D2.130 - Genetic Associations of TSLP SNPs with Asthma Susceptibility and Severity

Asthma is a heterogeneous disease influenced by a variety of factors, including genetic predispositions. Single nucleotide polymorphisms (SNPs), which are variations at a single nucleotide position in the genome, can significantly influence the expression and function of proteins involved in disease processes. Thymic stromal lymphopoietin (TSLP) is an alarmin cytokine that has been extensively implicated in the pathology of asthma. Variations in SNPs associated with the TSLP gene, including rs2289276 and rs3806933, have been shown to be negatively and positively associated with asthma susceptibility, respectively, making them promising candidates for further investigation.

Cohorts of asthmatic and non-asthmatic participants were classified into categories moderate-to-severe asthma, mild asthma, and normal controls. All asthmatics had a positive methacholine challenge test. Mild asthmatics were defined as using intermittent short-acting beta-agonists (SABA) only, while moderate-to-severe cases were treated with inhaled corticosteroids (ICS) ±oral corticosteroids (OCS). DNA from blood samples was analyzed to evaluate thymic stromal lymphopoietin TSLP SNPs rs2289276 and rs3806933 for their association with asthma prevalence and severity using binary and multinomial regression tests.

When comparing all asthmatics to controls, a significant negative association was observed between the mutant allele (T) of rs2289276 and the prevalence of asthma (p<0.001, OR=0.156). This protective association was also evident in both mild and moderate-to-severe asthma. Interestingly, this protective pattern was also observed in a sex-specific manner, being significant in females only (p<0.001, OR=0.071). Conversely, no statistically significant differences were observed in the distribution of rs3806933 genotypes across the groups (p=0.2), and there was no association of either SNP with asthma severity in these small cohorts.

The results confirm previous findings that carrying the mutant allele (T) of rs2289276 is associated with a protective advantage against asthma and may play a role in mitigating disease susceptibility. Inclusion of varying asthma severities and multiple SNP assessments provides a novel perspective on the genetic underpinnings of asthma. These findings highlight rs2289276 as a biomarker for asthma susceptibility, likely due to its impact on TSLP production and/or isoforms. Additional experiments are underway to clarify the molecular mechanisms behind this SNP’s protective role, particularly whether it directly impacts protein production.