Pharmacogenetics: ethnicity, treatment and health in Latin American populations.

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 studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura. The results of 17 years of uninterrupted work by RIBEF, the Declaration of Mérida/T'Hó and the call for the Dr José María Cantú Award for studies focused on the pharmacogenetics of native populations in Latin America were presented.

The Placental Function Beyond Pregnancy: Insights from Latin America.

Currently, more than 100,000 papers had been published studying the placenta in both physiological and pathological contexts. However, relevant health conditions affecting placental function, mostly found in low-income countries, should be evaluated deeper. This review will raise some - of what we think necessary - points of discussion regarding challenging topics not fully understood, including the paternal versus maternal contribution on placental genes imprinting, placenta-brain communication, and some environmental conditions affecting the placenta. The discussions are parts of an international effort to fulfil some gaps observed in this area, and Latin-American research groups currently evaluate that.

Preeclampsia association of placental nucleotide variations in eNOS, VEGFA, and FLT-1 genes in Latin American pregnant women.

INTRODUCTION: Preeclampsia is a leading cause of maternal and fetal morbidity in low- and middle-income countries, including those in Latin America. Placental vascular alterations are crucial in the pathophysiology of preeclampsia and few studies have evaluated nucleotide variations on genes associated with vascular regulation in the human placenta. This study aimed to evaluate whether placental nucleotide variations on eNOS, VEGFA, and FLT-1 genes are more frequently associated with preeclampsia in the Latin American population. METHODS: This case-control study included placental tissue from 88 controls and 82 cases that were genotyped through Taqman probes for eNOS, VEGFA, and FLT-1 genes. The intergroup comparisons were analyzed with the Mann-Whitney U test. Genotype and allele frequencies were compared by the X2 test. The association between the nucleotide variants with preeclampsia was evaluated through logistic regression analysis. RESULTS: A significant association was observed for VEGFA SNV rs2010963 (OR 1.95; CI 95% 1.13-3.37), after adjusting for population substructure. The allele combination T, G, G, C, C, C (rs2070744, rs1799983, rs2010963, rs3025039, rs699947 and rs4769613 respectively), showed a negative association with preeclampsia (OR 0.08; CI 95% 0.01-0.93). DISCUSSION: Placental SNV rs2010963 in the VEGFA gene was a risk factor for preeclampsia, while the allele combination T, G, G, C, C, C may represent potential protective factors for preeclampsia within Latin American women.

Unraveling Signatures of Local Adaptation among Indigenous Groups from Mexico.

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/ß 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.

Evaluation of the PLAC8 Gene in Mexican Women With and Without Preeclampsia and Obesity.

Preeclampsia (PE) is a leading cause of maternal-fetal mortality worldwide, and obesity is an important risk factor. Genes associated with pathophysiological events common to preeclampsia and obesity, such as PLAC8, remain to be studied; therefore, the aim of the present study was to evaluate this gene in the placentas of women affected with preeclampsia and healthy pregnant women. This case-controlled study included 71 healthy and 64 preeclampsia pregnancies. Gene expression was evaluated in primary human cytotrophoblasts (PHCT) from six normal and six preeclampsia pregnancies, and protein expression was verified in placentas from five healthy and six preeclampsia pregnancies. The whole coding and 5' regions of the PLAC8 gene were sequenced from healthy (n = 10) and preeclamptic (n = 10) pregnancies. The presence of the observed nucleotide variations was analyzed by RT-PCR in the total population. Statistical analyses were performed accordingly. Obesity was associated with severe preeclampsia (SPE) (OR = 3.34; CI 95% 1.3-8.2, p < 0.01). Significantly higher mRNA and protein expression was observed in preeclamptic vs. healthy placentas (p < 0.05). After sequencing, a single nucleotide variation was identified in 10 cases and one control (p < 0.01), which was then evaluated in the total population showing no association with preeclampsia. This preliminary study confirms the association of SPE with obesity and suggests higher expression of PLAC8 mRNA and protein in placentas from preeclampsia. No differences in nucleotide variations between cases and controls of the whole population were observed. Further research is required to evaluate the implications of higher gene/protein expression in preeclampsia and the causes of such variation.

