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1.
Mol Biol Evol ; 39(4)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35460423

RESUMO

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.


Assuntos
Genética Populacional , Genoma Humano , Genômica/métodos , Humanos , México , Peru
2.
HGG Adv ; 3(2): 100099, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35399580

RESUMO

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

3.
J Pers Med ; 11(12)2021 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-34945825

RESUMO

The efficacy of anti-obesity drugs usually does not consider the high degree of interindividual variability in responses to the drug which could affect the decision to withdraw the drug early due to ineffectiveness or to continue therapy according to specific expectations of success. The aim of this study was to analyze body weight loss in kilograms during the first month (1 mo-BWLkg) of treatment with 30 mg phentermine and development of tolerance to phentermine, on its 6-month efficacy. One hundred sixty-six subjects with obesity were individually or jointly analyzed in the study. Subjects with 1 mo-BWLkg of <1 kg, 1-3 kg, 3-5 kg, and ≥5 kg reached 6-month mean percentage body weight reductions (BWR%) of approximately 3%, 5%, 10%, and 15%, respectively. Development of late tolerance (4-6 months) to phentermine had a lower impact than early tolerance (2-3 months). Subjects with 1 mo-BWLkg < 3 kg who developed early tolerance did not achieve relevant BWR% (≥5%) at month 6, while the rest of the subgroups achieved increasing and progressive BWR%, according to their 1 mo-BWLkg range and time of onset of tolerance. The 1 mo-BWLkg and development of tolerance to phentermine could be useful to predict the expected 6-month efficacy trends in obese patients treated with 30 mg phentermine.

4.
Nutrients ; 13(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34836148

RESUMO

Dietary fiber (DF) is a major substrate for the gut microbiota that contributes to metabolic health. Recent studies have shown that diet-metabolic phenotype effect might be related to individual gut microbial profiles or enterotypes. Thus, the aim of this study was to examine whether microbial enterotypes modify the association between DF intake and metabolic traits. This cross-sectional study included 204 children (6-12 years old) and 75 adults (18-60 years old). Habitual DF intake was estimated with a Food Frequency Questionnaire and biochemical, clinical and anthropometric data were obtained. Gut microbiota was assessed through 16S sequencing and participants were stratified by enterotypes. Correlations adjusting for age and sex were performed to test the associations between dietary fiber components intake and metabolic traits. In children and adults from the Prevotella enterotype, a nominal negative correlation of hemicellulose intake with insulin and HOMA-IR levels was observed (p < 0.05), while in individuals of the other enterotypes, these associations were not observed. Interestingly, the latter effect was not related to the fecal short-chain-fatty acids profile. Our results contribute to understanding the enterotype influence on the diet-phenotype interaction, which ultimate could provide evidence for their use as potential biomarkers for future precision nutrition strategies.


Assuntos
Fibras na Dieta/análise , Ingestão de Alimentos/fisiologia , Microbioma Gastrointestinal/fisiologia , Resistência à Insulina/fisiologia , Adolescente , Adulto , Biomarcadores/sangue , Criança , Estudos Transversais , Inquéritos sobre Dietas , Ingestão de Alimentos/etnologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Resistência à Insulina/etnologia , Masculino , México/etnologia , Pessoa de Meia-Idade , Fenótipo , RNA Ribossômico 16S/análise , Adulto Jovem
5.
Metabolites ; 11(9)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34564420

RESUMO

Recent evidence shows that obesity correlates negatively with bone mass. However, traditional anthropometric measures such as body mass index could not discriminate visceral adipose tissue from subcutaneous adipose tissue. The visceral adiposity index (VAI) is a reliable sex-specified indicator of visceral adipose distribution and function. Thus, we aimed to identify metabolomic profiles associated with VAI and low bone mineral density (BMD). A total of 602 individuals from the Health Workers Cohort Study were included. Forty serum metabolites were measured using the targeted metabolomics approach, and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical, and biochemical parameters. The analysis showed a serum amino acid signature composed of glycine, leucine, arginine, valine, and acylcarnitines associated with high VAI and low BMD. In addition, we found a sex-dependent VAI in pathways related to primary bile acid biosynthesis, branched-chain amino acids, and the biosynthesis of pantothenate and coenzyme A (CoA). In conclusion, a metabolic profile differs by VAI and BMD status, and these changes are gender-dependent.

