Relevance of NR1I2 variants on carbamazepine therapy in Mexican Mestizos with epilepsy at a tertiary-care hospital

Aim: We evaluated the potential influence of genetic ( CYP3A5, EPHX1, NR1I2, HNF4A, ABCC2, RALBP1, SCN1A, SCN2A and GABRA1) and nongenetic factors on carbamazepine (CBZ) response, adverse drug reactions and CBZ plasma concentrations in 126 Mexican Mestizos (MM) with epilepsy. Subjects & methods: Patients were genotyped for 27 variants using TaqMan® assays. Results: CBZ response was associated with NR1I2 variants and lamotrigine cotreatment. CBZ-induced adverse drug reactions were related to antiepileptic polytherapy and SCN1A rs2298771/rs3812718 haplotype. CBZ plasma concentrations were influenced by NR1I2-rs2276707 and -rs3814058, and by phenytoin cotreatment. CBZ daily dose was also influenced by NR1I2-rs3814055 and EPHX1-rs1051740. Conclusion: Interindividual variability in CBZ treatment was partly explained by NR1I2, EPHX1 and SCN1A variants, as well as antiepileptic cotreatment in MM with epilepsy.

Population Diversity of Three Variants of the SLC47A2 Gene (MATE2-K transporter) in Mexican Mestizos and Native Americans

Background. MATE2-K is an efflux transporter protein of organic cation expressed mainly in the kidney and encoded by the SLC47A2 gene. Different variants of this gene have shown an impact on the pharmacokinetics of various drugs, including metformin, which represents one of the most widely used drugs in treating type 2 diabetes. The SLC47A2 gene variants have been scarcely studied in Mexican populations, especially in Native American groups. For this reason, we analyzed the distribution of the variants rs12943590, rs35263947, and rs9900497 within the SLC47A2 gene in 173 Native Americans (Tarahumara, Huichol, Maya, Puerépecha) and 182 Mestizos (admixed) individuals from Mexico. Methods and Results . Genotypes were determined through TaqMan probes (qPCR). The Hardy-Weinberg agreement was confirmed for all three SLC47A2 gene variants in all the Mexican populations analyzed. When worldwide populations were included for comparison purposes, for alleles and genotypes, a relative interpopulation homogeneity was observed for rs35263947 (C allele; range: 48.9–76.7%) and rs9900497 (G allele; range: 59.1–81.4%). Conversely, heterogeneity was evident for rs12943590 (G allele, range 40.9–77.9%), where the most differentiated population was the Huichol, with high frequencies of the risk genotype associated with decreased response to metformin treatment (A/A= 40.9%).Conclusions. Although the SLC47A2 gene variants allow predicting favorable response to the metformin treatment in Mexican populations, the probable high frequency of ineffectiveness should be discarded in Huichols.

Differences in MTHFR and LRRK2 variant’s association with sporadic Parkinson’s disease in Mexican Mestizos correlated to Native American ancestry

Parkinson’s disease (PD), a common neurodegenerative disorder, has a complex etiology where environmental and genetic factors intervene. While a number of genes and variants have been identified in recent decades as causative or protective agents of this condition, a limited number of studies have been conducted in mixed populations, such as Mexican Mestizos. The historical convergence of two founding groups and three ethnicities, and the increasing north-to-south gradient of Native American ancestry in Mexico resulted in a subpopulation structure with considerable genetic diversity. In this work, we investigate the influence of 21 known susceptibility variants for PD. Our case–control study, with a cohort of 311 Mexican Mestizo subjects, found a significant risk association for the variant rs1491942 in LRRK2. However, when stratification by ancestry was performed, a risk effect for MTHFR rs1801133 was observed only in the group with the highest percentage of European ancestry, and the PD risk effect for LRRK2 rs1491942 was significant in subjects with a higher ratio of Native American ancestry. Meta-analyses of these SNP revealed the effect of LRRK2 rs1491942 to be even more significant than previously described in populations of European descent. Although corroboration is necessary, our findings suggest that polymorphism rs1491942 may be useful as a risk marker of PD in Mexican Mestizos with greater Native American ancestry. The absence of associations with the remaining known risk factors is, in itself, a relevant finding and invites further research into the shared risk factors’ role in the pathophysiological mechanisms of this neurodegenerative disorder.