Population genetics of PDE4B (phosphodiesterase-4B) in neglected Native Americans: Implications for cancer pharmacogenetics.

PDE4B (phosphodiesterase-4B) has an important role in cancer and in pharmacology of some disorders, such as inflammatory diseases. Remarkably in Native Americans, PDE4B variants are associated with acute lymphoblastic leukemia (ALL) relapse, as this gene modulates sensitivity of glucocorticoids used in ALL chemotherapy. PDE4B allele rs6683977.G, associated with genomic regions of Native American origin in US-Hispanics (admixed among Native Americans, Europeans, and Africans), increases ALL relapse risk, contributing to an association between Native American ancestry and ALL relapse that disappeared with an extra-phase of chemotherapy. This result insinuates that indigenous populations along the Americas may have high frequencies of rs6683977.G, but this has never been corroborated. We studied ancestry and PDE4B diversity in 951 healthy individuals from nine Latin American populations. In non-admixed Native American populations rs6683977.G has frequencies greater than 90%, is in linkage disequilibrium with other ALL relapse associated and regulatory variants in PDE4B-intron-7, conforming haplotypes showing their highest worldwide frequencies in Native Americans (>0.82). Our findings inform the discussion on the pertinence of an extra-phase of chemotherapy in Native American populations, and exemplifies how knowledge generated in US-Hispanics is relevant for their even more neglected and vulnerable Native American ancestors along the American continent.

Effect of levetiracetam on the gene expression of placental transporters in a murine model.

OBJECTIVE: Levetiracetam (LEV) is an antiseizure medication prescribed to women during childbearing age. The impact of LEV on placental transporters is poorly understood. This study aimed to assess the effect of LEV exposure on the messenger RNA (mRNA) expression of placental transporters for hormones and nutrients and to correlate their expression with the drug's serum concentration in pregnant mice. METHODS: Studies were conducted on gestational days (GD) 13 and 18, following oral treatment with 100 mg/kg LEV or the vehicle every 24 h after weaning. Serum LEV measurements were performed by High-performance liquid chromatography with a UV detector (HPLC-UV). The weight, height, and width of the fetuses were also analyzed. In addition, the placental expression of transporters xCt, Lat1, Oatp4a1, Fr-α, Rfc, and Snat4 was evaluated through semi-quantitative real-time polymerase chain reaction (qPCR). The Kruskal-Wallis and the Mann-Whitney U tests were used to determine the statistical significance (p < .05). The correlation between serum LEV concentration and placental gene expression was evaluated using the Spearman test. RESULTS: The weight, height, and width were lower in the fetuses exposed to LEV compared with the control group (p < .05). The number of fetuses was lower in the LEV-exposed group than in the control GD 13 group (p < .001). No significant differences were detected in the mRNA expression level at GD 13. At GD 18, the expression of Lat1, Oatp4a1, xCT, and Snat4 was higher in the group treated with LEV compared with the control group (p < .05), whereas the expression of Rfc was lower (p < .05). No correlation was identified between serum LEV concentrations and gene expression levels. SIGNIFICANCE: The repression of the Rfc transcript by LEV at GD 18 suggests that the protein expression would be abolished contributing to the observed intrauterine growth restriction (IUGR). Furthermore, the significant increase in mRNA of xCt, Snat4, Oatp4a1, and Lat1 might be a compensatory mechanism for fetal survival at GD 18.

The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas.

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15-30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4-9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.

