D2.107 - Genotype–Phenotype Segregation in Chronic Rhinosinusitis with Nasal Polyp and associated comorbid Asthma: Multivariate Clustering of Interleukin-4, Interleukin-6, Interleukin-13, and TNF-α Variants with Type-2 Biomarkers and Clinical Traits

This study examined the association between IL-4, IL-6, IL-13, and TNF-α gene polymorphisms and chronic rhinosinusitis with nasal polyps (CRSwNP) in patients with comorbid asthma and explored how these variants aligned with inflammatory phenotypes.

Eighty-one patients with CRSwNP and asthma were compared with 120 healthy controls using PCR-RFLP analysis of IL-4 (C590T), IL-6 (−174G/C), IL-13 (R130Q), and TNF-α (G308A) polymorphisms. Clinical and biomarker data were available for 65 patients and were used for phenotype–genotype clustering.

IL-6 polymorphisms showed the strongest association with disease; the GG genotype was significantly enriched in CRSwNP patients (OR 2.39, p = 0.03), supported by both dominant and recessive models. IL-4 showed no significant genotype differences, although the CT+TT recessive model demonstrated borderline association (OR 1.73, p = 0.05). IL-13 genotypes did not differ significantly between groups. TNF-α AG and GG genotypes were more frequent in patients, and the dominant model emphasized enrichment of the GG genotype. Logistic regression identified age, IL-4 CT+TT, IL-6 CC+CG, IL-13 RQ+RR, and TNF-α AA+AG as independent predictors of CRSwNP. In adjusted analyses, 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 risk, while IL-6 CC+CG (OR 0.36, p = 0.04) and TNF-α AA+AG (OR 0.10, p < 0.001) showed protective effects. Clinically, patients demonstrated a predominantly Type-2–high inflammatory profile, with elevated IgE, blood eosinophils, and FeNO, and a high prevalence of severe asthma and allergic rhinitis. Multivariate clustering revealed three biologically distinct CRS-NP phenotypes: a dominant Type-2–high group enriched with IL-4, IL-6, IL-13, and TNF-α variants; an intermediate mixed-inflammation group; and a low-inflammation group with sparse cytokine polymorphisms. An ordination plot showed how these variants aligned along major genetic axes, illustrating coordinated and independent contributions of interleukin and TNF polymorphisms to patient divergence.

IL-6 (−174G/C) and TNF-α (G308A) polymorphisms demonstrated protective effects, whereas IL-4 (C590T) and IL-13 (R130Q) variants increased susceptibility to CRSwNP with asthma. Genotype–phenotype clustering revealed structured biological heterogeneity, with specific cytokine variants aligning with the most pronounced Type-2–high inflammatory profiles. These findings support the role of immunogenetic variation in shaping CRSwNP pathogenesis and may inform future subtype-specific therapeutic strategies.