Gene Variants in Components of the microRNA Processing Pathway in Chronic Myeloid Leukemia.

Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk.

Decreased DNA repair capacity caused by exposure to metal mixtures is modulated by the PARP1 rs1136410 variant in newborns from a polluted metropolitan area.

BACKGROUND: DNA damage caused by exposure to metal mixtures and the potential modulating role of genes involved in DNA repair and the antioxidant response have not been evaluated in newborns. AIM: The aim was to evaluate the association between prenatal exposure to metal mixtures and DNA repair capacity (DRC) in newborns from the Metropolitan Area of Mexico City (MAMC), a heavily polluted area, and the impact of variants in genes involved in DNA repair and the antioxidant response on this association. METHODS: We analyzed cord blood samples obtained at delivery from 125 healthy newborns from the MAMC. Twenty-four elements were determined by inductively coupled plasma mass spectrometry (ICP‒MS), but only 12 (Cu, I, Se, Zn, As, Ba, Cs, Mn, Sb, Sr, Pb, and Ti) were quantified in most samples. DRC was assessed by the challenge-comet assay, and OGG1, PARP1, and NFE2L2 genotyping was performed with TaqMan probes. Metal mixtures were identified and analyzed using principal component analysis (PCA) and weighted quantile sum (WQS) regression. Independent adjusted linear regression models were used to evaluate the associations. RESULTS: A null DRC was observed in 46% of newborns. The metals with the highest concentrations were Mn, Sr, Ti, and Pb. Essential elements showed normal levels. Only the mixture characterized by increased As, Cs, Cu, Se, and Zn levels was inversely associated with DRC. As was the principal contributor (37.8%) in the negative direction in the DRC followed by Ba and Sb, according to the WQS regression. Newborns carrying of the derived (G) allele of the PARP1 rs1136410 variant showed decreased DRC by exposure to some potentially toxic metals (PTMs) (As, Cs, and Ba). CONCLUSION: Prenatal exposure to metal mixtures negatively affected DRC in newborns, and the PARP1 rs1136410 variant had a modulating role in this association.

Plasma MicroRNAs Related to Metabolic Syndrome in Mexican Women.

INTRODUCTION: The metabolic syndrome (MetS) is a cluster of abnormalities related to cardiovascular disease (CVD). Circulating miRNAs (c-miRNAs) are non-coding RNAs associated with different phenotypes, some of them integrating the MetS. The aim of the study was to compare the c-miRNAs profile in plasma between women with MetS and controls and explore their possible association with dysregulation of metabolic pathways. METHODS: The study was conducted in two phases. At the screening phase, miRNA composition in fasting plasma was compared between 8 participants with MetS and 10 healthy controls, using microarray technology. The validation phase included the analysis by qRT-PCR of 10 selected c-miRNAs in an independent sample (n = 29). RESULTS: We found 21 c-miRNAs differentially expressed between cases and controls. The concentration in plasma of the c-miRNAs hsa-miR-1260a, hsa-miR-4514, and hsa-miR-4687-5p were also correlated with risk factors for CVD. Differences of hsa-miR-1260a between cases and controls were validated using qRT-PCR (fold-change = 7.0; p = 0.003). CONCLUSION: The signature of plasma c-miRNAs differed between women with MetS and controls. The identified miRNAs regulate pathways related to the MetS such as insulin resistance and adipokine activity. The role of c-miR-1260a in the MetS remains to be elucidated.

Genetic alterations in the BCR-ABL1 fusion gene related to imatinib resistance in chronic myeloid leukemia.

Use of the potent tyrosine kinase inhibitor imatinib as the first-line treatment in chronic myeloid leukemia (CML) has decreased mortality from 20% to 2%. Approximately 30% of CML patients experience imatinib resistance, however, largely because of point mutations in the kinase domain of the BCR-ABL1 fusion gene. The aim of this study was to use next-generation sequencing (NGS) to identify mutations related to imatinib resistance. The study included 22 patients diagnosed with CML and experiencing no clinical response to imatinib. Total RNA was used for cDNA synthesis, with amplification of a fragment encompassing the BCR-ABL1 kinase domain using a nested-PCR approach. Sanger and NGS were applied to detect genetic alterations. HaplotypeCaller was used for variant calling, and STAR-Fusion software was applied for fusion breakpoint identification. After sequencing analysis, F311I, F317L, and E450K mutations were detected respectively in three different participants, and in another two patients, single nucleotide variants in BCR (rs9608100, rs140506, rs16802) and ABL1 (rs35011138) were detected. Eleven patients carried e14a2 transcripts, nine had e13a2 transcripts, and both transcripts were identified in one patient. One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.

