CYP2C:TG Haplotype in Native Mexicans, Molecular Ancestry and Its Implications for CYP2C19 Genotype–Phenotype Correlation

Background: Recent studies have associated the presence of the CYP2C:TG haplotype with increased metabolism of CYP2C19 substrates such as escitalopram and sertraline, suggesting a potential regulatory interaction between CYP2C18 and CYP2C19. However, this association has not been demonstrated for other CYP2C19 substrates. Objective: This study aims to elucidate the role of the CYP2C:TG haplotype in modulating CYP2C19 activity using the omeprazole metabolic ratio (MR) within a cocktail drug approach, to characterize its distribution and prevalence among Native Mexican populations, and to evaluate its potential impact on CYP2C19 metabolic phenotypes. Materials and Methods: A total of 256 volunteers from various ethnic native groups from Mexico were genotyped for CYP2C19 (*2, *3, *4, *5, *17) and the CYP2C haplotype (rs2860840 and rs11188059). The MR of omeprazole to 5-hydroxyomeprazole was analyzed to determine individual CYP2C19 metabolic phenotypes and assess metabolic capacity. Results: The CYP2C:TG haplotype was the most prevalent (42.77%), followed by CYP2C:CG (35.74%) and CYP2C:TA (21.48%). The CYP2C:TG haplotype was consistently associated with the CYP2C19*1 allele. Significant differences in logMR values were observed between individuals with and without the TG haplotype (p = 0.02). A trend toward increased metabolic activity associated with CYP2C:TG was observed across most CYP2C19 metabolizer groups, except for rapid metabolizers. No significant association was found between molecular ancestry and the presence or functionality of the haplotype. Conclusions: The CYP2C:TG haplotype appears to be associated with increased CYP2C19 activity, warranting further functional validation before clinical implementation.