6.
Mol Med ; 27(1): 108, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525937

RESUMO

BACKGROUND: Elevations of circulating branched-chain amino acids (BCAA) are observed in humans with obesity and metabolic comorbidities, such as insulin resistance. Although it has been described that microbial metabolism contributes to the circulating pool of these amino acids, studies are still scarce, particularly in pediatric populations. Thus, we aimed to explore whether in early adolescents, gut microbiome was associated to circulating BCAA and in this way to insulin resistance. METHODS: Shotgun sequencing was performed in DNA from fecal samples of 23 early adolescents (10-12 years old) and amino acid targeted metabolomics analysis was performed by LC-MS/MS in serum samples. By using the HUMAnN2 algorithm we explored microbiome functional profiles to identify whether bacterial metabolism contributed to serum BCAA levels and insulin resistance markers. RESULTS: We identified that abundance of genes encoding bacterial BCAA inward transporters were negatively correlated with circulating BCAA and HOMA-IR (P < 0.01). Interestingly, Faecalibacterium prausnitzii contributed to approximately ~ 70% of bacterial BCAA transporters gene count. Moreover, Faecalibacterium prausnitzii abundance was also negatively correlated with circulating BCAA (P = 0.001) and with HOMA-IR (P = 0.018), after adjusting for age, sex and body adiposity. Finally, the association between Faecalibacterium genus and BCAA levels was replicated over an extended data set (N = 124). CONCLUSIONS: We provide evidence that gut bacterial BCAA transport genes, mainly encoded by Faecalibacterium prausnitzii, are associated with lower circulating BCAA and lower insulin resistance. Based on the later, we propose that the relationship between Faecalibacterium prausnitzii and insulin resistance, could be through modulation of BCAA.


Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Faecalibacterium prausnitzii/fisiologia , Microbioma Gastrointestinal , Adolescente , Fatores Etários , Aminoácidos de Cadeia Ramificada/metabolismo , Biomarcadores , Pesos e Medidas Corporais , Criança , Feminino , Humanos , Resistência à Insulina , Masculino , Metabolômica/métodos , Metagenoma , Metagenômica/métodos , Obesidade/metabolismo , Vigilância em Saúde Pública
7.
J Diabetes Complications ; 35(11): 108025, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34420811

RESUMO

AIM: To identify associations among allelic variants of the genes FTO, ABCA1, ADRB3, and PPARG with anthropometric and biochemical traits, metabolic diseases (obesity, T2D or metabolic syndrome) in an adult population from Northwest Mexico. METHODS: Blood samples were collected from 846 subjects including 266 normal weight subjects, 285 with obesity, and 295 with T2D. Of the 846 persons in the study, 365 presented metabolic syndrome diagnostic criteria. Anthropometric and biochemical traits were recorded and 4 single nucleotide polymorphisms (SNPs): FTO rs9939609 A-allele, ABCA1 rs9282541 A-allele, ADRB3 rs4994 G-allele, and PPARG rs1801282 G-allele were genotyped by real-time PCR. RESULTS: FTO rs9939609 A-allele was significantly associated with obesity (p: 8.3 × 10-4), and metabolic syndrome (p: 0.001), but no individual SNPs were significantly associated with T2D. Finally, the cumulative risk of the four SNPs was significantly associated with obesity (p: 1.95 × 10-4). CONCLUSION: Associations in FTO, ABCA, ADRB3, and PPARG SNPs presented in this study with obesity and metabolic syndrome could represent a risk for developing metabolic diseases in Northwest Mexican adult subjects.


Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Obesidade , Transportador 1 de Cassete de Ligação de ATP , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Genótipo , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , México/epidemiologia , Obesidade/complicações , Obesidade/genética , PPAR gama/genética , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 3/genética
8.
iScience ; 24(8): 102900, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34409269

RESUMO

Changes in the human gut microbiome are associated with obesity and metabolic syndrome, but the role of the gut virome in both diseases remains largely unknown. We characterized the gut dsDNA virome of 28 school-aged children with healthy normal-weight (NW, n = 10), obesity (O, n = 10), and obesity with metabolic syndrome (OMS, n = 8), using metagenomic sequencing of virus-like particles (VLPs) from fecal samples. The virome classification confirmed the bacteriophages' dominance, mainly composed of Caudovirales. Notably, phage richness and diversity of individuals with O and OMS tended to increase, while the VLP abundance remained the same among all groups. Of the 4,611 phage contigs composing the phageome, 48 contigs were highly prevalent in ≥80% of individuals, suggesting high inter-individual phage diversity. The abundance of several contigs correlated with gut bacterial taxa; and with anthropometric and biochemical parameters altered in O and OMS. To our knowledge, this gut phageome represents one of the largest datasets and suggests disease-specific phage alterations.

9.
Cell ; 184(16): 4268-4283.e20, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34233163

RESUMO

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.


Assuntos
Fator de Transcrição Associado à Microftalmia/metabolismo , NADP Trans-Hidrogenases/metabolismo , Pigmentação da Pele/efeitos da radiação , Raios Ultravioleta , Animais , Linhagem Celular , Estudos de Coortes , AMP Cíclico/metabolismo , Dano ao DNA , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Predisposição Genética para Doença , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanossomas/efeitos dos fármacos , Melanossomas/metabolismo , Melanossomas/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , NADP Trans-Hidrogenases/antagonistas & inibidores , Oxirredução/efeitos dos fármacos , Oxirredução/efeitos da radiação , Polimorfismo de Nucleotídeo Único/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Proteólise/efeitos da radiação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pigmentação da Pele/efeitos dos fármacos , Pigmentação da Pele/genética , Ubiquitina/metabolismo , Peixe-Zebra
10.
Arterioscler Thromb Vasc Biol ; 41(9): 2494-2508, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34233476

RESUMO

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.


Assuntos
HDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Hiperlipoproteinemia Tipo II/genética , Proteínas de Transporte de Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Análise da Randomização Mendeliana , México/epidemiologia , Camundongos , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleotídeos/metabolismo , Fenótipo , Medição de Risco
11.
Forensic Sci Int Genet ; 53: 102517, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33865096

RESUMO

Here we evaluate the accuracy of prediction for eye, hair and skin pigmentation in a dataset of > 6500 individuals from Mexico, Colombia, Peru, Chile and Brazil (including genome-wide SNP data and quantitative/categorical pigmentation phenotypes - the CANDELA dataset CAN). We evaluated accuracy in relation to different analytical methods and various phenotypic predictors. As expected from statistical principles, we observe that quantitative traits are more sensitive to changes in the prediction models than categorical traits. We find that Random Forest or Linear Regression are generally the best performing methods. We also compare the prediction accuracy of SNP sets defined in the CAN dataset (including 56, 101 and 120 SNPs for eye, hair and skin colour prediction, respectively) to the well-established HIrisPlex-S SNP set (including 6, 22 and 36 SNPs for eye, hair and skin colour prediction respectively). When training prediction models on the CAN data, we observe remarkably similar performances for HIrisPlex-S and the larger CAN SNP sets for the prediction of hair (categorical) and eye (both categorical and quantitative), while the CAN sets outperform HIrisPlex-S for quantitative, but not for categorical skin pigmentation prediction. The performance of HIrisPlex-S, when models are trained in a world-wide sample (although consisting of 80% Europeans, https://hirisplex.erasmusmc.nl), is lower relative to training in the CAN data (particularly for hair and skin colour). Altogether, our observations are consistent with common variation of eye and hair colour having a relatively simple genetic architecture, which is well captured by HIrisPlex-S, even in admixed Latin Americans (with partial European ancestry). By contrast, since skin pigmentation is a more polygenic trait, accuracy is more sensitive to prediction SNP set size, although here this effect was only apparent for a quantitative measure of skin pigmentation. Our results support the use of HIrisPlex-S in the prediction of categorical pigmentation traits for forensic purposes in Latin America, while illustrating the impact of training datasets on its accuracy.