Chasing the Ghost of the Imperial Woodpecker

This chapter illustrates how the author became thoroughly obsessed with the imperial woodpecker after dreaming about it. The author spent years searching for its closest relative, the ivory-billed woodpecker, and actually had a sighting canoeing through an Arkansas bayou in 2004. A year or so later, the author was photographing woodpecker specimens at Harvard's Museum of Comparative Zoology when an assistant curator brought out a tray containing more than a dozen imperial woodpeckers. For millennia, the imperial's pounding drumbeat echoed like the blows of a wild axman through the old-growth forests of the Sierra Madre as it bored into the massive, grub-infested pines, hammering on them powerfully for weeks at a time until they groaned, shuddered, and finally toppled with an impact that shook the ground. Victorian ornithologist John Gould dubbed it the imperial woodpecker. But it had already been named long before. To the Aztecs, it was cuauhtotomi; to the Tarahumaras, cumecocari; to the Tepehuans, uagam; and to the Mexican Mestizos, the pitoreal.

G6PC2 rs560887 Gene Variant is Associated with Fasting Blood Glucose in the Admixed Mexican Population

Background: In Mexico, type 2 diabetes prevalence is 13.7%, which has a huge impact on Mexican public health. There is an urgent need to focus on the prevention of pre-diabetes to decrease the likelihood of type 2 diabetes onset. Gene variants predisposed to increase Fasting Blood Glucose (FBG) and glycosylated hemoglobin (HbA1c) levels could be helpful for prevention purposes. This study aimed to analyze the association of the G6PC2 rs560887 variant with pre-diabetes in a Mexican-Mestizo population. Methods: A cross-sectional case-control study was performed in 960 Mexican Mestizos participants. The association of G6PC2 rs560887 with pre-diabetes was analyzed by logistic regression and with Fasting Blood Glucose (FBG) and glycosylated hemoglobin (HbA1c) by linear regression. Results: The G6PC2 rs560887 variant was significantly associated with FBG (β -1.80, p=0.03), but not with HbA1c or the presence of pre-diabetes. Conclusion: The G6PC2 rs560887 loci could be a potential early marker of type 2 diabetes.

Pharmacogenetic Evaluation of Metformin and Sulphonylurea Response in Mexican Mestizos with Type 2 Diabetes

Background: In Mexico, approximately 25% of patients with type 2 diabetes (T2D) have adequate glycemic control. Polymorphisms in pharmacogenetic genes have been shown to have clinical consequences resulting in drug toxicity or therapeutic inefficacy. Objective: The study aimed to evaluate the impact of variants in genes known to be involved in response to oral hypoglycemic drugs, such as CYP2C9, OCT, MATE, ABCA1 and C11orf65, in the Mexican Mestizo population of T2D patients. Methods: In this study, 265 patients with T2D were enrolled from the Hospital Juárez de México, Mexico City. Genotyping was performed by TaqMan® assays. SNP-SNP interactions were analyzed using the multifactor dimensionality reduction (MDR) method. Results: Carriers of the del allele of rs72552763 could achieve better glycemic control than noncarriers. There was a significant difference in plasma glucose and HbA1c levels among rs622342 genotypes. The results suggested an SNP-SNP interaction between rs72552763 and rs622342 OCT1 and rs12943590 MATE2. Conclusion: The interaction between rs72552763 and rs622342 in OCT1, and rs12943590 in MATE2 suggested an important role of these polymorphisms in metformin response in T2D Mexican Mestizo population.