Estudo de associação de polimorfismos no gene adenilato ciclase tipo 9 com fenótipos de asma e a resposta ao broncodilatador em pacientes acompanhados pelo proar

Abstract

Asthma is a chronic inflammatory disease of the lower airways, characterized by hyperreactivity, mucus production, and airway obstruction. The adverse effects and lack of response to standard medications have led to studies seeking individualized treatments based on the genetic profile of the patient. ADCY9 (adenylate cyclase type 9) is a candidate gene related to asthma. The adenylate cyclase product, cAMP, produced by regulatory T cells, is described as a T lymphocyte suppressor, inhibitor of the expression of inflammatory cytokines and also helps in bronchial relaxation. The objective of this work is to investigate how polymorphisms in ADCY9 are associated with asthma, atopy and therapeutic response. The first study performed in the SCAALA population with 1309 children from Salvador, 194 SNVs were extracted from the Illumina genotyping chip and 29 SNVs were associated with asthma and allergic markers. In silico analysis revealed the functional impact of 6 SNVs on the expression of ADCY9. The second work replicated 2 SNVs in the PROAR population, where 1335 samples were genotyped. The association analyzes were performed using Plink. The variant rs2601796 (G allele) increased ADCY9 expression and was negatively associated with asthma and atopy. The variant rs2532019 (G) increased ADCY9 expression and was negatively associated with asthma and positively associated with lack of asthma control. It can be concluded that these variants are significantly associated with asthma and/or atopy due to the cAMP-regulated immunomodulatory response. Individuals with GG genotype (rs2532019) have a worse basal pulmonary function probably due to β2-AR desensitization in individuals chronically exposed to the adrenergic agonist, impacting on the lack of asthma control. Therefore, these SNVs may aid in the pharmacogenetics of asthma and in individualized therapy for severe asthma patients.