Martha Sosa-Macías

Vincristine-induced peripheral neuropathy (VIPN) is a common dose-limiting toxicity in pediatric acute lymphoblastic leukemia (ALL), and pharmacogenetic evidence in admixed populations remains limited. We evaluated variants in ABCC1, ABCC2, ABCB1, CYP3A4, CYP3A5, and CEP72 in Mexican pediatric patients with ALL using an ambispective case–control design (n = 43; aged 2–18 years). VIPN was graded using CTCAE v4.0; cases were defined as grade ≥ 2 (n = 11) and controls grade 0–1 (n = 32). Nine single nucleotide variants (SNVs) were genotyped by allele-specific qPCR and analyzed under codominant, dominant, recessive, and log-additive models, including haplotype analyses. VIPN occurred in 25.6% of patients, with 90.9% of cases occurring during induction (p = 0.001). ABCC2 rs11190298 was nominally associated with VIPN under codominant (OR = 0.21; 95% CI: 0.04–0.97), dominant (OR = 0.15; 95% CI: 0.03–0.71), and log-additive (OR = 0.17; 95% CI: 0.04–0.66) models, and ABCC2 haplotypes showed a nominal global association (p = 0.003). These associations did not withstand correction for multiple testing. No significant associations were found for ABCC1, ABCB1, CYP3A4, CYP3A5, or CEP72. Early-onset toxicity may reflect differences in drug exposure or treatment intensity, which pharmacokinetic data could clarify. These hypothesis-generating findings require replication in larger prospective cohorts.

The aim of this study was to assess the effect of sertraline on the gene expression of placental transporters for hormones, folates, nutrients and drugs over the course of pregnancy in rats. The studies were conducted on gestational days (GDs) 16 and 20 following oral treatment with 10 mg/kg/day sertraline or the vehicle, administered from weaning onward. The weight and area of the fetuses and placentas were analyzed, and maternal plasma sertraline concentrations were measured. Gene expression of ATP-binding cassette transporter b1a and b1b (Abcb1a and Abcb1b), organic anion-transporting polypeptide 4a1(Slco4A1/Oatp4a1), folate receptor-α (Folr1), reduced folate carrier (Slc19A1/Rfc), and L-type amino acid transporter (Slc7A5/Lat1) was evaluated in the placenta. Sertraline reduced fetal weight (p < 0.001) and fetal area (p < 0.01) at GD 16, while no significant differences were observed in placental weight or area between exposed and unexposed groups. Sertraline concentration was significantly lower at GD20 than at GD16 (p < 0.001). At GD 16, sertraline reduced the expression of Abcb1a (p = 0.027), Abcb1b (p < 0.01), and Oatp4a1 (p = 0.037) compared with controls. Conversely, sertraline induced Folr1 expression in both GDs and increased Rfc expression at GD 20, while Lat1 was not affected. These findings indicate that sertraline alters placental drug transporter gene expression and may impair nutrient transfer to the fetus.

Mitochondrial DNA plays a key role in understanding the demographic history of human populations. Particularly in the Americas#nine widespread Native American specific mitochondrial lineages have been identified. Here we performed the whole mitogenome sequencing of 572 Indigenous individuals from 60 populations spanning the Mexican territory. To minimize the effects of European and African admixture#we focused on individuals with at least 90% Native American ancestry#estimated by ADMIXTURE. We identified all the five major Native American haplogroups clades#with A2 being the most prevalent (53.9%)#followed by B2 (24.0%)#C1 (17.6%)#D1 (4.3%)#and D4h3a (0.2%). We also identified 82 different subhaplogroup widespread across the country#revealing shared mtDNA haplogroups in populations from distant regions. Moreover#mitochondrial DNA variation in the Mexican Native populations is not structured by geography or linguistic affiliation#suggesting complex gene flow across regions. Demographic reconstructions based on whole mitogenomes showed an exponential increase the maternal Ne around 10 kya in all tested regions. All these findings suggest a mitochondrial genetic persistence through Mexico and possibly the Americas.

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.

