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

• Grant number: 16/13118-8
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2016
• End date: April 30, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Rosario Dominguez Crespo Hirata
• Grantee: Rosario Dominguez Crespo Hirata
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated 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

(6)

(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; et al. 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. (16/13118-8)

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. (11/10039-6, 16/13118-8)

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. (16/13118-8)

COSTA DE FREITAS, RENATA CAROLINE; BORTOLIN, RAUL HERNANDES; VECCHIA GENVIGIR, FABIANA DALLA; BONEZI, VIVIAN; CRESPO HIRATA, THIAGO DOMINGUEZ; FELIPE, CLAUDIA ROSSO; TEDESCO-SILVA, JR., HELIO; MEDINA-PESTANA, JOSE OSMAR; CERDA, ALVARO; DOI, SONIA QUATELI; et al. Differentially expressed urinary exo-miRs and clinical outcomes in kidney recipients on short-term tacrolimus therapy: a pilot study. Epigenomics, v. 12, n. 22, DEC 2020. (16/13118-8)

BONEZI, VIVIAN; GENVIGIR, FABIANA DALLA VECCHIA; SALGADO, PATRICIA DE CASSIA; FELIPE, CLAUDIA ROSSO; TEDESCO-SILVA JR, HELIO; MEDINA-PESTANA, JOSE OSMAR; CERDA, ALVARO; DOI, SONIA QUATELI; HIRATA, MARIO HIROYUKI; CRESPO HIRATA, ROSARIO DOMINGUEZ. Differential expression of genes related to calcineurin and mTOR signaling and regulatory miRNAs in peripheral blood from kidney recipients under tacrolimus-based therapy. ANNALS OF TRANSLATIONAL MEDICINE, v. 8, n. 17, p. 14-pg., 2020-09-01. (11/10039-6, 16/13118-8)

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; et al. CYP3A5*3 and CYP2C8*3 variants influence exposure and clinical outcomes of tacrolimus-based therapy. PHARMACOGENOMICS, v. 21, n. 1, p. 15-pg., 2020-01-01. (16/13118-8)