Characterization of pharmacogenetic markers related to Acute Lymphoblastic Leukemia toxicity in Amazonian native Americans population

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children. Differences are found among ethnic groups in the results of the treatment of pediatric ALL. In general, children with a high level of native American ancestry tend to respond less positively to ALL treatments, which may be related to specific genomic variants found in native American groups. Despite the evidence, few data are available on the distribution of the pharmacogenomic variants relevant to the treatment of ALL in traditional Amerindian populations, such the those of the Amazon region. Given this, the present study investigated 27 molecular markers related to the treatment of ALL in Amerindians from Brazilian Amazonia and compared the frequencies with those recorded previously on five continents, that are available in the 1,000 Genomes database. The variation in the genotype frequencies among populations was evaluated using Fisher's exact test. The False Discovery Rate method was used to correct the results of the multiple analyses. Significant differences were found in the frequencies of the majority of markers between the Amerindian populations and those of other regions around the world. These findings highlight the unique genetic profile of the indigenous population of Brazilian Amazonia, which may reflect a distinct therapeutic profile for the treatment of ALL in these populations.

Figure 1

Mosaic plots of the distribution of the genotypes of the 12 markers investigated in the six study populations (AFR, AMR, EAS, EUR, SAS, and NAT). Genotypes: Alt/Alt = mutant homozygote, Alt/Wt = heterozygote, and Wt/Wt = wild homozygote.

Figure 2

Plots of the adjusted p values (FDR) for the comparison of the 12 markers investigated in the present study between the NAT population and the five continental populations (AFR, AMR, EAS, EUR, SAS), based on Fisher’s exact test. The significance threshold (p = 0.05) is represented by the bold horizontal line.

Figure 3

Plot of the results of the multidimensional spacing analysis of the genetic profiles of the six study populations investigated in the present study (AFR, AMR, EAS, EUR, SAS, and NAT), based on the 12 polymorphisms selected for analysis.

Figure 4

Mosaic plots of the genotype distribution of the 12 markers investigated in Amerindian populations (NAT) and ALL patients (ALL_NAT). Genotypes: Alt/Alt = mutant homozygote, Alt/Wt = heterozygote, and Wt/Wt = wild homozygote. The p values from right to left are: 1; 1; 1; 0.292; 0.07; ≤ 0.001; 0.154; ≤ 0.001; 0.986; 0.051; ≤ 0.001; 0.112.