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Loss of gut microbial diversity1-6 in industrial populations is associated with chronic diseases7, underscoring the importance of studying our ancestral gut microbiome. However, relatively little is known about the composition of pre-industrial gut microbiomes. Here we performed a large-scale de novo assembly of microbial genomes from palaeofaeces. From eight authenticated human palaeofaeces samples (1,000-2,000 years old) with well-preserved DNA from southwestern USA and Mexico, we reconstructed 498 medium- and high-quality microbial genomes. Among the 181 genomes with the strongest evidence of being ancient and of human gut origin, 39% represent previously undescribed species-level genome bins. Tip dating suggests an approximate diversification timeline for the key human symbiont Methanobrevibacter smithii. In comparison to 789 present-day human gut microbiome samples from eight countries, the palaeofaeces samples are more similar to non-industrialized than industrialized human gut microbiomes. Functional profiling of the palaeofaeces samples reveals a markedly lower abundance of antibiotic-resistance and mucin-degrading genes, as well as enrichment of mobile genetic elements relative to industrial gut microbiomes. This study facilitates the discovery and characterization of previously undescribed gut microorganisms from ancient microbiomes and the investigation of the evolutionary history of the human gut microbiota through genome reconstruction from palaeofaeces.
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Bactérias/isolamento & purificação , Biodiversidade , Evolução Biológica , Fezes/microbiologia , Microbioma Gastrointestinal , Genoma Bacteriano/genética , Interações entre Hospedeiro e Microrganismos , Antibacterianos/administração & dosagem , Bactérias/classificação , Bactérias/genética , Doença Crônica , Países Desenvolvidos , Países em Desenvolvimento , Dieta Ocidental , História Antiga , Humanos , Desenvolvimento Industrial/tendências , Methanobrevibacter/classificação , Methanobrevibacter/genética , Methanobrevibacter/isolamento & purificação , México , Comportamento Sedentário , Sudoeste dos Estados Unidos , Especificidade da Espécie , SimbioseRESUMO
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
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Diabetes Mellitus Tipo 2/genética , Sequenciamento do Exoma , Exoma/genética , Animais , Estudos de Casos e Controles , Técnicas de Apoio para a Decisão , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos KnockoutRESUMO
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.
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Indígenas Norte-Americanos/estatística & dados numéricos , Síndrome Metabólica/epidemiologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Síndrome Metabólica/etnologia , México/epidemiologia , Pessoa de Meia-Idade , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/etnologia , Prevalência , Fatores de RiscoRESUMO
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.
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Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Obesidade/genética , Adipogenia , Adulto , Índice de Massa Corporal , Ilhas de CpG , Epigênese Genética , Ontologia Genética , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Pessoa de Meia-Idade , TranscriptomaRESUMO
INTRODUCTION: In Mexico, the prevalence of neurocognitive disorders (NCDs) has increased in parallel with the increase in life expectancy. The E4 allele of the gene that encodes apolipoprotein E (APOE) is the main genetic risk factor for cognitive impairment. OBJECTIVE: To replicate the association of APOE-E4 allele with neurocognitive impairment in a Mexican population, as well as to implement a genetic risk-detection program with the APOE-E4 allele. METHOD: A program was structured for the detection of APOE-E4 allele risk in different recruiting centers from the central zone of the Mexican Republic, with three stages: recruitment and selection of candidates for the detection of the risk-allele, genetic risk analysis and delivery of results. RESULTS: In the genetic-association study to replicate the association with neurocognitive disorders by means of multivariate logistic models, the APOE-E4 allele increased the risk for cognitive impairment in the Mexican populations by approximately 6 % (OR: 5.83, p = 0.0025). In addition, 367 genetic risk results were delivered. CONCLUSIONS: The present program is the first one to be implemented in Mexico with the purpose to inform on a genetic risk factor for neurocognitive disorders in several centers of the country.
INTRODUCCIÓN: En México, la prevalencia de los trastornos neurocognitivos (TNC) han aumentado a la par del incremento en la esperanza de vida. El alelo E4 del gen que codifica la apolipoproteína E (APOE) es el principal factor de riesgo genético para deterioro neurocognitivo. OBJETIVO: Reproducir la asociación en población mexicana entre APOE-E4 y el deterioro neurocognitivo, así como implementar un programa de detección de riesgo genético con el alelo APOE-E4. MÉTODO: Se estructuró un programa de detección de riesgo basado en APO-EA en diferentes centros de reclutamiento en la zona centro de la República Mexicana, con tres etapas: reclutamiento y selección de los candidatos para la detección del alelo de riesgo, análisis del riesgo genético y entrega del resultado. RESULTADOS: El análisis de asociación genética para replicar la asociación con trastornos neurocognitivos mediante modelos logísticos multivariados mostró que el alelo E4 de APOE incrementó aproximadamente 6 % el riesgo en población mexicana (RM = 5.83, p = 0.0025). Se entregaron 367 resultados de riesgo genético. CONCLUSIONES: El presente programa es el primero en México implementado para dar a conocer un factor de riesgo genético para trastornos neurocognitivos en varios centros del país.
