Influence of Genetic Admixture Components on CYP3A5*3 Allele-Associated Hypertension in Amerindian Populations From Northwest Mexico

Galavíz-Hernández, Carlos; Lazalde-Ramos, Blanca Patricia; Lares-Assef, Ismael; Macías-Salas, Alejo; Ortega-Chávez, Margarita; Rangel-Villalobos, Héctor; Sosa-Macías, Martha

doi:10.3389/fphar.2020.00638

Cited by 8 publications

(6 citation statements)

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“…According to our results, the CYP3A5*3 allele seems to be predominant in the Chilean population, which could be due in part to the genetic structure of Chileans as a consequence of the admixture between Native Amerindians, the historical migration of individuals from Europe and, to a lesser extent, the arrival of African individuals ( Eyheramendy et al, 2015 ). Similar results have been observed in other admixed Latin American populations in terms of the presence of the three CYP3A5 genotypes, the association with different TAC pharmacokinetic patterns and the influence of ancestry ( Ferraris et al, 2011 ; Cusinato et al, 2014 ; Galaviz-Hernández et al, 2020 ). GWAS studies in North American, Caucasian, African and Asiatic populations have validated the role of CYP3A5 as the main predictor of TAC metabolism, although a few other common variants in cytochrome P450 enzymes and drug transporters have been suggested as contributing to the variability in plasma drug levels ( Oetting et al, 2018 ; Bruckmueller et al, 2015 ; Oetting et al, 2016 ).…”

Section: Discussionsupporting

confidence: 87%

CYP3A5 and UGT1A9 Polymorphisms Influence Immunosuppressive Therapy in Pediatric Kidney Transplant Recipients

et al. 2021

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Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on CYP3A5, MRP2 and UGT1A9 genes in Chilean pediatric kidney recipients using TAC and MPA.Patients and Methods: A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1–Q3 4.5–11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The CYP3A5 polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while MRP2 -24G > A, UGT1A9 -275T > A, and UGT1A9 -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C0), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C0/D), and area under the curve in 12 h normalized by dose requirements (AUC0–12h/D).Results: The frequencies of the variant alleles CYP3A5*3, MRP2-24A, UGT1A9-275A, and UGT1A9-2152T were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC0–12h/TAC-D were 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1 carriers (CYP3A5*1/*3 and CYP3A5*1/*1). When analyzing patients with steroid withdrawal, CYP3A5*3/*3 patients had 1.7-fold higher AUC0–12h/TAC-D than the other genotypes. Patients carrying the CYP3A5*3/*3 genotype had higher TAC-C0, lower TAC-D and higher TAC-C0/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between MRP2 and UGT1A9 genotypes were observed in MPA-C0, MPA-D or MPA-C0/D. However, patients carrying the UGT1A9-275A allele had lower AUC0–12h/MPA-D than those carrying the UGT1A9-275T ancestral allele.Conclusions: These results support that CYP3A5 and UGT1A9 genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.

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Section: Discussionsupporting

confidence: 87%

CYP3A5 and UGT1A9 Polymorphisms Influence Immunosuppressive Therapy in Pediatric Kidney Transplant Recipients

et al. 2021

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“…Consequently, CYP3A5 gene expression showed higher expression in Vervet females compared to males, although this change was not significant (p = 0:09, difference = − 0:4171 ± 0:2346) (Figure 2). This was correlated to the previous studies in the human population, which showed that the CYP3A5 gene is significantly higher in females than in males [40,41].…”

Section: Discussionsupporting

confidence: 90%

The Association between Genetic Variants and Gene Expression in RAAS Genes Using Captive-Bred Vervet Monkeys (Chlorocebus aethiops)

