Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

Abstract

BackgroundCyclic guanosine monophosphate (cGMP)‐specific phosphodiesterase (PDE5A) is the target of phosphodiesterase inhibitors such as sildenafil. Polymorphisms in the PDE5A gene that may predict response to therapy with sildenafil and nitric oxide, be linked to disease progression, and aid in risk assessment have been identified in human beings. Identification of polymorphisms in PDE5A could affect the physiologic actions of PDE5A and the effects of phosphodiestrase type 5 inhibitor drugs.Hypothesis/ObjectiveFunctional polymorphisms exist in the canine PDE5A gene. Specific objectives were to identify PDE5A polymorphisms and evaluate their functional relevance.AnimalsSeventy healthy dogs.MethodsThe exonic, splice‐site, 3′ and 5′ untranslated regions of the canine PDE5A gene were sequenced in 15 dogs and aligned with the canine reference sequence. Identified polymorphisms were evaluated in 55 additional, healthy, unrelated dogs of 20 breeds. Plasma was collected from 51 of these dogs and cGMP was measured. An unpaired t‐test and one‐way ANOVA with Dunnett's test of multiple comparisons were used to evaluate the effect of genotype on cGMP.ResultsA common exonic polymorphism was identified that changed glutamic acid to lysine and resulted in significantly lower cGMP concentrations in the group with polymorphism versus the wild type group (P = .014). Additionally, 6 linked single nucleotide polymorphisms in the 3′ untranslated region were identified that did not alter cGMP concentrations.Conclusions and Clinical ImportanceA polymorphism exists in the canine PDE5A gene that is associated with variable circulating cGMP concentrations in healthy dogs and warrants investigation in diseases such as pulmonary hypertension.

Clinical features and outcome in 25 dogs with respiratory‐associated pulmonary hypertension treated with sildenafil

“…This dosage was not only effective but also appeared to be safe because no adverse events were reported. Finally, genetic polymorphism in the phosphodiesterase 5A gene could contribute to variable response of the TRPG to sildenafil in different groups of dogs.…”

Retrospective evaluation of moderate‐to‐severe pulmonary hypertension in dogs naturally infected with Angiostrongylus vasorum

“…Although no significant difference was determined, the sample size of only 11 available PH patients for genotyping may mean that this comparison was under‐powered to detect a smaller difference between groups. The homozygous genotype has been shown to result in the greatest reduction of cGMP levels in healthy dogs (Stern et al ). A higher proportion of the PH dogs were homozygous for the polymorphism, but the difference was not statistically significant.…”

“…DNA was stored at −80 °C before transport for batch analysis at the Stern Cardiac Genetics Laboratory (University of California Davis, California, USA), where genotyping was performed using the previously described polymerase chain reaction (PCR) technique (Stern et al . ). Dogs were classified as wild‐type, heterozygous or homozygous for the PDE5a:E90K polymorphism.…”

“…(), was associated with a reduced expression of cyclic guanine monophosphate (cGMP), supporting a possible role in predisposition to PH (Stern et al . ).…”

Polimorfismos do gene PDE5A e as suas implicações sobre a resposta ao sildenafil na disfunção erétil

“…Nesse estudo, observaram que a presença do polimorfismo PDE5A E90K estava associado a menores pontuações na qualidade de vida dos cães (Ueda et al, 2019). Noutro estudo desse mesmo grupo, associaram a presença do polimorfismo E90K a menores valores de concentração de GMPc, o que poderia explicar a baixa eficácia (Stern et al, 2014).…”