Variabilidad interétnica de los polimorfismos genéticos de "UGT1A4" y "CYP2C9 IVS8-109 A>T" en las poblaciones española e iberoamericanas

Resum

The enzymes CYP2C9 y UGT1A4 are involved in the biotransformation of a large number of drugs. The frequencies of allelic variants UGT1A4 hadn't been described in the Spanish population. Recently, it has been described a new intronic polymorphism (IVS8-109A>T) in the gene CYP2C9, whose presence appears to influence the activity of the enzyme in vivo. Objective: To determine whether there is variability of UGT1A4 gene and CYP2C9 SNP IVS8-109 A>T in the Spanish population compared to other Latin American populations, as well as checking the potential influence of the variant CYP2C9 IVS8-109A>T on the metabolism of losartan. Materials and Methods: The frequency of SNP IVS8-109A>T was determined by a new method of PCR-RFLP in 92 Spaniards, 87 Ecuadorians, 105 Caucasians Cubans, and 108 Mestizos Cubans and this were compared with other populations. The potential influence of this SNP on the metabolic rate of losartan/E-3174 in 161 healthy volunteers was evaluated. The allelics and genotypics frequencies of the variants UGT1A4*1b, *2, and *3 were determined in 318 healthy volunteers and 248 Mestizos Mexicans. Results and Discussion: The frequency of allele CYP2C9 IVS8-109A>T in the Spanish population was similar to the Caucasian Cuban population, higher than that found in Ecuadorian healthy volunteers and lower than in Mestizan Cubans healthy volunteers. The presence of allele IVS8-109T was associated with an increased activity CYP2C9 in individuals CYP2C9*1/*1 with mutant homozygous genotype for this SNP (IVS8-109T/T). The frequencies of allelics variants UGT1A4*1b, *2 y *3 in the Spanish population were 0.17 and 0.09, respectively, while the Mestizo Mexican population allelics frequencies found were 0.08, 0.03 and 0.13 respectively. It was observed that the frequency of allele UGT1A4*2 was twice as high in the Spanish population than in the Mestizos Mexicans, unlike the allele UGT1A4*3 which was lower in Spanish than in Mestizos-Mexicans. The allele UGT1A4*1b is more common in Europeans and very rare in Asians and Africans. Conclusions: Existence an interethnic variability in the frequency of SNP CYP2C9 IVS8-109A>T and of the allelics and genotypics variants of UGT1A4 among the Spanish population and other Latin American populations. It has been demonstrated the potential influence of SNP IVS8-109A>T in an increase in hydroxylation activity of CYP2C9.