Analysis of intronic SNP (rs4147358) and expression of SMAD3 gene in Atopic Dermatitis: A case-control study

Abstract

BackgroundAtopic Dermatitis (AD) is a multifactorial cutaneous disorder associated with chronic inflammation of the skin. Growing evidence points to TGF-β/SMAD signaling as a key player in mediating inflammation and the subsequent tissue remodeling, often resulting in fibrosis. This study investigates the role of a core transcription factor involved in TGF-β signaling i.e., SMAD3 genetic variants (rs4147358) in AD predisposition and its association with SMAD3 mRNA expression, serum IgE levels, and sensitization to various allergens in AD patients. MethodsA total of 246 subjects including 134 AD cases and 112 matched healthy controls were genotyped for SMAD3 intronic SNP by PCR-RFLP. mRNA expression of SMAD3 was determined by quantitative Real-Time PCR (qRT-PCR), Vitamin-D levels by chemiluminescence, and total serum IgE levels by ELISA. In-vivo allergy testing was performed for the evaluation of allergic reactions to house dust mites (HDM) and food allergens. ResultsA significantly higher frequency of mutant genotype AA (cases: 19.4% vs controls: 8.9%) (OR = 2.8, CI = 1.2 – 6.7, p = 0.01) was observed in AD cases. The mutant allele ‘A’ also showed a 1.9-fold higher risk for AD compared to the wild allele ‘C’ indicating that the carriers of the A allele have a higher risk for AD predisposition (OR-1.9, CI = 1.3–2.8, p < 0.001). In addition, quantitative analysis of SMAD3 mRNA in peripheral blood showed 2.8-fold increased expression in AD cases as compared to healthy controls. Stratification analysis revealed the association of the mutant AA genotype with deficient serum Vitamin D levels (p = 0.02) and SMAD3 mRNA overexpression with HDM sensitization (p = 0.03). Furthermore, no significant association of genotypes with SMAD3 mRNA expression was observed. ConclusionOur study indicates that SMAD3 intronic SNP bears a significant risk of AD development. Moreover, overexpression of SMAD3 mRNA and its association with HDM sensitization highlights the possible role of this gene in AD pathogenesis.