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Apolipoproteína E4/genética , Transtornos Cognitivos/genética , Disfunção Cognitiva/genética , Predisposição Genética para Doença , Alelos , Transtornos Cognitivos/epidemiologia , Disfunção Cognitiva/epidemiologia , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
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.
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Arsenic (As) exposure is a major risk for several types of cancer and metabolic diseases such as diabetes. The transcription factor nuclear factor erythroid 2-related factor (Nrf2) is a key mediator in the cellular defense against As-induced adverse effects. The -653G/A and -617C/A gene variants modulate expression levels of the Nrf2 coding gene (NFE2L2) and are postulated to be associated with several illnesses. In this study the functional effect of these polymorphisms was investigated in the cellular sensitivity to As-mediated effects. Using quantitative real-time polymerase chain reaction (qRT-PCR) the basal levels of NFE2L2 mRNA and the induced levels of NFE2L2 and its target gene NQO1 were measured in lymphoblastoid cells carrying different genotypes for -653G/A and -617C/A polymorphisms following As exposure. The effects of different NFE2L2 gene genotypes on cell proliferation were also explored after chronic metal exposure. A tendency toward reduction in basal levels of NFE2L2 mRNA was noted in the heterozygous (GA/CA) and risk homozygous (AA/AA) genotypes of both polymorphisms in immortalized lymphoblastoid cells. Although the expression of NFE2L2 and NQO1 after acute acute iAs exposure was not markedly influenced by -653G/A and -617C/A genotype, it was found that these single-nucleotide polymorphisms (SNPs) were correlated with a differential sensitivity to chronic exposure to the metalloid. Further studies are needed to completely understand the role of -653G/A and -617C/A SNPs in regulation of the NFE2L2 gene.
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Arsênio/toxicidade , Poluentes Ambientais/toxicidade , Fator 2 Relacionado a NF-E2/genética , Polimorfismo de Nucleotídeo Único , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Humanos , Linfócitos/citologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Chronic myeloid leukemia (CML) is one of the most frequent hematological neoplasia worldwide. The abnormal accumulation of reactive oxygen species may be an important factor in CML development. The transcription factor NRF2 can regulate the transcription of a battery of antioxidant and detoxificant genes after heterodimerizing with small-Maf proteins. Although the participation of NRF2 in the development of chronic degenerative diseases has been thoroughly studied, the role of small-Maf genes has not been documented. We have identified polymorphisms in the three MAF genes (F, G and K) and assessed their association with CML. Over 266 subjects with CML and 399 unrelated healthy donors have been studied. After sequencing each MAF gene by Sanger technology, we found 17 variants in MAFF gene, eight in MAFG and seven in MAFK. In the case-control study, the homozygote genotype CC for the rs9610915 SNP of MAFF was significantly associated with CML. The frequency of the ACC haplotype from MAFK was significantly lower than controls. After stratification by gender, the ACC and GTG haplotypes were associated only with males with CML. These novel data suggest an association between MAFF and MAFG and the development of CML.
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Variação Genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas Proto-Oncogênicas c-maf/genética , Adulto , Alelos , Estudos de Casos e Controles , Biologia Computacional , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Fator de Transcrição MafF/genética , Fator de Transcrição MafK/genética , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores SexuaisRESUMO
IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.