Single nucleotide variants in microRNA biosynthesis genes in Mexican individuals.

Background: MicroRNAs (miRNAs) are important regulators in a variety of biological processes, and their dysregulation is associated with multiple human diseases. Single nucleotide variants (SNVs) in genes involved in the processing of microRNAs may alter miRNA regulation and could present high allele heterogeneity in populations from different ethnic groups. Thus, the aim of this study was to genotype 15 SNVs in eight genes involved in the miRNA processing pathway in Mexican individuals and compare their frequencies across 21 populations from five continental groups. Methods: Genomic DNA was obtained from 399 healthy Mexican individuals. SNVs in AGO2 (rs2293939 and rs4961280), DGCR8 (rs720012), DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), GEMIN3 (rs197388 and rs197414), GEMIN4 (rs7813, rs2740349, and rs4968104), TNRC6B (rs9611280), and XP05 (rs11077 and rs34324334) were genotyped using TaqMan probes. The minor allele frequency of each SNV was compared to those reported in the 1,000 Genomes database using chi-squared. Sankey plot was created in the SankeyMATIC package to visualize the frequency range of each variant in the different countries analyzed. Results: In Mexican individuals, all 15 SNVs were found in Hardy-Weinberg equilibrium, with frequencies ranging from 0.04 to 0.45. The SNVs rs4961280, rs2740349, rs34324334, and rs720012 in Mexican individuals had the highest minor allele frequencies worldwide, whereas the minor allele frequencies of rs197388, rs10719, rs197414, and rs1107 were among the lowest in Mexican individuals. The variants had high allele heterogeneity among the sub-continental populations, ranging from monomorphic, as was the case for rs9611280 and rs34324334 in African groups, to >0.50, which was the case for variants rs11077 and rs10719 in most of the populations. Importantly, the variants rs197388, rs720012, and rs197414 had FST values > 0.18, indicating a directional selective process. Finally, the SNVs rs13078 and rs10719 significantly correlated with both latitude and longitude. Conclusion: These data indicate the presence of high allelic heterogeneity in the worldwide distribution of the frequency of SNVs located in components of the miRNA processing pathway, which could modify the genetic susceptibility associated with human diseases in populations with different ancestry.

The Nurr7 agonist Cytosporone B differentially regulates inflammatory responses in human polarized macrophages.

The orphan nuclear receptor Nur77 is involved in diverse cellular processes such as inflammation, proliferation, differentiation and survival. Stimuli like lipopolysaccharide (LPS) and tumor necrosis factor (TNF) increase Nur77 expression in human and murine macrophages, and it has been proposed that Nur77 plays a major role in dampening the inflammatory response. Here, we evaluated the expression and function of Nur77 in human anti-inflammatory and pro-inflammatory macrophages derived from blood monocytes cultured with macrophage colony-stimulating factor (M-MDMs) or granulocyte/macrophage colony-stimulating factor (GM-MDMs), respectively. Nur77 mRNA expression was significantly enhanced in M-MDMs compared with GM-MDMs, both constitutively and upon exposure to Toll-like receptor (TLR)2, 3, and 4 ligands. Nur77 activation with the agonist Cytosporone B (CsnB) significantly suppressed the production of TNF, interleukin (IL)-1ß, IL-6, and IL-8 in GM-MDMs stimulated with LPS. In contrast, it tended to enhance the production of the anti-inflammatory cytokine IL-10. This effect was associated with reduced NF-κB p65 nuclear translocation. Similarly, Nur77 knockdown enhanced TNF production in GM-MDMs. CsnB effectively stimulated the transactivation activity of Nur77 in M-MDMs, but it did not alter cytokine synthesis or p65 nuclear translocation. However, Nur77 seemed to have a role in maintaining the anti-inflammatory profile of M-MDMs, since Nur77-deficient M-MDMs constitutively produced higher levels of TNF transcripts. Thus, in the absence of exogenous agonists, Nur77 activity favors the anti-inflammatory function of M-MDMs, whereas agonistic activation of this receptor preferentially drives attenuation of inflammation in inflammatory macrophages.

