Evaluation of genetic variation in alpha and beta adrenergic receptors and its association with clinical response to vasoactive drugs in critically ill pediatric patients

• Grant number: 23/09419-6
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Ana Paula de Carvalho Panzeri Carlotti
• Grantee: Ana Paula de Carvalho Panzeri Carlotti
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Riccardo Lacchini

Abstract

Genetic differences, called polymorphisms in genes that encode target proteins in transport or drug-metabolizing enzymes, are responsible, among other factors, for the variation observed in patients' responses to medications. Catecholamines are often used in the ICU for patients with hemodynamic deterioration and shock. The pharmacological actions of adrenergic drugs are mediated by adrenergic receptors, whose coding genes are polymorphic. There are no studies in the literature on the association between polymorphisms and response to adrenergic agonists in children. Therefore, knowledge of individual characteristics related to adrenergic receptors can contribute to the use of drugs according to the patient's genetic profile, in order to obtain better results and with fewer adverse effects related to medications. The general objective of this study is to evaluate the association between genetic factors in pediatric critically ill patients and response to vasoactive drugs and clinical outcome. The specific objectives are: to verify the association of four genetic markers in alpha1-A adrenoceptors [c.1039C>T (p.Arg347Cys)], alpha2-B [c.901_909del (p.Glu301_Glu303del)], beta1 [c.1165C> G (p.Arg389Gly)], and beta2 [c.46G>A (p.Gly16Arg)] with differences in hemodynamic and cardiac response to the catecholamines epinephrine, norepinephrine, dopamine and dobutamine. This is a clinical, observational and prospective study. The study group will consist of all children who require one or more catecholamines (epinephrine, norepinephrine, dopamine, or dobutamine) for inotropic/vasopressor support in the ICU. Exclusion criteria will be receiving a blood transfusion before sample collection for genotyping when it is not possible to collect a buccal swab or refusal to participate in the study. The control group will consist of children matched by age and gender, but who did not receive vasoactive drugs for cardiovascular support, in a 1:1 ratio. Blood samples and/or oral swabs will be collected for DNA extraction and genotyping of the polymorphisms by the qPCR system with Taqman probes. The sample size will be a convenience sample. We estimate to include 300 children in the study group and 300 children in the control group, in the period of 12 to 18 months. Patients will be divided into groups according to the need for inotropic / vasopressor therapy to achieve hemodynamic stability: use of only one vasoactive drug vs. combined therapy. The frequencies of adrenergic receptor polymorphisms will be evaluated and compared between groups. Continuous variables will be expressed as median and range and categorical variables, as number and percentage. Comparisons of continuous variables between groups will be made using the Mann-Whitney U test and comparison of categorical variables by Fisher's exact test. Relative risks (RRs) and 95% confidence intervals (CIs) will be obtained after fitting log-binomial regression models to verify the association of polymorphisms with response to catecholamines. The significance level adopted will be 5%. (AU)