Immune Gene Variants Cluster With Severe Nasal Polyp and Asthma Phenotype

Patients who suffer from both chronic rhinosinusitis with nasal polyps and severe asthma may carry a recognizable genetic signature, according to a new study published in Allergy, Asthma & Clinical Immunology. Researchers examined four immune-related gene variants and found that specific versions of the TNF-α and IL-6 genes were strongly enriched in people with the combined disease, while clustering analysis revealed three biologically distinct patient groups defined by their inflammatory profiles.

The study, led by Mona Al-Ahmad, Asmaa Ali and Wafaa Talat, compared 81 patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and comorbid asthma against 120 healthy controls. Using a laboratory technique called PCR-RFLP, the team analyzed polymorphisms in four genes involved in immune signaling: IL-4 (C590T), IL-6 (−174G/C), IL-13 (R130Q) and TNF-α (G308A). Clinical and biomarker data were available for 65 of the patients, and this subset was used for the phenotype–genotype clustering analysis.

The strongest single association involved TNF-α. The GG genotype was markedly enriched in patients and showed the strongest association with disease in the study, with an odds ratio of 5.30 (p < 0.001).

IL-6 polymorphisms also showed a significant association. The GG genotype was significantly enriched among CRSwNP–severe asthma patients, with an odds ratio of 2.39 (p = 0.03), and both the dominant and recessive inheritance models demonstrated increased odds of disease. By contrast, IL-4 showed no significant genotype differences overall, although the CT + TT recessive model reached a borderline association with an odds ratio of 1.73 (p = 0.05). IL-13 genotypes did not differ significantly between the groups, though the dominant and recessive models showed non-significant trends toward increased disease susceptibility.

When the researchers moved from single-gene comparisons to logistic regression, a more complex picture emerged. Age, IL-4 CT + TT, IL-6 CC + CG, IL-13 RQ + RR and TNF-α AA + AG were all identified as independent predictors of CRSwNP–severe asthma in the initial model. However, in adjusted analyses, the direction of some associations shifted. IL-13 RQ + RR (OR 2.24, p = 0.03) and IL-4 CT + TT (OR 1.89, p = 0.05) remained associated with increased odds of the combined phenotype, whereas IL-6 CC + CG (OR 0.36, p = 0.04) and TNF-α AA + AG (OR 0.10, p < 0.001) were associated with lower odds in the adjusted regression model.

Clinically, the patient group displayed a predominantly Type 2-high (T2-high) inflammatory profile. This was reflected in elevated IgE, elevated blood eosinophil counts and elevated fractional exhaled nitric oxide (FeNO), the standard biomarkers of Type 2 airway inflammation. The patients also showed a high prevalence of severe asthma and allergic rhinitis.

The most visually striking result came from multivariate clustering. The analysis revealed three biologically distinct CRSwNP phenotypes. The first and dominant group was T2-high and was enriched with IL-4, IL-6, IL-13 and TNF-α variants, suggesting that carriers of these cytokine gene variants tend to cluster in the most inflamed clinical subgroup. The second was an intermediate mixed-inflammation group, and the third was a low-inflammation group with sparse cytokine polymorphisms. An ordination plot showed how the variants aligned along major genetic axes, illustrating both coordinated and independent contributions of the interleukin and TNF polymorphisms to patient divergence.

In plain terms, the study suggests that the genetic architecture of this disease is not uniform. Rather than a single risk gene acting alone, different variants appear to segregate with different inflammatory phenotypes, with the cytokine variants converging in the patients who show the most pronounced Type 2-high biology.

The authors themselves are careful about the limits of the work. The study concludes that these findings provide additional insight into the immunogenetic heterogeneity of the combined CRSwNP–severe asthma phenotype and should be considered exploratory pending validation in larger independent cohorts. With 81 patients and clinical data for 65, the sample is modest, and the shifting directions of association between unadjusted and adjusted models underline how sensitive such results can be to sample size and covariate structure.

Subject of Research: Genetic polymorphisms in immune signaling genes and their association with chronic rhinosinusitis with nasal polyps and severe asthma

Article Title: Genotype–phenotype segregation in chronic rhinosinusitis with nasal polyp and associated comorbid severe asthma: multivariate clustering of interleukin-4, interleukin-6, interleukin-13, and TNF-α variants with type 2 biomarkers and clinical traits

Article References: Al-Ahmad, M., Ali, A., & Talat, W. (2026). Genotype–phenotype segregation in chronic rhinosinusitis with nasal polyp and associated comorbid severe asthma: multivariate clustering of interleukin-4, interleukin-6, interleukin-13, and TNF-α variants with type 2 biomarkers and clinical traits. Allergy, Asthma & Clinical Immunology. https://doi.org/10.1186/s13223-026-01075-5

Image Credits: AI Generated

DOI: 10.1186/s13223-026-01075-5

Keywords: chronic rhinosinusitis, nasal polyps, severe asthma, TNF-α, IL-6, IL-4, IL-13, genetic polymorphisms, Type 2 inflammation, PCR-RFLP, phenotype clustering, immunogenetics