Assuntos
Cor de Olho/genética , Cor de Cabelo/genética , Polimorfismo de Nucleotídeo Único , Pigmentação da Pele/genética , Conjuntos de Dados como Assunto , Genética Populacional , Genótipo , Humanos , América Latina , Modelos Logísticos , Fenótipo
12.
Sci Adv ; 7(6)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33547071

RESUMO

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.


Assuntos
Face , Polimorfismo de Nucleotídeo Único , Proteínas de Transporte Vesicular , Animais , Face/anatomia & histologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Camundongos , Fenótipo , Proteínas de Transporte Vesicular/genética
13.
Cell Mol Gastroenterol Hepatol ; 11(2): 389-406, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32942044

RESUMO

BACKGROUND & AIMS: The etiology of nonalcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate kinase (L-PK or Pklr), in NAFLD by using patient samples and mouse models. METHODS: We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis. After treatment, we measured several metabolic phenotypes including obesity, insulin resistance, dyslipidemia, liver steatosis, and fibrosis. Liver tissues were used for gene expression and immunoblotting, and liver mitochondria bioenergetics was characterized. RESULTS: In both mice and humans, L-PK expression is up-regulated in males via testosterone and is strongly associated with NAFLD severity. In a steatosis model, L-PK silencing in male mice improved glucose tolerance, insulin sensitivity, and lactate/pyruvate tolerance compared with controls. Furthermore, these animals had reduced plasma cholesterol levels and intrahepatic triglyceride accumulation. Conversely, L-PK overexpression in male mice resulted in augmented disease phenotypes. In contrast, female mice overexpressing L-PK were unaffected. Mechanistically, L-PK altered mitochondrial pyruvate flux and its incorporation into citrate, and this, in turn, increased liver triglycerides via up-regulated de novo lipogenesis and increased PNPLA3 levels accompanied by mitochondrial dysfunction. Also, L-PK increased plasma cholesterol levels via increased PCSK9 levels. On the other hand, L-PK silencing reduced de novo lipogenesis and PNPLA3 and PCSK9 levels and improved mitochondrial function. Finally, in fibrosis model, we demonstrate that L-PK silencing in male mice reduced both liver steatosis and fibrosis, accompanied by reduced de novo lipogenesis and improved mitochondrial function. CONCLUSIONS: L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Because NAFLD/nonalcoholic steatohepatitis exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics.


Assuntos
Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/genética , Piruvato Quinase/genética , Adulto , Animais , Modelos Animais de Doenças , Feminino , Mutação com Ganho de Função , Perfilação da Expressão Gênica , Inativação Gênica , Predisposição Genética para Doença , Humanos , Fígado/enzimologia , Fígado/patologia , Mutação com Perda de Função , Masculino , Camundongos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Piruvato Quinase/metabolismo , Fatores Sexuais , Regulação para Cima
14.
Hepatology ; 73(5): 1783-1796, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32893372

RESUMO

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.