Exome Sequencing Data Analysis and a Case-Control Study in Mexican Population Reveals Lipid Trait Associations of New and Known Genetic Variants in Dyslipidemia-Associated Loci.

Background: Plasma lipid levels are a major risk factor for cardiovascular diseases. Although international efforts have identified a group of loci associated with the risk of dyslipidemia, Latin American populations have been underrepresented in these studies. Objective: To know the genetic variation occurring in lipid-related loci in the Mexican population and its association with dyslipidemia. Methods: We searched for single-nucleotide variants in 177 lipid candidate genes using previously published exome sequencing data from 2838 Mexican individuals belonging to three different cohorts. With the extracted variants, we performed a case-control study. Logistic regression and quantitative trait analyses were implemented in PLINK software. We used an LD pruning using a 50-kb sliding window size, a 5-kb window step size and a r2 threshold of 0.1. Results: Among the 34251 biallelic variants identified in our sample population, 33% showed low frequency. For case-control study, we selected 2521 variants based on a minor allele frequency ≥1% in all datasets. We found 19 variants in 9 genes significantly associated with at least one lipid trait, with the most significant associations found in the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster on chromosome 11. Notably, all 11 variants associated with hypertriglyceridemia were within this cluster; whereas variants associated with hypercholesterolemia were located at chromosome 2 and 19, and for low high density lipoprotein cholesterol were in chromosomes 9, 11, and 19. No significant associated variants were found for low density lipoprotein. We found several novel variants associated with different lipemic traits: rs3825041 in BUD13 with hypertriglyceridemia, rs7252453 in CILP2 with decreased risk to hypercholesterolemia and rs11076176 in CETP with increased risk to low high density lipoprotein cholesterol. Conclusions: We identified novel variants in lipid-regulation candidate genes in the Mexican population, an underrepresented population in genomic studies, demonstrating the necessity of more genomic studies on multi-ethnic populations to gain a deeper understanding of the genetic structure of the lipemic traits.

The Polyphenols α-Mangostin and Nordihydroguaiaretic Acid Induce Oxidative Stress, Cell Cycle Arrest, and Apoptosis in a Cellular Model of Medulloblastoma.

Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols α-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma cells yet. This study aimed to examine the proapoptotic effects of these polyphenols on human medulloblastoma cells. Medulloblastoma cell line Daoy was incubated with increasing concentrations of α-mangostin or NDGA for 24 h. The cell viability was analyzed using crystal violet and trypan blue dyes. Determination of the glutathione (GSH)/glutathione disulfide (GSSG) ratio and levels of carbonylated proteins was performed to evaluate the oxidative stress. Cell cycle progression and induction of cell death by fluorochrome-couple and TUNEL assays were evaluated using flow cytometry assays. Individual treatments with α-mangostin or NDGA decreased the viability of Daoy cells in a dose-dependent manner, inducing G2/M and S-G2/M cell cycle arrest, respectively. Both polyphenols induced cell death and increased oxidative stress. Very interestingly, α-mangostin showed more potent effects than NDGA. Our results indicate that α-mangostin and NDGA exert important cytostatic and cytotoxic effects in the Daoy cell line. These data highlight the potential usefulness of these compounds as an alternative strategy in medulloblastoma treatment.

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.

Curcumin sensitizes Epstein-Barr-immortalized lymphoblastoid cell lines to inorganic arsenic toxicity.