Placental SLC38A4 gene polymorphisms 1304 G > A and 292 C > T, and their association with glucose > 95 mg/dL in normal weight full-term healthy newborns / Polimorfismos 1304 G > A y 292 C > T del gen placentario SLC38A4 y su asociación con glucosa > 95 mg/dL en recién nacidos a término, sanos y con peso normal al nacimiento

Abstract Background: The SLC38A4 gene encodes for the SNAT4 protein, which has been related to glucose metabolic alterations in human newborns. This study aimed to determine whether the 1304 G > A and 292 C > T polymorphisms of the SLC38A4 gene are associated with the presence of glucose levels > 95 mg/dL in normal weight full-term healthy newborns. Methods: We conducted a case–control study and analyzed 50 normal weight full-term healthy newborns. Groups were defined based on glucose levels: > 95 mg/dL (cases; n = 13) and < 95 mg/dL (controls; n = 37). The 1304 G > A and 292 C > T polymorphisms of the SLC38A4 gene were determined through quantitative polymerase chain reaction using placental DNA. The association between polymorphism and glucose levels > 95 mg/dL was established using multivariate logistic regression analysis. Results: No significant differences were observed either for gestational age or body weight at birth between groups. In the case group, newborns showed significantly higher homeostatic model assessment for insulin resistance than those in the control group (p < 0.0005). The odds ratio (OR) between the SLC38A4 gene 292 C > T single-nucleotide polymorphism (SNP) and glucose levels > 95 mg/dL was 7.78 (p = 0.024), whereas no significant association was found for the 1304 G > A SNP (OR 1.46; p = 0.77). Conclusions: Our results suggest that the SLC38A4 gene 292 C > T SNP is associated with glucose levels > 95 mg/dL in normal weight full-term healthy newborns.

Resumen Introducción: El gen SLC38A4 codifica la proteína SNAT4, que se ha relacionado con alteraciones en el metabolismo de la glucosa en los humanos. El objetivo de este estudio fue determinar si los polimorfismos 1304 G > A y 292 C > T del gen SLC38A4 se asocian con concentraciones de glucosa > 95 mg/dL en recién nacidos a término Métodos: Se llevó a cabo un estudio de casos y controles con 50 recién nacidos a término, sanos, con peso normal al nacimiento. Los grupos se definieron de acuerdo con las concentraciones de glucosa: > 95 mg/dL (casos; n = 13) y < 95 mg/dL (controles; n = 37). Los polimorfismos 1304 G > A y 292 C > T del gen SLC38A4 se genotipificaron por qPCR utilizando ADN de la placenta. La asociación entre los polimorfismos y la concentración de glucosa > 95 mg/dL se estableció mediante la estimación de la razón de momios (RM) en un análisis múltiple de regresión logística. Resultados: No se observaron diferencias estadísticamente significativas para la edad gestacional y el peso al nacer entre los grupos de estudio. El modelo homeostático para evaluar la resistencia a la insulina (HOMA-IR) fue significativamente más alto en los recién nacidos del grupo de casos que en el grupo control (p < 0.0005). La RM mostró asociación significativa entre el polimorfismo de nucleótido único (SNP) 292 C > T del gen SLC38A4 y la concentración de glucosa > 95 mg/dL (RM: 7.78; p = 0.024); el SNP 1304 G > A no mostró asociación significativa (RM: 1.46; p = 0.77). Conclusiones: Los resultados de este estudio sugieren que el SNP 292 C > T del gen SLC38A4 se asocia con concentraciones de glucosa > 95 mg/dL en recién nacidos a término.

Syncytiotrophoblast stress in early onset preeclampsia: The issues perpetuating the syndrome.

