Pharmacogenomics and epigenomics factors associated with response to immunosuppressive drugs in renal transplant recipients

• Grant number: 16/13118-8
• Support type: Regular Research Grants
• Duration: November 01, 2016 - April 30, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Rosario Dominguez Crespo Hirata
• Grantee: Rosario Dominguez Crespo Hirata
• Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Assoc. researchers: Alvaro Danilo Cerda Maureira ; Claudia Rosso Felipe Bonato ; Fabiana Dalla Vecchia Genvigir ; Helio Tedesco Silva Junior ; Jose Osmar Medina de Abreu Pestana ; Mario Hiroyuki Hirata ; Sonia de Quateli Doi

Abstract

Pharmacogenomics and epigenomics may help to understand the mechanisms involved in therapeutic response and nephropathy and/or rejection of renal allograft. This project aims to investigate the role of pharmacogenomics and epigenomics factors in response to immunosuppressive drugs used in the therapy of kidney transplant recipients. Patients submitted to kidney transplant who participated in clinical trials TIMO (n=274) and BIP (n=258) were selected. The TIMO group (pharmacogenomics study) was treated with everolimus (Eve) and tacrolimus (Tac) or mycophenolate sodium (MPS), and Tac. The BIP group (epigenomics study) was treated with Tac and MPS for 3 months and then one group was treated with sirolimus (Srl). Renal function parameters, therapeutic monitoring, metabolic profile, rejection episodes and adverse events were evaluated. Polymorphisms in pharmacokinetics (CYP3A4, CYP3A5, CYP2C8, CYP2J2, UGT2B7, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3 and SLCO2B1) and pharmacodynamics genes (MTOR, PPP3CA, FKBP1A, FKBP1B, FBKP2 and FOXP3) will be analyzed by real time PCR. The profile of global expression of microRNAs (miRnoma) will be analyzed in urinary exosomes of 40 patients from BIP group by DNA sequencing. Interactions between microRNAs and target mRNAs will be detected using the Ingenuity Pathway Analysis and other bioinformatics tools. The results will contribute to the knowledge of the molecular mechanisms involved in clinical response of immunosuppressive drugs and its relationship with adverse events and graft rejection, and to the discovery of potential biomarkers that can aid in the individualized therapy of renal transplant recipients. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GENVIGIR, FABIANA DALLA VECCHIA; BRAYAN CAMPOS-SALAZAR, ANTONY; FELIPE, CLAUDIA ROSSO; TEDESCO-SILVA JR, HELIO; MEDINA-PESTANA, JOSE OSMAR; DOI, SONIA DE QUATELI; CERDA, ALVARO; HIRATA, MARIO HIROYUKI; HERRERO, MARIA JOSE; ALINO, SALVADOR FRANCISCO; CRESPO HIRATA, ROSARIO DOMINGUEZ. CYP3A5{*}3 and CYP2C8{*}3 variants influence exposure and clinical outcomes of tacrolimus-based therapy. PHARMACOGENOMICS, v. 21, n. 1, p. 7-21, JAN 2020. Web of Science Citations: 0.

BRAYAN CAMPOS-SALAZAR, ANTONY; GENVIGIR, FABIANA DALLA VECCHIA; FELIPE, CLAUDIA ROSSO; TEDESCO-SILVA, HELIO; MEDINA-PESTANA, JOSE; MONTEIRO, GABRIELA VIEIRA; BASSO, RODRIGO DE GOUVEIA; CERDA, ALVARO; HIRATA, MARIO HIROYUKI; CRESPO HIRATA, ROSARIO DOMINGUEZ. Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients. FRONTIERS IN PHARMACOLOGY, v. 9, NOV 14 2018. Web of Science Citations: 1.

GENVIGIR, FABIANA D. V.; NISHIKAWA, ALVARO M.; FELIPE, CLAUDIA R.; TEDESCO-SILVA, JR., HELIO; OLIVEIRA, NAGILLA; SALAZAR, ANTONY B. C.; MEDINA-PESTANA, JOSE O.; DOI, SONIA Q.; HIRATA, MARIO H.; HIRATA, ROSARIO D. C. Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium-Based Treatment in Brazilian Kidney Transplant Recipients. PHARMACOTHERAPY, v. 37, n. 5, p. 535-545, MAY 2017. Web of Science Citations: 6.