Chronic exposure to inorganic arsenic (iAs) through contaminated drinking water is an important health problem in certain countries. The use of phytochemicals such as curcumin has recently emerged as an alternative strategy for preventing cellular damage caused by iAs. The Epstein-Barr virus (EBV) affects ~90% of the population and experimental evidence suggested that curcumin mediates cytotoxicity against EBV-infected cells. Due to the potential for an interaction of these factors, the aim of the present study was to evaluate the effect of this phytochemical on iAs-related toxicity in EBV-infected cells. Two independent EBV-immortalized human lymphoblastoid cell lines (LCLs) were used as the model. The cell lines were first incubated with increasing concentrations of curcumin or iAs for 24 and 15 h, respectively, to determine the individual effects of each exposure on cell death. In the next experiment, cell cultures were pre-incubated with 5 µM curcumin for 9 h prior to treatment with 10 µM iAs for 15 h, followed by evaluation of cell death and the cell cycle profile via flow cytometry. The results indicated that individual treatment with either curcumin or iAs induced cell death in a concentration-dependent manner. Furthermore, curcumin pre-treatment enhanced iAs-induced cell death and promoted cell cycle arrest in G1 phase. Taken together, these results suggested that curcumin sensitizes EBV-positive LCLs to the cytotoxic effects of iAs.

Chronic restraint stress induces serotonin transporter expression in the rat adrenal glands.

Chronic restraint stress (CRS) magnifies restraint-induced corticosterone secretion through a mechanism involving increased adrenocortical 5-HT content and turnover. We analysed the impact of CRS on serotonin transporter (SERT) expression and distribution in rat adrenal glands. Male Wistar rats were submitted to CRS (20 min/day) or undisturbed control conditions for 14 days. Exposure to CRS induced a remarkable increase in SERT-like immunoreactivity in the adrenal cortex, which closely matched that of chromogranin A immunostaining, along with a significant increase in SERT protein and mRNA levels in whole adrenals as determined by immunohistochemistry, Western blot and RT-PCR assays, respectively; all these CRS-induced changes occurred almost exclusively in left adrenals. Closely similar results were obtained in animals that received a 14-day chronic corticosterone treatment. These results unravel an interesting association between chronic stress exposure and SERT expression in adrenocortical chromogranin A-positive cells, which seems to be a glucocorticoid-dependent phenomenon.

Metabolic syndrome in indigenous communities in Mexico: a descriptive and cross-sectional study.

BACKGROUND: An Amerindian genetic background could play an important role in susceptibility to metabolic diseases, which have alarmingly increased in recent decades. Mexico has one of the highest prevalences of metabolic disease worldwide. The purpose of this study was to determine the prevalence of metabolic syndrome and its components in a population with high Amerindian ancestry. METHODS: We performed a descriptive, quantitative, and analytical cross-sectional study of 2596 adult indigenous volunteers from 60 different ethnic groups. Metabolic syndrome and its components were evaluated using the American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement criteria. RESULTS: The overall prevalence of metabolic syndrome in the indigenous Mexican population was 50.3%. Although females had a higher prevalence than males (55.6% vs. 38.2%), the males presented with combinations of metabolic syndrome components that confer a higher risk of cardiovascular disease. The most frequent metabolic syndrome component in both genders was low HDL-cholesterol levels (75.8%). Central obesity was the second most frequent component in females (61%), though it had a low prevalence in males (16.5%). The overall prevalence of elevated blood pressure was 42.7% and was higher in males than females (48.8 vs. 40%). We found no gender differences in the overall prevalence of elevated triglycerides (56.7%) or fasting glucose (27.9%). CONCLUSIONS: We documented that individuals with Amerindian ancestry have a high prevalence of metabolic syndrome. Health policies are needed to control the development of metabolic disorders in a population with high genetic risk.

Genetic variability of five ADRB2 polymorphisms among Mexican Amerindian ethnicities and the Mestizo population.

The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P<0.05). The non-synonymous ADRB2 Glu27 allele (rs1042714G), which is associated with several common conditions, showed the lowest frequency in MAs (0.03) compared to other populations worldwide. Among MEZs, this allele showed a frequency of 0.15, intermediate between that in MAs and in Iberians (0.43). Moreover, Glu27 was the only SNP exhibiting a geographic gradient within the MEZ population (from 0.22 to 0.11), reflecting admixed mestizo ancestry across the country. Population differentiation analysis demonstrated that Glu27 had the highest FST value in MAs compared with Europeans (CEU) (0.71), and the lowest between MAs and Japanese (JPT) (0.01), even lower than that observed between MAs and MEZs (0.08). This analysis demonstrated the genetic diversity among Amerindian ethnicities, with the most extreme FST value (0.34) found between the Nahuatls from Morelos and the Seris. This is the first study of ADRB2 genetic variants among MA ethnicities. Our findings add to our understanding of the genetic contribution to variability in disease susceptibility in admixed populations.