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Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Adulto , Idade de Início , Idoso , Feminino , Genótipo , Hispânico ou Latino/genética , Humanos , Masculino , México , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Análise de Sequência de DNA , Estados UnidosRESUMO
Background: Molecular diagnosis of cystic fibrosis (CF) is challenging in Mexico due to the population's high genetic heterogeneity. To date, 46 pathogenic variants (PVs) have been reported, yielding a detection rate of 77%. We updated the spectrum and frequency of PVs responsible for this disease in mexican patients. Methods: We extracted genomic DNA from peripheral blood lymphocytes obtained from 297 CF patients and their parents. First, we analyzed the five most frequent PVs in the Mexican population using PCR-mediated site-directed mutagenesis. In patients with at least one identified allele, CFTR sequencing was performed using next-generation sequencing tools and multiplex ligation-dependent probe amplification. For variants not previously classified as pathogenic, we used a combination of in silico prediction, CFTR modeling, and clinical characteristics to determine a genotype-phenotype correlation. Results: We identified 95 PVs, increasing the detection rate to 87.04%. The most frequent variants were p.(PheF508del) (42.7%), followed by p.(Gly542*) (5.6%), p.(Ser945Leu) (2.9%), p.(Trp1204*) and p.(Ser549Asn) (2.5%), and CFTRdel25-26 and p.(Asn386Ilefs*3) (2.3%). The remaining variants had frequencies of <2.0%, and some were exclusive to one family. We identified 10 novel PVs localized in different exons (frequency range: 0.1-0.8%), all of which produced structural changes, deletions, or duplications in different domains of the protein, resulting in dysfunctional ion flow. The use of different in silico software and American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) criteria allowed us to assume that all of these PVs were pathogenic, causing a severe phenotype. Conclusions: In a highly heterogeneous population, combinations of different tools are needed to identify the variants responsible for CF and enable the establishment of appropriate strategies for CF diagnosis, prevention, and treatment.
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The altered functions of adipose tissue are one of the main issues in obesity. Bariatric surgery is associated with improvement of obesity associated comorbidities. Here DNA methylation remodeling in adipose tissue after bariatric surgery is examined. After six months postoperative, DNA methylation shows changes in 1155 CpG sites, 66 of these sites correlate with body mass index. Some sites also show correlation with LDL-C, HDL-C, total cholesterol, and triglycerides. CpG sites are located in genes that have not previously been linked to obesity or metabolic diseases. GNAS complex locus is one of those that presented CpG site with the greatest changes after surgery, and the most significant correlation with BMI and lipid profiles. These results show that epigenetic regulation may be involved in the alteration of adipose tissue functions in obesity.
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Cirurgia Bariátrica , Metilação de DNA , Humanos , Epigênese Genética , Cirurgia Bariátrica/efeitos adversos , Obesidade/genética , Obesidade/cirurgia , Obesidade/complicações , Tecido Adiposo/metabolismoRESUMO
BACKGROUND: The human genome presents variation at distinct levels, copy number variants (CNVs) are DNA segments of variable lengths that range from several base pairs to megabases and are present at a variable number of copies in human genomes. Common CNVs have no apparent influence on the phenotype; however, some rare CNVs have been associated with phenotypic traits, depending on their size and gene content. CNVs are detected by microarrays of different densities and are generally visualized, and their frequencies analysed using the HapMap as default reference population. Nevertheless, this default reference is inadequate when the samples analysed are from people from Mexico, since population with a Hispanic genetic background are minimally represented. In this work, we describe the variation in the frequencies of four common CNVs in Mexican-Mestizo individuals. RESULTS: In a cohort of 147 unrelated Mexican-Mestizo individuals, we found that the common CNVs 2p11.2 (99.6%), 8p11.22 (54.5%), 14q32.33 (100%), and 15q11.2 (71.1%) appeared with unexpectedly high frequencies when contrasted with the HapMap reference (ChAS). Yet, while when comparing to an ethnically related reference population, these differences were significantly reduced or even disappeared. CONCLUSION: The findings in this work contribute to (1) a better description of the CNVs characteristics of the Mexican Mestizo population and enhance the knowledge of genome variation in different ethnic groups. (2) emphasize the importance of contrasting CNVs identified in studied individuals against a reference group that-as best as possible-share the same ethnicity while keeping this relevant information in mind when conducting CNV studies at the population or clinical level.
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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.
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The total antioxidant capacity (TAC) has been related to the development of and complications associated with chronic diseases, but its importance during obesity is not entirely clear. We conducted a systematic review and meta-analysis to clarify whether there are differences or similarities in the TAC between subjects with obesity (SO) and subjects with normal weight (NW). Following the recommendations of PRISMA and Cochrane, we performed a systematic search in the PubMed, Scopus, Web of Science, Cochrane, and PROSPERO databases, identifying 1607 studies. Among these, 22 studies were included in the final analysis, comprising 3937 subjects (1665 SO and 2272 NW) in whom serum TAC was measured, and from these 19,201 subjects, the correlation of serum TAC with anthropo-metabolic parameters was also estimated. The Newcastle-Ottawa method was used for the evaluation of the risk of bias. Using a random-effect model (REM), TAC was reduced in SO independently of age (SMD, -0.86; 95% CI -1.38 to -0.34; p = 0.0012), whereas malondialdehyde (SMD, 1.50; 95% CI 0.60 to 2.41), oxidative stress index (SMD, 1.0; 95% CI 0.16 to 1.84), and total oxidant status (SMD, 0.80; 0.22 to 1.37) were increased. There were seven significant pooled correlations of TAC with anthropometric and metabolic parameters: weight (r = -0.17), hip circumference (r= -0.11), visceral adipose index (r = 0.29), triglycerides (r = 0.25), aspartate aminotransferase (r = 0.41), alanine aminotransferase (r = 0.38), and uric acid (r = 0.53). Our results confirm a decrease in TAC and an increase in markers of oxidative stress in SO and underpin the importance of these serum biomarkers in obesity.
