ABSTRACT Over the years, accumulating evidence has been associating interleukin‐13 gene ( IL‐13 ) variants with a wide array of chronic inflammatory diseases. Also, recent findings have associated the potential role of a single nucleotide polymorphism (SNP) of IL‐13, rs20541, to promote either anti‐ or pro‐inflammatory responses in chronic inflammatory diseases. Although rs20541 has been widely associated with various immune‐related and inflammatory conditions, its precise functional relevance in the pathogenesis of human diseases has yet to be fully clarified. Nonetheless, its consistent associations and known effects on IL‐13 signalling underscore its potential biological importance. Hence, this meta‐analysis aimed to investigate the associations between IL‐13 SNP rs20541 with distinct groups of chronic inflammatory diseases. Eligible studies were selected from seven databases including PubMed, EBSCO Host (all databases), Medline, CINAHL Plus, Scopus, SNPedia and GWAS. In total, 45 case–control studies with 16,045 cases and 23,312 controls were categorised into four major groups: atopic, cardiopulmonary and autoimmune diseases as well as cancer and tumour. While no consistent associations emerged for asthma or overall atopic and cardiopulmonary groups, protective associations for psoriasis and glioma were observed across multiple genetic contrasts. The A allele of rs20541 was significantly associated with higher risk of chronic obstructive pulmonary diseases (COPDs) 1.17 (1.03–1.32) but reduced risk of cardiovascular diseases (CVDs) 0.87 (0.75–1.00), psoriasis allele model: 0.71 (0.65–0.77); dominant model: 0.69 (0.62–0.76), overall cancer allele model: 0.82 (0.66–0.98); dominant model: 0.82 (0.67–0.98) and glioma [allele model: 0.82 (0.68–0.95); dominant model: 0.72 (0.57–0.87). In subgroup analysis and meta‐regression, sources of between‐study heterogeneity were associated with ethnicity, age, gender and sample size in respective disease groups ( p z 0.05). Overall, this meta‐analysis demonstrates that IL‐13 rs20541 is a key immunogenetic variant exerting context‐dependent effects, either via direct lgE‐dependent or indirect regulatory effects across chronic inflammatory diseases. These mechanistic differences help explain why rs20541 confers susceptibility in some diseases while providing protection in others, reflecting the pleiotropic and tissue‐specific functions of IL‐13. Future research should integrate transcriptional studies and eQTL analyses of rs20541 to clarify its downstream impact on inflammation‐specific genes, ultimately informing cytokine‐targeted therapies to more precisely manage and prevent chronic inflammatory disease.
Letchumanan et al. (Tue,) studied this question.