A homozygous CEP57 c.915_925dupCAATGTTCAGC mutation in a patient with mosaic variegated aneuploidy syndrome with rhizomelic shortening in the upper and lower limbs and a narrow thorax.

Mosaic variegated aneuploidy syndrome (MVA) is a rare autosomal recessive disorder characterized by random chromosome gains and losses. Mutations in BUB1B and CEP57 genes have been involved in MVA. Here we report on a male child with MVA due to c.915_925dupCAATGTTCAGC mutation in the CEP57 gene. Our patient was homozygous for this mutation and he is the first case with rhizomelic shortening of both the upper and lower limbs and mild respiratory insufficiency due to a narrow thorax. It is also the second MVA Mexican family reported with this mutation that lives in the northwestern region of Mexico, suggesting a "local founding effect". Additional cases are needed to better understand the MVA genotype-phenotype relationship.

Gene variants in AKT1, GCKR and SOCS3 are differentially associated with metabolic traits in Mexican Amerindians and Mestizos.

Amerindian ancestry appears to be a risk factor for metabolic diseases (MetD), making Mexicans an ideal population to better understand the genetic architecture of metabolic health. In this study, we determine the association of genetic variants previously reported with metabolic entities, in two Mexican populations, including the largest sample of Amerindians reported to date. We investigated the association of eigth single-nucleotide polymorphisms (SNPs) in AKT1, GCKR, and SOCS3 genes with different metabolic traits in 1923 Mexican Amerindians (MAs) belonging to 57 ethnic groups, and 855 Mestizos (MEZs). The allele frequency of 7/8 SNPs showed significant differences between MAs and MEZs. Interestingly, some alleles were monomorphic in particular ethnic groups, and highly frequent in other ones. With the exception of GCKR rs1260326T, as expected, all SNP frequencies in the MEZ population had intermediate values between its two main ancestral populations (MAs and Iberian populations in Spain [IBS]). We detected ethnic differences in linkage disequilibrium patterns and haplotype structure between MAs and MEZs, possibly due to the high genetic heterogeneity in these populations. Remarkably, AKT1 was associated with hypertension in MEZs, but not in MAs. GCKR was associated with protection against type 2 diabetes (T2D) in MAs, and with hypertriglyceridemia and protection against low HDL Cholesterol (HDL-C) levels in MEZs. The CAT haplotype in SOCS3 was associated with metabolic syndrome (MetS) in MEZs, and correlated with protection against high blood pressure (HBP) and risk for high waist circumference and T2D in MAs. Our results show differential genetic associations with metabolic traits between MAs and MEZs, possibly due to the differences in genetic structure between these Mexican populations.

Curcumin differentially affects cell cycle and cell death in acute and chronic myeloid leukemia cells.

Curcumin is a phytochemical with potent anti-neoplastic properties. The antitumoral effects of curcumin in cells derived from chronic or acute myeloid leukemia have been already described. However, a comparative study of the cytostatic and cytotoxic effects of curcumin on chronic and acute myeloid leukemia cells has not yet been performed. In the present study, the cellular effects of curcumin on cell lines derived from chronic or acute myeloid leukemia were examined. Dose and time-response assays were performed with curcumin on HL-60 and K562 cells. Cell viability was evaluated with trypan blue exclusion test and cell death by flow cytometry using a fluorescent molecular probe. A cell cycle profile was analyzed, and protein markers of cell cycle progression and cell death were investigated. In the present study, the K562 cells showed a higher sensitivity to the cytostatic and cytotoxic effects of curcumin compared with HL-60. In addition, curcumin induced G1 phase arrest in HL-60 cells and G2/M phase arrest in K562 cells. Furthermore, curcumin-related cell death in HL-60 was associated with the processed forms of caspases-9 and -3 proteins, whereas in K562 cells, both the processed and the unprocessed forms were present. Accordingly, activity of these caspases was significantly higher in HL-60 cells compared with that in K562. In conclusion, curcumin elicits different cellular mechanisms in chronic or acute myeloid leukemia cells and the powerful antitumoral effect was more potent in K562 compared with HL-60 cells.