Assuntos
Índice de Massa Corporal , Proteína C-Reativa/análise , Neoplasias da Vesícula Biliar/etiologia , Cálculos Biliares/complicações , Adulto , Fatores Etários , Chile/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias da Vesícula Biliar/genética , Cálculos Biliares/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco
15.
Microorganisms ; 8(11)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105628

RESUMO

The effect of microbiota composition and its health on bone tissue is a novel field for research. However, their associations with bone mineral density (BMD) have not been established in postmenopausal women. The present study investigates the relation of diet, the microbiota composition, and the serum metabolic profile in postmenopausal women with normal-BMD or with low-BMD. Ninety-two Mexican postmenopausal women were classified into normal-BMD (n = 34) and low-BMD (n = 58). The V4 hypervariable region was sequenced using the Miseq platform. Serum vitamin D was determined by chemiluminescence immunoassay. Serum concentrations of acyl-carnitines and amino acids were determined by electrospray tandem mass spectrometry. Diet was assessed by a food frequency questionnaire. The low-BMD group had fewer observed species, higher abundance of γ-Proteobacteria, lower consumption of lycopene, and lower concentrations of leucine, valine, and tyrosine compared with the normal-BMD group. These amino acids correlated positively with the abundance of Bacteroides. Lycopene consumption positively correlated with Oscillospira and negatively correlated with Pantoea genus abundance. Finally, the intestinal microbiota of women with vitamin D deficiency was related to Erysipelotrichaceae and Veillonellaceae abundance compared to the vitamin D non-deficient group. Associations mediated by the gut microbiota between diet and circulating metabolites with low-BMD were identified.

16.
Sci Rep ; 10(1): 13706, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792643

RESUMO

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10-6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10-10). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.


Assuntos
/genética , Aquaporina 4/genética , Predisposição Genética para Doença , Antígenos HLA/genética , Neuromielite Óptica/epidemiologia , Neuromielite Óptica/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Masculino , México/epidemiologia
17.
Microb Cell Fact ; 19(1): 61, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143621

RESUMO

BACKGROUND: In the last decade, increasing evidence has shown that changes in human gut microbiota are associated with diseases, such as obesity. The excreted/secreted proteins (secretome) of the gut microbiota affect the microbial composition, altering its colonization and persistence. Furthermore, it influences microbiota-host interactions by triggering inflammatory reactions and modulating the host's immune response. The metatranscriptome is essential to elucidate which genes are expressed under diseases. In this regard, little is known about the expressed secretome in the microbiome. Here, we use a metatranscriptomic approach to delineate the secretome of the gut microbiome of Mexican children with normal weight (NW) obesity (O) and obesity with metabolic syndrome (OMS). Additionally, we performed the 16S rRNA profiling of the gut microbiota. RESULTS: Out of the 115,712 metatranscriptome genes that codified for proteins, 30,024 (26%) were predicted to be secreted, constituting the Secrebiome of the gut microbiome. The 16S profiling confirmed an increased abundance in Firmicutes and decreased in Bacteroidetes in the obesity groups, and a significantly higher richness and diversity than the normal weight group. We found novel biomarkers for obesity with metabolic syndrome such as increased Coriobacteraceae, Collinsela, and Collinsella aerofaciens; Erysipelotrichaceae, Catenibacterium and Catenibacterium sp., and decreased Parabacteroides distasonis, which correlated with clinical and anthropometric parameters associated to obesity and metabolic syndrome. Related to the Secrebiome, 16 genes, homologous to F. prausniitzi, were overexpressed for the obese and 15 genes homologous to Bacteroides, were overexpressed in the obesity with metabolic syndrome. Furthermore, a significant enrichment of CAZy enzymes was found in the Secrebiome. Additionally, significant differences in the antigenic density of the Secrebiome were found between normal weight and obesity groups. CONCLUSIONS: These findings show, for the first time, the role of the Secrebiome in the functional human-microbiota interaction. Our results highlight the importance of metatranscriptomics to provide novel information about the gut microbiome's functions that could help us understand the impact of the Secrebiome on the homeostasis of its human host. Furthermore, the metatranscriptome and 16S profiling confirmed the importance of treating obesity and obesity with metabolic syndrome as separate conditions to better understand the interplay between microbiome and disease.


