|Year : 2020 | Volume
| Issue : 4 | Page : 231-233
Thymic stromal lymphopoietin polymorphism and asthma: Pros and cons
Arjumand S Warsy
King Saud University, Riyadh, Saudi Arabia
|Date of Submission||09-Sep-2020|
|Date of Acceptance||10-Sep-2020|
|Date of Web Publication||02-Oct-2020|
Arjumand S Warsy
King Saud University, Riyadh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Warsy AS. Thymic stromal lymphopoietin polymorphism and asthma: Pros and cons. J Nat Sci Med 2020;3:231-3
A recent report by Moorehead et al. shows that protection from asthma may be provided by altering gene expression of the thymic stromal lymphopoietin (TSLP) gene, resulting from the presence of a single nucleotide polymorphism (SNP), rs1837253. Earlier, Harada et al. showed that SNPs rs3806933 and rs2289276 are significantly associated with disease susceptibility to childhood atopic and adult asthma. At about the same time, Birben et al. reported that two functional SNPs in the TSLP gene show gender-specific association with allergy. Furthermore, in an attempt to unveil the genetic determinants of asthma, extensive genome-wide association analysis (GWAS) has been reported in different populations on variants of asthma. In 2013, Hindorff et al. reported a catalog of published GWASs and identified variants in 18 loci, including TSLP, associated with asthma. These are just a few of several reports highlighting the significance of TSLP in asthma and other allergic conditions.
In Saudi Arabia, several studies have been conducted on asthma prevalence and distribution over the past three decades and have reported the prevalence to range from 8% to 25%. A recent cross-sectional study, which was designed as a school-based investigation in 13 regions of Saudi Arabia, reported that the prevalence of self-reported asthma was 8.2% during the screening of 11,348 intermediate and secondary school children. Several of the studies have emphasized the need for prevention and treatment for asthma. Identification of the high-risk groups and those genetically susceptible to asthma, followed by proper care, could help in the primary prevention of the disease or secondary prevention by appropriate treatment.
A timely contribution to the literature on asthma genetics is the paper published in this issue of JNSM by Alenazy et al., reporting their investigation on three common SNPs in the promoter region of the TSLP gene in Saudi asthmatic patients. They provide a valuable introduction to TSLP. The TSLP has, in recent years, received considerable attention as an interleukin (IL)-7-like cytokine, which plays a vital role in the etiology of several allergic diseases including allergic rhinitis, bronchial asthma, atopic dermatitis, allergic conjunctivitis, and other allergic conditions. It appears as a critical regulator of those inflammatory conditions, which are T helper type 2 (Th2) cytokine associated and is shown to promote (Th2) cytokine-mediated immunity and inflammation. Studies have shown an exaggerated expression of the TSLP gene in allergic states, where along with IL-25 and IL-33, it plays a role in the initiation and maintenance of allergic responses. The upregulation of TSLP regulates functionally distinct basophil production during hematopoiesis, which promotes the Th2 cytokine-mediated inflammation. In addition to the other immunological effectors (the B-cells, the T-cells, eosinophils, and the mast cells), the dendritic cells (DCs) are shown to play an integral role in the induction of Th2 cell, which secretes IL-4, IL-5, and IL-13 and hence Th2 type inflammation in response to an allergen.,, The TSLP gene is constitutively expressed in several different cell types including the epithelial cells, airway smooth muscle cells, fibroblasts, keratinocytes, DCs, trophoblasts, and the astrocytes. Two isoforms, encoded by the same gene, are reported, which differ in their molecular weight, are referred to as the short (TSLP-S, 7 kDa) and the long (TSLP-L, 18.1 kDa) form and exert opposing effects on the target cells. Several studies on TSLP have been conducted to investigate the mechanism of action of the short and long forms. They bind to the heterodimeric receptor thymic stromal lymphopoietin receptor, which is a cytokine receptor-like factor 2. This binding results in multiple and varied signaling effects on the target cells. The level of TSLP and its signaling pathways are being assessed as potential therapeutic targets for several allergic inflammatory states including asthma. Both endogenous and exogenous factors influence the up- or downregulation of the TSLP gene and the TSLP protein level. Studies are investigating this, intending to control the allergic state by control of these factors, possibly.