Altered DNA methylation in liver and adipose tissues derived from individuals with obesity and type 2 diabetes.

BACKGROUND: Obesity is a well-recognized risk factor for insulin resistance and type 2 diabetes (T2D), although the precise mechanisms underlying the relationship remain unknown. In this study we identified alterations of DNA methylation influencing T2D pathogenesis, in subcutaneous and visceral adipose tissues, liver, and blood from individuals with obesity. METHODS: The study included individuals with obesity, with and without T2D. From these patients, we obtained samples of liver tissue (n = 16), visceral and subcutaneous adipose tissues (n = 30), and peripheral blood (n = 38). We analyzed DNA methylation using Illumina Infinium Human Methylation arrays, and gene expression profiles using HumanHT-12 Expression BeadChip Arrays. RESULTS: Analysis of DNA methylation profiles revealed several loci with differential methylation between individuals with and without T2D, in all tissues. Aberrant DNA methylation was mainly found in the liver and visceral adipose tissue. Gene ontology analysis of genes with altered DNA methylation revealed enriched terms related to glucose metabolism, lipid metabolism, cell cycle regulation, and response to wounding. An inverse correlation between altered methylation and gene expression in the four tissues was found in a subset of genes, which were related to insulin resistance, adipogenesis, fat storage, and inflammation. CONCLUSIONS: Our present findings provide additional evidence that aberrant DNA methylation may be a relevant mechanism involved in T2D pathogenesis among individuals with obesity.

GSTT1 and GSTM1 null variants in Mestizo and Amerindian populations from northwestern Mexico and a literature review

Abstract The GSTT1 and GSTM1 genes are key molecules in cellular detoxification. Null variants in these genes are associated with increase susceptibility to developing different types of cancers. The aim of this study was to determine the prevalence of GSTT1 and GSTM1 null genotypes in Mestizo and Amerindian individuals from the Northwestern region of Mexico, and to compare them with those reported worldwide. GSTT1 and GSTM1 null variants were genotyped by multiplex PCR in 211 Mestizos and 211 Amerindian individuals. Studies reporting on frequency of GSTT1 and GSTM1 null variants worldwide were identified by a PubMed search and their geographic distribution were analyzed. We found no significant differences in the frequency of the null genotype for GSTT1 and GSM1 genes between Mestizo and Amerindian individuals. Worldwide frequencies of the GSTT1 and GSTM1 null genotypes ranges from 0.10 to 0.51, and from 0.11 to 0.67, respectively. Interestingly, in most countries the frequency of the GSTT1 null genotype is common or frequent (76%), whereas the frequency of the GSMT1 null genotype is very frequent or extremely frequent (86%). Thus, ethnic-dependent differences in the prevalence of GSTT1 and GSTM1 null variants may influence the effect of environmental carcinogens in cancer risk.

GSTT1 and GSTM1 null variants in Mestizo and Amerindian populations from northwestern Mexico and a literature review.

The GSTT1 and GSTM1 genes are key molecules in cellular detoxification. Null variants in these genes are associated with increase susceptibility to developing different types of cancers. The aim of this study was to determine the prevalence of GSTT1 and GSTM1 null genotypes in Mestizo and Amerindian individuals from the Northwestern region of Mexico, and to compare them with those reported worldwide. GSTT1 and GSTM1 null variants were genotyped by multiplex PCR in 211 Mestizos and 211 Amerindian individuals. Studies reporting on frequency of GSTT1 and GSTM1 null variants worldwide were identified by a PubMed search and their geographic distribution were analyzed. We found no significant differences in the frequency of the null genotype for GSTT1 and GSM1 genes between Mestizo and Amerindian individuals. Worldwide frequencies of the GSTT1 and GSTM1 null genotypes ranges from 0.10 to 0.51, and from 0.11 to 0.67, respectively. Interestingly, in most countries the frequency of the GSTT1 null genotype is common or frequent (76%), whereas the frequency of the GSMT1 null genotype is very frequent or extremely frequent (86%). Thus, ethnic-dependent differences in the prevalence of GSTT1 and GSTM1 null variants may influence the effect of environmental carcinogens in cancer risk.

A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.