An Ile to Met polymorphism in ADCY9 promotes airway obstruction and remodeling in asthma

Airway remodeling is a key point in asthma. Airway smooth muscle cells (ASMCs) play a pivotal role in airway remodeling. Cyclic AMP (cAMP) provides energy which is necessary for airway relaxation. Lack of energy in ASMCs results in dysregulation of airway relaxation as well as airway remodeling. The type 9 adenylyl cyclase (ADCY9) is a widely distributed adenylyl cyclase and contributes to basal cAMP production. However, the role of ADCY9 in asthma was still poorly understood. In this study, firstly ADCY9 rs2230739 gene polymorphism in asthma patients was investigated. There was a single nonsynonymous sequence variant at nucleotide 2316 where it was noted an A (wild-type) or G which was corresponding an Ile changed to Met at position 772 (Ile772Met). Next, we found this Ile to Met polymorphism in ADCY9 decreased reversibility of FEV1/FVC%. Moreover, changes of the Ile to Met in ADCY9 predicted further decline of FEV1/FVC% and FEV1% by Cox proportional hazard regression model. Then mechanisms of ADCY9 in asthma were explored. Asthma-related cytokines decreased ADCY9 expression and cellular cAMP levels which reduced airway relaxation ability and promoted airway remodeling. On the contrary, over-expression of ADCY9 protein attenuated airway remodeling. However, ADCY9 over-expression with missense mutant protein (ADCY9-772Met) failed to prevent airway smooth muscle remodeling. Taken together, An Ile to Met polymorphism in ADCY9 promoted airway obstruction and remodeling in asthma.