Genetic profiling of patients with Atopic Dermatitis reveals immune and skin barrier variants associated with generalized eczema and optimal response to Dupilumab therapy
Background: Atopic dermatitis (AD) is a clinically heterogeneous immune-mediated skin-disorder. The lack of reliable clinical stratification tools and predictive biomarkers for therapeutic response remains a critical unmet need to optimize treatment and advance precision dermatology. Objective: To investigate the association between genetic variants and AD phenotypes and response to Dupilumab as a potential approach to individualize therapy in moderate-to-severe AD.Methods:120 patients with moderate-to-severe AD treated with Dupilumab were enrolled at two Italian centers. Clinical data, including phenotypes, severity, and comorbidities, were collected at baseline and after 48 weeks treatment with Dupilumab. Its efficacy was assessed as EASI75 and EASI90 achievements at week 48. Genotyping of 521 SNPs was performed using next-generation sequencing (NGS). Cluster analysis and univariate logistic regression explored associations between genetic profiles and clinical variables.Results: NGS-based genotyping enabled the stratification of patients into four distinct genetic clusters, each characterized by unique combinations of polymorphisms in skin barrier-related genes, namely FLG and KIF3A. A combined variant pattern in KIF3A and FLG was strongly associated with a generalized eczema phenotype. Some allelic variants of genes were found to be associated with conjunctivitis (FLG), rhinitis (KIF3A), bronchial asthma (IL5RA) comorbidities and high IgE levels (ADAM33).Conclusions: This study identified genetic signatures in skin barrier and Th2 pathway genes associated with clinical phenotypes and differential responses to Dupilumab in AD. Findings support incorporating genotypic profiling into practice to guide personalized therapy in moderate-to-severe AD.