Estudo de associação de polimorfismos no gene DENND1B com fenótipos de asma e atopia em adultos brasileiros acompanhados pelo proar

Abstract

Asthma is a complex and heterogeneous disease characterized by bronchial hyperresponsiveness, obstruction and chronic inflammation of the airways. Its heterogeneity is associated with environmental factors and individual variability and, therefore, the interest in the study of asthma genetics has grown over the years. Variants in the DENND1B gene have been described and associated with increasing susceptibility to asthma. It is known that its attributions are related to the negative modulation of the T cell receptor (TCR), through the control of its internalization in T cells; mutations or decreased expression of DENND1B are associated with increased Th2 response and asthma. The aim of this work was to investigate the association of polymorphisms in DENND1B, as well as their respective functional impacts, with atopy and the different asthma phenotypes, in adult individuals monitored by the Asthma Control Program in Bahia (ProAR). Genotyping was performed using an Illumina commercial panel (MEGA) in 1,177 ProAR participants. The associations between gene polymorphisms and asthma and markers of atopy were analysed using logistic regression, using the covariables sex, age and ancestry markers as confounding. Twelve polymorphisms in DENND1B have been associated with different phenotypes, such as asthma, severe asthma and atopy markers. The comparison of cytokine levels according to the genotype was performed using the T test (parametric) or Mann-Whitney (non-parametric). Only two SNPs showed a significant result for IL-33 production. The gene expression of DENND1B was analysed using the comparative CT method (method 2 – ΔΔCT) and there was no statistically significant result. In conclusion, polymorphisms in DENND1B were significantly associated with asthma and atopy and in silico analysis demonstrated that these polymorphisms can influence the expression of this gene.