Ancestralidade genômica subcontinental e variantes de interesse farmacogênico

Abstract

Variation in the DNA sequence may cause changes in the function of enzymes, which can cause variability in drug response. Pharmacogenomics seeks to understand this response variability and thus propose a more individualized treatment. CYPs are a family of genes responsible for encoding enzymes that act on cytochrome P450, enzymes that are part of the metabolism pathways of endogenous and xenobiotic compounds. Among these genes, the CYP2C19 and CYP2C9 genes stand out for their high allelic variability, in addition to participating in the metabolism of most drugs available on the market. It is also important to consider that alleles vary in frequency between populations and ethnicities; this frequency difference can be used to infer genomic ancestry and be associated with health issues. Genomic ancestry is the genetic information of an individual that reveals which parental population he descends from, and when associated with health issues, it can help in the diagnosis of treatment. This work aims to correlate subcontinental genomic ancestry of parental components with the frequency of alleles of pharmacogenomic interest of the CYP2C19 and CYP2C9 genes. We used the Admixture software to infer the genomic ancestry with 8 parental components of 2504 individuals belonging to 26 populations around the world, we also inferred, using Stargazer, the star alleles and predicted phenotype then we calculated allele and phenotype frequency in the populations and finally we performed the correlation between the allele and phenotype frequency with the parental components. The parental components were separated into Native American, Northern Europe, Southern Europe, West African, East African, South Asian, East Asian -West and East Asian -East and the star alleles found were for CYP2C19, 15 alleles and for CYP2C9, 18 alleles. CYP2C19*2 and CYP2C19*3 showed a higher frequency in Asian populations, while CYP2C19*5, CYP2C19*8, CYP2C19*9 and CYP2C19*17 had a higher frequency in African populations. Regarding CYP2C9*2, its frequency was higher in Europeans, CYP2C9*7 was found only in South Asians and CYP2C9*13 only East Asians. A positive correlation was found between CYP2C19*2 and the EAS2 and SAS and a negative correlation with the EUR2 and NAT components, while CYP2C19*3 showed a positive correlation with EAS and EAS2 and CYP2C19*17 demonstrated positive correlation with AFR and AFR2 and a negative correlation with EAS and EAS2. The CYP2C9*2 had a positive correlation with the EUR2 component, and the CYP2C9*3 had a negative correlation with AFR and AFR2 components and a positive correlation with the SAS. Therefore, it is important that, when including or not alleles in pharmacogenetic test panels, consider which population will use them and which alleles are correlated with that population.