Preeclampsia is a pregnancy-specific syndrome characterized by a sudden increase in blood pressure accompanied by proteinuria and/or maternal multi-system damage associated to poor fetal outcome. In early-onset preeclampsia, utero-placental perfusion is altered, causing constant and progressive damage to the syncytiotrophoblast, generating syncytiotrophoblast stress. The latter leads to the detachment and release of syncytiotrophoblast fragments, anti-angiogenic factors and pro-inflammatory molecules into maternal circulation, resulting in the emergence and persistence of the characteristic symptoms of this syndrome during pregnancy. Therefore, understanding the origin and consequences of syncytiotrophoblast stress in preeclampsia is vital to develop new therapeutic alternatives, focused on reducing the burden of this syndrome. In this review, we describe five central characteristics of syncytial stress that should be targeted or prevented in order to reduce preeclampsia symptoms: histological alterations, syncytiotrophoblast damage, antiangiogenic protein export, placental deportation, and altered syncytiotrophoblast turnover. Therapeutic management of these characteristics may improve maternal and fetal outcomes.

Placental SLC38A4 gene polymorphisms 1304 G > A and 292 C > T, and their association with glucose > 95 mg/dl in normal weight full-term healthy newborns.

BACKGROUND: The SLC38A4 gene encodes for the SNAT4 protein, which has been related to glucose metabolic alterations in human newborns. This study aimed to determine whether the 1304 G > A and 292 C > T polymorphisms of the SLC38A4 gene are associated with the presence of glucose levels > 95 mg/dL in normal weight full-term healthy newborns. METHODS: We conducted a case-control study and analyzed 50 normal weight full-term healthy newborns. Groups were defined based on glucose levels: > 95 mg/dL (cases; n = 13) and < 95 mg/dL (controls; n = 37). The 1304 G > A and 292 C > T polymorphisms of the SLC38A4 gene were determined through quantitative polymerase chain reaction using placental DNA. The association between polymorphism and glucose levels > 95 mg/dL was established using multivariate logistic regression analysis. RESULTS: No significant differences were observed either for gestational age or body weight at birth between groups. In the case group, newborns showed significantly higher homeostatic model assessment for insulin resistance than those in the control group (p < 0.0005). The odds ratio (OR) between the SLC38A4 gene 292 C > T single-nucleotide polymorphism (SNP) and glucose levels > 95 mg/dL was 7.78 (p = 0.024), whereas no significant association was found for the 1304 G > A SNP (OR 1.46; p = 0.77). CONCLUSIONS: Our results suggest that the SLC38A4 gene 292 C > T SNP is associated with glucose levels > 95 mg/dL in normal weight full-term healthy newborns.

Association of the 5HTTLPR Polymorphism with Obesity in Mexican Women with High Native American Ancestry.

Aims: The 5HTT gene has been associated with obesity; this study aimed to determine the association between L- and S-alleles at the 5HTTLPR polymorphism with obesity in indigenous Mexican populations. Materials and Methods: A total of 362 individuals, 289 belonging to eight Native American (NA) groups; 40 Mexican mestizos; and 33 Caucasian Mennonites were enrolled in a cross-sectional study. High (≥90%) and low (<90%) NA ancestry was molecularly determined. A body mass index >30 kg/m2 was considered as obese. The L- and S-alleles of the 5HTTLPR locus were identified by PCR; the association between alleles and obesity was performed by logistic regression analysis. Results: A significantly lower prevalence of obesity (35%) was observed in participants from communities with high NA ancestry (p < 0.005). Under a dominant heritance model the L-allele was associated with obesity in women with high NA ancestry (odds ratio [OR] 7.27; 95% confidence interval [CI] 1.6-32.5; p = 0.009) but not in women with low NA ancestry (OR 0.83; 95% CI 0.3-2.2; p = 0.71); no association was observed in men. Conclusion: Our results suggest that the 5HTTLPR L-allele is a risk factor for developing obesity in Mexican women with high NA ancestry (≥90%).

