• Dr. Suarez-Kurtz Guilherme

CV

Guilherme Suarez-Kurtz is Head of Pharmacogenomics Program at the Brazilian National Cancer Institute and Chair of the Brazilian National Pharmacogenetics Network. A pioneer of pharmacogenetic studies in the Brazilian population, his research explores the impact of genetic admixture on the conceptual development and clinical implementation of pharmacogenomics.  He is a Full Member of Brazilian Academy of Sciences, Senior Investigator of Brazilian National Research Council and chaired the Department of Clinical and Basic Pharmacology at Universidade do Brasil, in Rio de Janeiro. Prof. Suarez-Kurtz did postgraduate work at Faculté de Médecine de Paris, Columbia University/New York and University College London. He was the Editor of Pharmacogenomics in Admixed Populations (Landes Bioscience), a collection of essays on various aspects of pharmacogenomics from peoples of four continents.  He held the Chair of the Pharmacogenetics and Pharmacogenomics Section, and served as Councillor of the International Union of Basic and Clinical Pharmacology (IUPHAR).

ABSTRACT

Pharmacogenomics diversity in Latin American populations: Brazil as a model case

The current population of Latin America (~700 million) is highly heterogeneous as a result of five centuries of admixture of three major parental populations, namely Native (Amerindian), European, and subSaharan African. Data from the One Thousand Genomes Admixed American superpopulation (1KG_AMR) and from Brazilian cohorts are compared to assess the diversity of Latin American peoples and to explore its pharmacogenetic (PGx) implications regarding CYP3A5, NUDT15, TPMT and DPYD clinically-relevant variants.  I will show that: (i) the differential distribution of CYP3A5 alleles and predicted phenotypes across Latin America impacts the proportion of individuals at high risk for adverse response to tacrolimus and the number of individuals needed to be genotyped in order to prevent such adverse effects; (ii) the minor allele frequency (MAF) of NUDT15*3 (rs116855232) increases in parallel with the proportion of Native ancestry among 1KG_AMR and reaches the highest worldwide values in Kaingang (25.8 – 31.7%) from indigenous reservation areas in Brazil; (iii) our study of TPMT variants in indigenous groups of the Brazilian Amazon revealed that the MAFs  of rs1800460 (0.193) and rs1142345 (0.188) in Paiter-Surui are the largest reported globally, such that the CPIC recommendations to reduce or consider reduction of thiopurine dose, based on the combined TPMT/NUDT15 phenotypes, apply to 41% of Paiter-Suruí, i.e. 3- to 4-fold higher than any other population worldwide; (iv) the non-inclusion of DPYD rs115232898 – a reduced-function variant, associated with African ancestry – in commercially available DPYD genotyping panels in Brazil led to misclassification of DPD phenotypes and incorrect CPID/DPWG fluoropyrimidine dosing recommendations, in 90.9% of 300 gastrointestinal cancer patients from the Brazilian National Cancer Institute (INCA); this strikingly high rate of misclassification highlights the notion that population diversity must be taken into account in the design of PGx testing panels for LA populations. I will conclude by introducing the PGx testing programme implemented at INCA, presenting data for ~1,000 acute lymphoblastic leukemia patients from nine pediatric centers in different regions of Brazil. Of note, addition of NUDT15*4 (rs147290019) to the currently used genotyping panel (NUDT*15 rs116855232*3 and TPMT rs1142345, rs1800460 and 1800462) resulted in reclassification of 1.8% of patients, from NUDT15 normal to intermediate  metabolizers.