Global Pharmacogenomics: Distribution of CYP3A5 Polymorphisms and Phenotypes in the Brazilian Population

Abstract

The influence of self-reported “race/color”, geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black (“race/color” categories of the Brazilian census). The cohort was genotyped for CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343), CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables), and self-reported Color, geographical region and ancestry (explanatory variables). We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the diversity of the population. The relevance of this work extrapolates the Brazilian borders, and extends to other admixed peoples of the Americas, with ancestral roots in Europe, Africa and the American continent.

Effects of Major Transporter and Metabolizing Enzyme Gene Polymorphisms on Carbamazepine Metabolism in Chinese Patients with Epilepsy

“…CYP3A5 exhibited metabolic activity comparable to CYP3A4 (∼90%) toward CBZ epoxidation in vitro [40]. The CYP3A5*3 polymorphism is the most common and functionally important across all ethnic populations studied, and there was a statistically significant difference in the variant allele frequency among various populations [18,41]. CYP3A5 seemed to constitute up to 50% of total hepatic CYP3A protein in subjects carrying at least one CYP3A5*1 allele [42,43].…”

Multigene Predictors of Tacrolimus Exposure in Kidney Transplant Recipients

“…This difference may be due to genetic differences between the primarily Caucasian cohorts from The Netherlands compared with the Brazilian cohort which has strong African ancestry. The Brazilian cohort likely has other important low activity or nonfunctional CYP3A5 variants not present in Caucasians which may confound the analysis [43]. Recently, another group in The Netherlands reported CYP3A4*22 in 101 kidney transplant recipients receiving tacrolimus and found a trend toward reduced tacrolimus clearance but considered the effect too small to be clinically important [44].…”

Research Article Molecular analysis of the GSTT1 gene polymorphism in patients with clinical manifestation of atherosclerosis.

“…A study conducted with Chinese patients (Wang et al, 2012) found no significant differences between male and female in both control and case groups regarding the risk of stroke. The difference in results can be explained by the population used in each study, and it is noteworthy to say that the Brazilian population is marked by a high degree of miscegenation (Suarez-Kurtz et al, 2014).…”