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

CYP3A5 metabolizes endogenous substrates and ~30% of prescription drugs. The CYP3A5 gene contains an active CYP3A5*1 allele, and a non-functional version, the CYP3A5*3 (rs776746), with consequences for drug therapeutic responses and side effects. Both CYP3A5*1 and *3 have been associated with hypertension. The frequency of CYP3A5*3 varies between populations of different ancestries, with Europeans having the highest allele frequency (> 90%). Given the importance of CYP3A5*3 in drug response and hypertension development, the aim of the present study was to evaluate the frequency of this polymorphism and its association with hypertension in vulnerable indigenous populations in Mexico. A total of 372 subjects were recruited from eight ethnic groups in Northwest Mexico. Systolic (SBP), diastolic (DBP), and median (MBP) blood pressures as well as body mass index (BMI) were measured. Ancestry was evaluated through STR analysis, and the CYP3A5*1/*3 polymorphisms were identified using real-time PCR with TaqMan® probes. Higher frequencies of CYP3A5*1 and *3 were observed in groups with higher (>90%) and lower (<90%) Amerindian ancestry, respectively. The CYP3A5*3/*3 genotype was more frequent in indigenous women with higher SBP and DBP values. On the other hand, the *1 allele showed a protective effect against both high SBP (OR, 0.38; 95% CI, 0.17-0.83, p = 0.001) and DBP (OR 0.38, 95% CI 0.18-0.81, p = 0.007) in women. This association remained significant after adjusting for BMI and age for diastolic (OR, 0.38; 95% CI, 0.17-0.84, p = 0.011) and systolic BP (OR, 0.33; 95% CI, 0.15-0.76, p = 0.005) BP levels in women. Thus, the frequency of CYP3A5*3 varies between groups and seems to depend on ancestry, and CYP3A5*1 decreases the risk of hypertension in Mexican indigenous women. This population analysis of CYP3A5*1/*3 has profound implications not only for the susceptibility to diseases, such as hypertension, but also for safer drug administration regimens, assuring better therapeutic responses and fewer side effects.

Genomic Instability Decreases in HIV Patient by Complementary Therapy with Rosmarinus officinalis Extracts.

Genomic instability is associated with increased oxidative stress in patients with human immunodeficiency virus (HIV). The aim of this study was to determine the effect of intake of methanolic and aqueous extracts of Rosmarinus officinalis on genomic instability in HIV patients. We studied 67 HIV patients under pharmacological treatment with ATRIPLA who were divided into three groups: group 1, patients under ATRIPLA antiretroviral therapy; group 2, patients with ATRIPLA and rosemary aqueous extract (4 g/L per day); and group 3, patients with ATRIPLA and rosemary methanolic extract (400 mg/day). The genomic instability was evaluated through the buccal micronucleus cytome assay. Oral epithelial cells were taken at the beginning and 1 and 4 months later. The groups that received the pharmacological therapy with ATRIPLA and the complementary therapy with R. officinalis extracts showed a decrease in the number of cells with micronuclei and nuclear abnormalities compared with the group that only received ATRIPLA. The complementary therapy with R. officinalis decreased the genomic instability in HIV patients.

The role of xenobiotic-metabolizing enzymes in the placenta: a growing research field.

Introduction: The placenta is a temporary and unique organ that allows for the physical connection between a mother and fetus; this organ regulates the transport of gases and nutrients mediating the elimination of waste products contained in the fetal circulation. The placenta performs metabolic and excretion functions, on the basis of multiple enzymatic systems responsible for the oxidation, reduction, hydrolysis, and conjugation of xenobiotics. These mechanisms give the placenta a protective role that limits the fetal exposure to harmful compounds. During pregnancy, some diseases require uninterrupted treatment even if it is detrimental to the fetus. Drugs and other xenobiotics alter gene expression in the placenta with repercussions for the fetus and mother's well-being.Areas covered: This review provides a brief description of the human placental structure and function, the main drug and xenobiotic transporters and metabolizing enzymes, placenta-metabolized substrates, and alterations in gene expression that the exposure to xenobiotics may cause.Expert opinion: Research should be focused on the identification and validation of biological markers for the assessment of the harmful effects of some drugs in pregnancy, including the evaluation of polymorphisms and methylation patterns in chorionic villous samples and/or amniotic fluid.