Assuntos
Bactérias/classificação , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica , Síndrome Metabólica/microbiologia , Obesidade Pediátrica/microbiologia , Bactérias/metabolismo , Criança , Estudos de Coortes , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Expressão Gênica , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Síndrome Metabólica/etiologia , México , Obesidade Pediátrica/complicações , RNA Ribossômico 16S/genética , Via Secretória
18.
Bol Med Hosp Infant Mex ; 77(1): 3-14, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115585

RESUMO

Obesity prevalence has increased in the last decades worldwide leading to metabolic complications, such as type 2 diabetes, steatosis, cardiovascular disease, among others; its development is influenced by genetic factors and environmental factors, such as intestinal microbiome. In Mexico, 33.3% of the adults present this disease. Obesity is defined as an excessive adipose tissue accumulation, provoking its dysfunction. Adipose tissue remodeling, which involves angiogenesis, hypoxia and inflammation, is implicated in the developing of obesity and metabolic modifications. Bariatric surgery is the most used and successful intervention to control morbid obesity, leading a maintained loss of weight and remission of some of its comorbidities as type 2 diabetes. Here, we review some of the molecular aspects of the metabolic changes provoked by bariatric surgery and its impact in weight loss and comorbidities remission. In summary, this article reviews the genetic aspects, microbiome and molecular facts (adipose tissue remodeling) that are involved in obesity development. In addition, some of the molecular aspects about bariatric surgery are described and the mechanisms that are regulated to control obesity and its comorbidities.


En las últimas décadas, la prevalencia de la obesidad ha aumentado a escala mundial y ha provocado complicaciones metabólicas tales como diabetes de tipo 2, esteatosis, problemas cardiovasculares, entre otras. Su desarrollo puede estar influenciado por factores genéticos y ambientales, incluyendo la microbiota intestinal. En México, el 33.3% de la población adulta padece de este problema. La obesidad involucra un incremento excesivo del tejido adiposo que produce su disfunción. Se ha demostrado que la remodelación del tejido adiposo, dada por angiogénesis, hipoxia e inflamación, otorga susceptibilidad a desarrollar obesidad y conlleva a modificaciones metabólicas. La cirugía bariátrica ha sido el procedimiento más utilizado y más exitoso para tratar la obesidad mórbida en cuanto a la pérdida de peso corporal a largo plazo y a la remisión de comorbilidades como la diabetes tipo 2. En este artículo se revisan los aspectos moleculares por medio de los cuales la cirugía bariátrica provoca cambios metabólicos que se reflejan en la pérdida de peso y las mejoras metabólicas. Por lo tanto, se resumen aspectos genéticos, de microbioma y moleculares (remodelación del tejido adiposo) que influyen en el desarrollo de la obesidad. También se explican los aspectos moleculares a través de los cuales se puede modular la pérdida de peso y la mejoría de comorbilidades metabólicas.


Assuntos
Tecido Adiposo/metabolismo , Cirurgia Bariátrica/métodos , Obesidade Mórbida/epidemiologia , Adulto , Animais , Humanos , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/etiologia , México/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/cirurgia , Obesidade Mórbida/complicações , Obesidade Mórbida/cirurgia , Prevalência , Perda de Peso
19.
Bol. méd. Hosp. Infant. Méx ; 77(1): 3-14, ene.-feb. 2020. tab, graf
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1153223

