Molecular markers for analysis of genetic polymorphism related to the response of Plasmodium falciparum to antimalarials

• Grant number: 11/07380-8
• Support type: Regular Research Grants
• Duration: October 01, 2011 - September 30, 2013
• Field of knowledge: Health Sciences - Collective Health
• Principal Investigator: Silvia Maria Fátima Di Santi
• Grantee: Silvia Maria Fátima Di Santi
• Home Institution: Superintendência de Controle de Endemias (SUCEN). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Assoc. researchers: Aluisio Augusto Cotrim Segurado ; Angélica Domingues Hristov ; Giselle Fernandes Maciel de Castro Lima ; Marcos Boulos ; Marcos Vinicius da Silva ; Maria de Jesus Costa Nascimento

Abstract

Malaria is a disease caused by Plasmodium, with 243 million cases annually and 863 thousand deaths. In 2009, in Brazil, 306,469 cases were recorded. The selective pressure of drugs results in mutations, especially SNPs that confer resistance. Resistance to chloroquine is related to the pfcrt gene that encodes the protein PfCRT, carrier of drugs and metabolites. The response of P. falciparum to quinine is associated with an increased number of copies of the pfmdr1 gene and the mutations in the genes pfcrt and pfmrp, which encodes a protein PfMRP, that acts as a molecular pump, expelling drugs out of the parasite, in addition to gene pfnhe1 that encodes the protein responsible for the change Na+/H+. The decreased sensitivity to mefloquine is associated with amplification of copies of pfmdr1 that encodes a transmembrane glycoprotein (Pgh1) and is associated with a higher value of IC50 for quinine and chloroquine. Mutations in the DHFR-TS are associated with resistance to pyrimethamine, and SNPs in pfdhps gene with resistance to sulfadoxine The decreased sensitivity to artemisinin is related to pfATPase6 SNPs in the gene that encodes the protein SERCA. The increase in the number of copies of the pfmdr1 gene is also associated with decreased sensitivity to artemisinin. Recent data associate new mutations close to pfubp1, as well as a mutation in a gene denoted pfcmu, localized in chromosome 13, to lower in vitro susceptibility to artemisinin. In view of the multidrug resistance detected in Brazil, mainly based on phenotypic analysis, the use of different molecular markers for various antimalarials will map the genetic profile of P. falciparum with respect to mutations associated with resistance. (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)

INOUE, JULIANA; LOPES, DINORA; DO ROSARIO, VIRGILIO; MACHADO, MARTA; HRISTOV, ANGELICA D.; LIMA, GISELLE F. M. C.; COSTA-NASCIMENTO, MARIA J.; SEGURADO, ALUISIO C.; DI SANTI, SILVIA M. Analysis of polymorphisms in Plasmodium falciparum genes related to drug resistance: a survey over four decades under different treatment policies in Brazil. Malaria Journal, v. 13, SEP 19 2014. Web of Science Citations: 5.