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BACKGROUND: Glioblastoma is the most common and devastating primary brain cancer. Radiotherapy is standard of care; however, it is associated with brain radiation toxicity (BRT). This study used a multi-omics approach to determine whether BRT-related genes (RGs) harbor survival prognostic value and whether their encoded proteins represent novel therapeutic targets for glioblastoma. METHODS: RGs were identified through analysis of single-nucleotide variants associated with BRT (R-SNVs). Functional relationships between RGs were established using Protein-Protein Interaction networks. The influence of RGs and their functional groups on glioblastoma prognosis was evaluated using clinical samples from the Glioblastoma Bio-Discovery Portal database and validated using the Chinese Glioma Genome Atlas dataset. The identification of clusters of radiotoxic and putative pathogenic variants in proteins encoded by RGs was achieved by computational 3D structural analysis. RESULTS: We identified the BRT-related 15CAcBRT molecular signature with prognostic value in glioblastoma, by analysis of the COMT and APOE protein functional groups. Its external validation confirmed clinical relevance independent of age, MGMT promoter methylation status, and IDH mutation status. Interestingly, the genes IL6, APOE, and MAOB documented significant gene expression levels alteration, useful for drug repositioning. Biological networks associated with 15CAcBRT signature involved pathways relevant to cancer and neurodegenerative diseases. Analysis of 3D clusters of radiotoxic and putative pathogenic variants in proteins coded by RGs unveiled potential novel therapeutic targets in neuro-oncology. CONCLUSIONS: 15CAcBRT is a BRT-related molecular signature with prognostic significance for glioblastoma patients and represents a hub for drug repositioning and development of novel therapies.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Transcriptoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Prognóstico , Encéfalo/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteínas E/uso terapêuticoRESUMO
OBJECTIVES: The heme oxigenase 1 (HO-1), a rate-limiting enzyme for heme degradation, is an important cytoprotective protein. Transcriptional activity of HO-1 coding gene (HMOX1) can be regulated by the presence of a dinucleotide repeat polymorphism (GT)n at its promoter region. Accordingly, length of (GT)n repeat has been associated with susceptibility to several diseases. We investigated whether the HMOX1 (GT)n polymorphism was associated with childhood-onset systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA) susceptibility. METHODS: We studied 207 and 333 unrelated Mexican patients with JRA and childhood-onset SLE, respectively. The control population consisted of 653 individuals ethnically matched with cases. The HMOX1 (GT)n polymorphism was genotype by PCR and fluorescence technology. RESULTS: We found 27 different alleles, with the 22 and 29 repeats as the most common alleles. Distribution of short allele (n<25) and SS genotype was not statistically associated with JRA subjects. Interestingly, the frequency of both short allele and SS genotype was significantly associated with SLE susceptibility (OR=1.47, 95%CI [1.14-1.89], p=0.002; and OR=2.79, 95%CI [1.24-6.24], p=0.01, respectively). CONCLUSIONS: The distribution pattern of HMOX1 (GT) alleles was different in the Mexican population than those reported elsewhere. Our results suggest that HMOX1 (GT)n polymorphism was associated with susceptibility to childhood-onset SLE but not with JRA in Mexican individuals.