RESUMO

Resumen En las últimas décadas, la prevalencia de la obesidad ha aumentado a escala mundial y ha provocado complicaciones metabólicas tales como diabetes de tipo 2, esteatosis, problemas cardiovasculares, entre otras. Su desarrollo puede estar influenciado por factores genéticos y ambientales, incluyendo la microbiota intestinal. En México, el 33.3% de la población adulta padece de este problema. La obesidad involucra un incremento excesivo del tejido adiposo que produce su disfunción. Se ha demostrado que la remodelación del tejido adiposo, dada por angiogénesis, hipoxia e inflamación, otorga susceptibilidad a desarrollar obesidad y conlleva a modificaciones metabólicas. La cirugía bariátrica ha sido el procedimiento más utilizado y más exitoso para tratar la obesidad mórbida en cuanto a la pérdida de peso corporal a largo plazo y a la remisión de comorbilidades como la diabetes tipo 2. En este artículo se revisan los aspectos moleculares por medio de los cuales la cirugía bariátrica provoca cambios metabólicos que se reflejan en la pérdida de peso y las mejoras metabólicas. Por lo tanto, se resumen aspectos genéticos, de microbioma y moleculares (remodelación del tejido adiposo) que influyen en el desarrollo de la obesidad. También se explican los aspectos moleculares a través de los cuales se puede modular la pérdida de peso y la mejoría de comorbilidades metabólicas.


Abstract Obesity prevalence has increased in the last decades worldwide leading to metabolic complications, such as type 2 diabetes, steatosis, cardiovascular disease, among others; its development is influenced by genetic factors and environmental factors, such as intestinal microbiome. In Mexico, 33.3% of the adults present this disease. Obesity is defined as an excessive adipose tissue accumulation, provoking its dysfunction. Adipose tissue remodeling, which involves angiogenesis, hypoxia and inflammation, is implicated in the developing of obesity and metabolic modifications. Bariatric surgery is the most used and successful intervention to control morbid obesity, leading a maintained loss of weight and remission of some of its comorbidities as type 2 diabetes. Here, we review some of the molecular aspects of the metabolic changes provoked by bariatric surgery and its impact in weight loss and comorbidities remission. In summary, this article reviews the genetic aspects, microbiome and molecular facts (adipose tissue remodeling) that are involved in obesity development. In addition, some of the molecular aspects about bariatric surgery are described and the mechanisms that are regulated to control obesity and its comorbidities.

20.
Gut Microbes ; 11(4): 900-917, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31973685

RESUMO

BACKGROUND: Gut microbiota, by influencing multiple metabolic processes in the host, is an important determinant of human health and disease. However, gut dysbiosis associated with metabolic complications shows inconsistent patterns. This is likely driven by factors shaping gut microbial composition that have largely been under-evaluated, at a population level, in school-age children, especially from developing countries. RESULTS: Through characterization, by 16S sequencing, of the largest gut microbial population-based school-aged children cohort in Latin America (ORSMEC, N = 926, aged 6-12 y), we identified associations of 14 clinical and environmental covariates (PFDR<0.1), collectively explaining 15.7% of the inter-individual gut microbial variation. Extrinsic factors such as markers of socioeconomic status showed a major influence in the most abundant taxa and in the enterotypes' distribution. Age was positively correlated with higher diversity, but only in normal-weight children (rho = 0.138, P =2 × 10-3). In contrast, this correlation although not significant, was negative in overweight and obese children (rho = -0.125, P = 0.104 and rho = -0.058, P = 0.409, respectively). Finally, co-abundance groups (CAGs) were associated with the presence of metabolic complications. CONCLUSIONS: Our study offers evidence that the presence of overweight and obesity could impair the microbial diversity maturation associated with age. Furthermore, it provides novel results toward a better understanding of gut microbiota in the pediatric population that will ultimately help to develop therapeutic approaches to improve metabolic status.


Assuntos
Bactérias/crescimento & desenvolvimento , Microbioma Gastrointestinal , Adiposidade , Adolescente , Bactérias/classificação , Bactérias/genética , Variação Biológica da População , Criança , Estudos Transversais , Dieta , Feminino , Humanos , Estilo de Vida , Masculino , Síndrome Metabólica/microbiologia , Obesidade/microbiologia , Obesidade Pediátrica/microbiologia , Fatores Socioeconômicos
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