Khoza

Ghai

Chauke

et al. 2023

Advances in Cell and Gene Therapy

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Mendelian genetics contribute largely to the development of hypertension; therefore, the identification of genetic variants related to blood pressure (BP) regulation remains crucial and may reveal new therapeutic drug targets. The purpose of the present study was to screen the captive-bred Vervet colony for salt-sensitive sequence variants or single nucleotide polymorphisms (SNPs) in the selected Renin-Angiotensin-Aldosterone System (RAAS) genes associated with salt sensitivity. Blood samples were collected from 16 captive-bred Vervet monkeys for genotyping and gene expression analysis. The impact of the identified sequence variants was determined using online prediction tools. Sanger sequencing analysis revealed 21 sequence variants in AGT, CYP3A5, GRK4, and SCL4A5, of which 19 were novel and two were previously reported in humans. All novel variants were either predicted to be polymorphic, disease-causing, or possibly damaging by prediction tools. Furthermore, the mRNA expression for AGT was significantly higher in the normal BP group ( p value = 0.02), and a similar trend was observed for CYP3A5 and GRK4, whereas SCL4A5 was higher in the hypertensive group. The identified salt-sensitive variants specifically in GRK4 may be suggestive to be the attributing factor of the elevated BP levels in these captive-bred Vervet monkeys. Therefore, RAAS variants could be considered as a biomarker to identify the potential risk of developing hypertension in both humans and nonhuman primates.

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“…8 A recent study evaluated the frequency of the rs776746 polymorphism and its association with hypertension in eight indigenous populations from Mexico. 53 The analysis report that the CYP3A5*3/*3 genotype frequencies ranged from 23.5% in Mexicaneros to 93.3% in Mayos, and the mean observed in the Mexican indigenous groups was 67.5% (very similar to the frequency found in the Native Americans of our study). Also, Galaviz-Hernandez et al found that the CYP3A5*3/*3 genotype was more frequent in indigenous women with higher systolic and diastolic blood pressures values.…”

Section: Cyp3a5supporting

confidence: 87%

Genetic Diversity of Drug-Related Genes in Native Americans of the Brazilian Amazon

Fernandes¹,

Rodrigues²,

Maroñas³

et al. 2021

PGPM

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Introduction: The genetic admixture of the Brazilian population has considerable relevance to the implementation of the principles of pharmacogenomics (PGx), as it may compromise the extrapolation of data obtained in more homogeneous world populations. Purpose: This study aims to investigate a panel of 117 polymorphisms in 35 pharmacogenes, which contains label recommendations or clinical evidence by international drug regulatory agencies, in Amazonian Native American populations, and compare the results obtained with continental population data from the 1000 Genomes Project Consortium. Patients and Methods: The study population is composed of 109 Native American individuals from three Brazilian Amazon groups. The genotyping of the PGx polymorphisms was performed by allelic discrimination using TaqMan ® OpenArray Genotyping with a panel of 120 customized assays on the QuantStudio™ 12K Flex Real-Time PCR System. Results: Statistical differences within the Native American populations were observed regarding both genotypes and phenotypes of some genes of the CYP family. The discriminant analysis of principal components (DAPCs) between the NAM group and the continental populations of the 1000 Genomes Project resulted in the clustering of the three Native American populations. Additionally, in general, the NAM group was determined to be closely situated between East Asia, America, and South Asia groups, which enabled us to infer a genetic similarity between these populations. The DAPC analysis further demonstrated that eight polymorphisms and six polymorphisms were more relevant in differentiating the NAM from the continental populations and the NAM populations among themselves, respectively. Conclusion: Some investigated polymorphisms show differences among world populations, particularly with populations of European origin, for whom precision medicine protocols are primarily designed. The accumulated knowledge regarding these variations may assist in the design of specific protocols for Native American populations and populations admixed with them.

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Influence of Genetic Admixture Components on CYP3A5*3 Allele-Associated Hypertension in Amerindian Populations From Northwest Mexico

Abstract: safer drug administration regimens, assuring better therapeutic responses and fewer side effects.

Cited by 8 publications

References 33 publications

CYP3A5 and UGT1A9 Polymorphisms Influence Immunosuppressive Therapy in Pediatric Kidney Transplant Recipients

CYP3A5 and UGT1A9 Polymorphisms Influence Immunosuppressive Therapy in Pediatric Kidney Transplant Recipients

The Association between Genetic Variants and Gene Expression in RAAS Genes Using Captive-Bred Vervet Monkeys (Chlorocebus aethiops)

Genetic Diversity of Drug-Related Genes in Native Americans of the Brazilian Amazon

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