, hence leading to enhanced TSLP promoter activity and induction of TSLP mRNA and protein expression,[22] whereas rs1837253's T allele purportedly exert an opposite effect to that of rs3806933 and rs2289276, by decreasing significantly TSLP release from nasal epithelial cells.[30] However, the above-mentioned functional analyses have not been reproduced nor confirmed by others, thus underlining the necessity to validate them in the corresponding specific context of interest, namely, asthma, rather than extrapolating results from a particularin vitro condition.

On the other hand, it has been noticed that TSLP appears to exert two apparently opposing effects: the short isoform-TSLP-S maintains homeostasis and exerts anti-microbial and anti-inflammatory activities, while the long isoform-TSLP-L is a pro-inflammatory mediator and promotes immune pathologies.[1],[2] Such a contrasting dichotomy complicates the interpretation of population-based, gene-disease association data, which should take into account the existence of both isoforms, encoded by transcripts for which their differential expression patterns are directed by distinct mechanisms.[1],[6] For instance, TSLP-L expression is predominantly induced and repressed by several Toll-like receptor ligands and glucocorticoid, respectively, in relation to TSLP-S.[7] Whereas most studies have focused on the pro-inflammatory long isoform, the role or function of the short isoform remains little documented; evidence of genetic effects of TSLP variants mediated through TSPL-S is missing, although it is speculated that it could explain at least in part, the antagonistic effects (e.g., protective vs. pathogenic) observed.[1]

A limitation of study would be lack of testing associations between TSLP-L and TSLP-S expression in relation to each of rs1837253, rs2289276, and rs3806933 SNPs of TSLP. For instance, it is known that in the airways of asthmatics, TSLP (arguably referring to the sum of both isoforms, for lack of specification) levels are elevated,[41] but, lack of information of each isoform levels (e.g., expressed as a ratio) precludes from a better understanding of how these isoforms interplay in this disease. Likewise, the minor alleles of rs183753 and rs3806932 variants, also located in the promoter region, were recently correlated with decreased TSLP release in BAL and in nasal epithelial cells.[29],[30]

However, these functional analyses did not distinguish between both isoforms, or at least, the observed expression was ascribed exclusively to TSLP-L. This does not rule out possible effects by SNPs on the activity of cis-elements responsible for driving the expression of either short or long isoforms.


  Conclusion Top


TSLP is without a doubt, a critical factor promoting allergic diseases and is currently considered a potential therapeutical target to control inflammation.[42] However, this study, like others, showed that there are no association between TSLP-related SNPs and asthma per se. However, it would be of clinical interest to investigate whether these SNPs could cause important changes in the relative ratios of long-to-short isoforms in the context of asthma, potentially disturbing homeostasis and leading toward a pathological condition.

Acknowledgment

This work was supported by the Deanship of Scientific Research through the Research Center of the Female Scientific and Medical Colleges at King Saud University, Riyadh, Saudi Arabia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.[46]



 
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  [Table 1], [Table 2], [Table 3]



 

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