The CYP2C19*2 and CYP2C19*17 Polymorphisms Influence Responses to Clozapine for the Treatment of Schizophrenia.

INTRODUCTION: Clozapine (CLZ) is the gold standard drug for treatment-refractory schizophrenia (TRS). However, approximately 30% of patients partially respond to CLZ, defining this subset with super refractory schizophrenia (SRS). Alterations in enzyme activity may affect CLZ responses; the CYP3A4, CYP1A2 and CYP2C19 genes are primarily responsible for CLZ metabolism. OBJECTIVE: The aim of this study was to assess if CYP2C19 variants were associated with TRS or SRS. METHODS: CYP2C19*2 loss-of-function and CYP2C19*17 gain-of-function polymorphism genotype testing were performed in 108 individuals undergoing pharmacological treatment for TRS or SRS. DNA was extracted and polymorphisms were analyzed by polymerase chain reaction (PCR) and sequencing. RESULTS: CYP2C19*17 had positive correlations with SRS and lower Brief Psychiatric Rating Scale (BPRS) scores for TRS. In addition, CYP2C19*2 was associated with lower CLZ dosages for TRS. CONCLUSION: These results show that CYP2C19*2 and CYP2C19*17 polymorphisms influence CLZ responses during schizophrenia treatment.

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans.

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel.

A shortened treatment with rosemary tea (rosmarinus officinalis) instead of glucose in patients with diabetes mellitus type 2 (TSD).

BACKGROUND: Rosemary leaves powder has been reported to reduce in a dose-dependent manner, glucose levels, lipid profile and lipid peroxidation in humans. However, patients should ingest high doses of powder contained in capsules. This formulation constitutes the intake of 10 capsules per day, so the active metabolite must first, be released and then absorbed (for which, rosemary leaf powder must be mixed with gastric juice). AIM: Evaluate whether a shortened dose and time of treatment as well as the pharmaceutical presentation in rosemary tea (Rosmarinus officinalis) instead of powder have a therapeutic effect in the treatment of T2D. METHOD: The complementary therapy with Rosemary tea (2g/1 litre of water per day) were evaluate on resistance to insulin, oxidative stress, biochemical parameters and anthropometric measurements in forty patients T2D under treatment with metformin and/or glibenclamide afther giving your authorization through informed consent. RESULTS: The data indicated that Rosemary tea intake after 90 days, statistically decreased (p < 0.05) anthropometric parameters like the body mass index and waist-hip ratio. Remarkably, this treatment decreased the percentages of glycated hemoglobin, insulin resistance, and the pancreatic ß-cell function and lastly, a significant difference in lipid peroxide levels was found. CONCLUSION: These data show that shortening time and dose, as well as changing the formulation of the Rosemary plant constitutes a promising treatment for drug-resistant T2D patients.

Mitochondria and Coenzyme Q10 in the Pathogenesis of Preeclampsia.

Hypertensive disorders during pregnancy constitute one of the main causes of maternal and perinatal morbidity and mortality across the world and particularly in developing countries such as Ecuador. However, despite its impact on public health, the primary pathophysiological processes involved are yet to be elucidated. It has been proposed, among other theories, that an abnormal placentation may induce an endothelial dysfunction, which is ultimately responsible for the final clinical manifestations. Mitochondria, particularly from trophoblastic cells, are responsible for the production of energy, which is extremely important for normal placentation. The malfunction in this supply of energy may produce higher levels of free radicals. In both production of energy and free radicals, coenzyme Q10 (CoQ10) plays a crucial role in electron transport. As such, the role of CoQ10 in the genesis and prevention of preeclampsia has become the focus of a number of research groups, including that of the authors. Developing an in-depth understanding of these mechanisms might allow us to design new and feasible strategies with which we can reduce preeclampsia, particularly in the Latin-American countries.

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.