PLAC8, expressed by interstitial extravillous trophoblasts (iEVTs), plays a crucial role in trophoblast invasion, differentiation, and immunotolerance. Its dysregulation may contribute to pregnancy complications, such as preeclampsia. This study investigates the role of PLAC8 in trophoblast invasiveness and endothelial-like differentiation under different oxygen tensions. Swan-71 cells were transiently transfected with PLAC8 overexpression or knockdown plasmids. Invasion was assessed using Matrigel-coated transwells, endothelial-like differentiation through tube formation assays, and vasculogenic marker expression (VEGF, PGF, ANGPT2) by RT-PCR. Hypoxia experiments were performed at different oxygen conditions. PLAC8 overexpression enhanced trophoblast invasion but reduced endothelial-like differentiation, downregulating VEGF and PGF while upregulating ANGPT2. Hypoxia increased PLAC8 expression, indicating oxygen tension as a regulatory factor. PLAC8 manipulation did not affect cell viability. PLAC8 modulates trophoblast behavior by promoting invasion while inhibiting endothelial-like differentiation. Its regulation of vasculogenic and angiogenic factors suggests a critical role in placental homeostasis and potential relevance to pregnancy disorders, such as preeclampsia.

Objective. To describe the prevalence of obesity, diabetes, hypertension, and cardiovascular risk factors in the Indigenous populations of Northwest Mexico. Method. A cross-sectional study was conducted among Indigenous and rural Mestizo populations of Northwest Mexico, including Coras, Huicholes, Mexicaneros, Tarahumaras, and Tepehuanos, and Mestizos. Obesity was defined by a body mass index (BMI) ≥30 kg/m2. The following cardiovascular risk factors were considered: high waist circumference, hyperglycemia or previous diagnosis of diabetes, elevated blood pressure or previous diagnosis of hypertension, hypertriglyceridemia, and low HDL-C. Results. A total of 472 subjects were enrolled in the study, including Mestizos (n = 48), Coras (n = 73), Huicholes (n = 93), Mexicaneros (n = 74), Tarahumaras (n = 81), and Tepehuanos (n = 103). The prevalence of obesity in the overall population was 11.2%, while specifically in Mestizos, Coras, Huicholes, Mexicaneros, Tarahumaras, and Tepehuanos it was 35%, 18%, 7.5%, 9.4%, 7.4%, and 1.9%, respectively. According to the presence of diabetes, the prevalence in the total population was 3.8%, which in Mestizos, Coras, Huicholes, Mexicaneros, Tarahumaras, and Tepehuanos was 2.0%, 7.8%, 0.0%, 4.0%, 9.8%, and 0.0%, respectively. Regarding hypertension, the prevalence in the overall population was 12.7, whilst in Mestizos, Coras, Huicholes, Mexicaneros, Tarahumaras, and Tepehuanos was 39%, 11.8%, 8.6%, 9.4%, 18.5%, and 1.9%, respectively. Conclusion. Our results revealed that Mexican Indigenous groups exhibit a high prevalence of obesity and hypertension, as well as high blood pressure, hypertriglyceridemia, and low HDL-C.

The study of mitochondrial DNA is a valuable tool to delve into the demographic history of human populations. Particularly in the Americas, five widespread Native American specific mitochondrial lineages have been identified. Here we included the complete mitogenome sequencing of 572 Indigenous individuals belonging to 60 populations spanning the Mexican territory. Our results show a great diversity of matrilineages widespread across the country, revealing shared mtDNA haplogroups in populations from distant regions. We identified all the five main Native American haplogroups clades, including 83 different subhaplogroups, from which nine are novel. The most frequent of the novel haplogroups was A2+64. A phylogenetic inference suggests that A2+64 comes from an ancestral maternal lineage that spread into the Caribbean islands. Additionally, a demographic reconstruction from whole mitogenomes showed an exponential increase in female Ne around 10 Ka ago in all the tested regions. All these findings suggest a genetic persistence through Mexico and possibly the Americas, in agreement with the model of the Mesoamerican-related expansion into the Caribbean and South America.

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studie... Tweetable abstract Pharmacogenetics in autochthonous populations from Latin America. Conference report.

Few studies have addressed how selective pressures have shaped the genetic structure of the current Native American populations, and they have mostly limited their inferences to admixed Latin American populations. Here, we searched for local adaptation signals, based on integrated haplotype scores and population branch statistics, in 325 Mexican Indigenous individuals with at least 99% Native American ancestry from five previously defined geographical regions. Although each region exhibited its own local adaptation profile, only PPARG and AJAP1, both negative regulators of the Wnt/β catenin signaling pathway, showed significant adaptation signals in all the tested regions. Several signals were found, mainly in the genes related to the metabolic processes and immune response. A pathway enrichment analysis revealed the overrepresentation of selected genes related to several biological phenotypes/conditions, such as the immune response and metabolic pathways, in agreement with previous studies, suggesting that immunological and metabolic pressures are major drivers of human adaptation. Genes related to the gut microbiome measurements were overrepresented in all the regions, highlighting the importance of studying how humans have coevolved with the microbial communities that colonize them. Our results provide a further explanation of the human evolutionary history in response to environmental pressures in this region.