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Artrite Juvenil/genética , Repetições de Dinucleotídeos , Heme Oxigenase-1/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Adolescente , Idade de Início , Artrite Juvenil/enzimologia , Artrite Juvenil/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , México/epidemiologia , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Medição de Risco , Fatores de RiscoRESUMO
Objective: Here we aimed to investigate the association of the Xq28 risk haplotype (H1) with susceptibility to childhood-onset systemic lupus erythematosus (SLE), and to compare its frequency and genetic structure in the Mexican population with those in other continental populations. Methods: We genotyped 15 single-nucleotide variants (SNVs) that form the H1 haplotype, using TaqMan real-time PCR. The association analysis [case-control and transmission disequilibrium test (TDT)] included 376 cases and 400 adult controls, all of whom were mestizos (MEZ). To identify risk alleles in Mexican Indigenous individuals, SNVs were imputed from whole-exome sequencing data of 1,074 individuals. The allelic frequencies determined in MEZ and Indigenous individuals were compared with those of the continental populations from the 1,000 Genomes database phase 3. Linkage disequilibrium (LD) analysis of risk alleles was performed on all populations. Interleukin-1 receptor associated kinase 1 (IRAK1) and methyl CpG binding protein 2 (MECP2) mRNA levels were determined using real-time PCR. Results: Case-control analysis revealed genetic association with childhood-onset SLE for all 15 SNVs (OR = 1.49-1.75; p = 0.0095 to 1.81 × 10-4) and for the Xq28 risk haplotype (OR = 1.97, p = 4 × 10-6). Comparing with individuals of European ancestry (0.14-0.16), the frequencies of the risk alleles were significantly higher in the MEZ individuals (0.55-0.68) and even higher in Indigenous individuals (0.57-0.83). LD analysis indicated a differential haplotype structure within the Indigenous groups, which was inherited to the MEZ population as a result of genetic admixture. Individuals homozygous for the Xq28 risk haplotype exhibited decreased levels of both MECP2A and B transcripts. Conclusion: We found that the H1 risk haplotype differs in its conformation in the Mexican population. This difference could be attributed to positive selection within the Indigenous population, with its inheritance now having an autoimmune health impact in both the Mexican Indigenous and MEZ populations.
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BACKGROUND: Obesity is accompanied by excess adipose fat storage, which may lead to adipose dysfunction, insulin resistance, and type 2 diabetes (T2D). Currently, the tendency to develop T2D in obesity cannot be explained by genetic variation alone-epigenetic mechanisms, such as DNA methylation, might be involved. Here, we aimed to identify changes in DNA methylation and gene expression in visceral adipose tissue (VAT) that might underlie T2D susceptibility in patients with obesity. METHODS: We investigated DNA methylation and gene expression in VAT biopsies from 19 women with obesity, without (OND = 9) or with T2D (OD = 10). Differences in genome-scale methylation (differentially methylated CpGs [DMCs], false discovery rate < 0.05; and differentially methylated regions [DMRs], p value < 0.05) and gene expression (DEGs, p value <0.05) between groups were assessed. We searched for overlap between altered methylation and expression and the impact of altered DNA methylation on gene expression, using bootstrap Pearson correlation. The relationship of altered DNA methylation to T2D-related traits was also tested. RESULTS: We identified 11 120 DMCs and 96 DMRs distributed across all chromosomes, with the greatest density of epigenomic alterations at the MHC locus. These alterations were found in newly and previously T2D-related genes. Several of these findings were supported by validation and extended multi-ethnic analyses. Of 252 DEGs in the OD group, 68 genes contained DMCs (n = 88), of which 24 demonstrated a significant relationship between gene expression and methylation (p values <0.05). Of these, 16, including ATP11A, LPL and EHD2 also showed a significant correlation with fasting glucose and HbA1c levels. CONCLUSIONS: Our results revealed novel candidate genes related to T2D pathogenesis in obesity. These genes show perturbations in DNA methylation and expression profiles in patients with obesity and diabetes. Methylation profiles were able to discriminate OND from OD individuals; DNA methylation is thus a potential biomarker.
Assuntos
Metilação de DNA , Diabetes Mellitus Tipo 2 , Obesidade , Feminino , Humanos , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Perfilação da Expressão Gênica , Obesidade/genéticaRESUMO
As a historical nomadic group in Central Asia, Kazaks have mainly inhabited the steppe zone from the Altay Mountains in the East to the Caspian Sea in the West. Fine scale characterization of the genetic profile and population structure of Kazaks would be invaluable for understanding their population history and modeling prehistoric human expansions across the Eurasian steppes. With this mind, we characterized the maternal lineages of 200 Kazaks from Jetisuu at mitochondrial genome level. Our results reveal that Jetisuu Kazaks have unique mtDNA haplotypes including those belonging to the basal branches of both West Eurasian (R0, H, HV) and East Eurasian (A, B, C, D) lineages. The great diversity observed in their maternal lineages may reflect pivotal geographic location of Kazaks in Eurasia and implies a complex history for this population. Comparative analyses of mitochondrial genomes of human populations in Central Eurasia reveal a common maternal genetic ancestry for Turko-Mongolian speakers and their expansion being responsible for the presence of East Eurasian maternal lineages in Central Eurasia. Our analyses further indicate maternal genetic affinity between the Sherpas from the Tibetan Plateau with the Turko-Mongolian speakers.
Assuntos
Genoma Mitocondrial , Humanos , Animais , Resolução de Problemas , Etnicidade , DNA Mitocondrial/genética , Gerbillinae , ChinaRESUMO
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.