Alenazy et al. have investigated polymorphism in TSLP by genotyping three SNPs in the TSLP gene. The interest in the study of polymorphisms associated with disease has grown over the years, especially since the technologies for such studies are very user friendly, and many SNPs associated with a particular disease have been identified and used for treatment strategy development. When the National Center for Biotechnology Information was searched, the number of manuscripts published every year on SNPs-disease association studies was over 58,600 (https://pubmed.ncbi.nlm.nih.gov/?term=
SNPs + and + disease + association + studies) (visited on September 07, 2020), and the majority were published during the past two decades [Figure 1]. During this period, SNPs have also been investigated in the promoter region, exons, introns, and untranslated regions of the TSLP gene, in several studies, to identify the association with different allergic conditions and to correlate with its gene expression. Several polymorphisms have been identified, some associated with asthma, though there are several population differences in the association, where some SNPs associate in one population and not in another. On the other hand, variations are also reported based on the gender of the studied population, and asthma variant or other conditions associated with asthma such as hay fever and rhinitis.
The study of Alenazy et al. is timely. It is carried out to identify the possible association of three SNPs with asthma in the Saudi population and identify potential therapeutic targets. They present an informative introduction to TSLP, its functions, mode of action on the target cells, its importance and role in asthma development, and its role as a potential therapeutic target. They genotyped three SNPs, rs1837253, rs2289276, and rs3806933, which occur in the TSLP gene promoter and may play a role in influencing its expression. It is a well-conducted study that has a sample size of 670, of whom 272 are asthmatics. The patients were well characterized clinically, and their age range varied from >3 to 65 years; the control group comprised 398 age-matched individuals. Genotyping involved sequencing of the DNA fragment encompassing (150–250 bp) the variant. The results confirmed that the alleles for all three SNPs were found in the Saudi population, occurred at a polymorphic frequency, and generally obeyed Hardy–Weinberg equilibrium in healthy individuals and asthmatic patients. The genotyping results in the patients, and controls showed no significant difference, suggesting that the three studied SNPs in the Saudi population do not associate with asthma development. Alenazy et al. have also studied dominant and recessive models for the three SNPs, but no significant differences were recorded. Studies have previously reported an association between these SNPs and asthma, though other reports contradict any association. Studies reported by He et al. have shown an association of rs1837253 with asthma; Hunninghake et al. showed that the TSLP polymorphisms are associated with asthma in a sex-specific fashion, where the SNPs rs1837253 associated with a reduced risk of asthma in males and rs2289276 associated with lower risk in females.
The population differences are a significant drawback of studies on SNPs. Even in the healthy population, allele frequencies differ considerably,, and when SNPs associated with a disease are investigated, population differences become very obvious. An SNP may significantly associate with a disease in one population but not in another and vice versa. Hence, it makes it essential for such studies to be carried out in every population. Furthermore, the number of samples analyzed should be high, and the distinction between the two genders' results must be made. Alenazy et al. discuss this point at considerable length and provide a useful collection of studies showing association with asthma and others contradicting it.
In this respect, the study of SNPs associated with the disease plays a vital role in presymptomatic diagnosis. Suppose a SNP is found to associate with susceptibility to disease, the presence of its predisposing allele in an individual, who has not yet shown any symptoms of the disease, provides a means of preclinical diagnosis. He may be protected from disease development by avoiding the environmental factors that may result in the disease's precipitation. Alenazy et al. study could have provided such a predictive method if a SNP was identified that was associated with disease development. Since the SNPs investigated during their research do not show any association, there is a need to study other SNPs and the gene expression of TSLP in the different genotypes of these SNPs. Such studies will shed a better light on the role of TSLP in asthma development in Saudis and may provide venues for therapeutic targeting. Although several SNPs have been associated with an altered expression rate of the TSLP gene,, TSLP gene expression studies are deficient. Future investigations on allergic disorders should target such an approach.
From the available literature, it is evident that TSLP presents itself as a valuable candidate contributing to different allergic conditions. Further detailed, well-designed studies are required in the Saudi population to investigate SNPs, distributed over the entire TSLP gene, to investigate the association with the different allergic states including different asthma phenotypes, and to study relative gene expression in the different genotypes of different SNPs.
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