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Metabolic diseases, including obesity, diabetes, and metabolic syndrome, are among the most important public health challenges worldwide. Metabolic diseases are classified as multifactorial diseases in which genetic variants such as single-nucleotide polymorphisms (SNPs) may play an important role. The present study aimed to identify associations linking allelic variants of the PCSK1, TMEM18, GPX5, ZPR1, ZBTB16, and PPARG1 genes with anthropometric and biochemical traits and metabolic diseases (obesity or metabolic syndrome) in an adult population from northwestern Mexico. METHODS: Blood samples were collected from 523 subjects, including 247 with normal weight, 276 with obesity, and 147 with metabolic syndrome. Anthropometric and biochemical characteristics were recorded, and single-nucleotide polymorphisms (SNPs) were genotyped by real-time PCR. RESULTS: PCSK1 was significantly (p < 0.05) associated with BMI, weight, and waist-to-hip ratio; TMEM18 was significantly associated with systolic blood pressure and triglyceride levels; GPX5 was significantly associated with HDL cholesterol levels. In addition, PCSK1 was associated with obesity (p = 1.0 × 10-4) and metabolic syndrome (p = 3.0 × 10-3), whereas PPARG1 was associated with obesity (p = 0.044). CONCLUSIONS: The associations found in this study, mainly between allelic variants of PCSK1 and metabolic traits, obesity, and metabolic syndrome, may represent a risk for developing metabolic diseases in adult subjects from northwestern Mexico.
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Síndrome Metabólica , Adulto , Humanos , Síndrome Metabólica/genética , México/epidemiologia , Alelos , Obesidade/genética , Genótipo , PPAR gama/genética , Pró-Proteína Convertase 1RESUMO
The loss of function melanocortin 4-receptor (MC4R) Ile269Asn mutation has been proposed as one of the most important genetic contributors to obesity in the Mexican population. However, whether patients bearing this mutation respond differently to weight loss treatments is unknown. We tested the association of this mutation with obesity in 1683 Mexican adults, and compared the response of mutation carriers and non-carriers to three different weight loss interventions: dietary restriction intervention, phentermine 30 mg/day treatment, and Roux-en-Y gastric bypass (RYGB) surgery. The Ile269Asn mutation was associated with obesity [OR = 3.8, 95% CI (1.5-9.7), p = 0.005]. Regarding interventions, in the dietary restriction group only two patients were MC4R Ile269Asn mutation carriers. After 1 month of treatment, both mutation carriers lost weight: -4.0 kg (-2.9%) in patient 1, and -1.8 kg (-1.5%) in patient 2; similar to the mean weight loss observed in six non-carrier subjects (-2.9 kg; -2.8%). Phentermine treatment produced similar weight loss in six carriers (-12.7 kg; 15.5%) and 18 non-carriers (-11.3 kg; 13.6%) after 6 months of pharmacological treatment. RYGB also caused similar weight loss in seven carriers (29.9%) and 24 non-carriers (27.8%), 6 months after surgery. Our findings suggest that while the presence of a single MC4R loss of function Ile269Asn allele significantly increases obesity risk, the presence of at least one functional MC4R allele seems sufficient to allow short-term weight loss in response to dietary restriction, phentermine and RYGB. Thus, these three different interventions may be useful for the short-term treatment of obesity in MC4R Ile269Asn mutation carriers.
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Cirurgia Bariátrica , Fentermina , Receptor Tipo 4 de Melanocortina , Adulto , Humanos , Mutação , Obesidade/genética , Obesidade/cirurgia , Redução de Peso/genética , Receptor Tipo 4 de Melanocortina/genéticaRESUMO
Preterm newborns are extremely vulnerable to morbidities, complications, and death. Preterm birth is a global public health problem due to its socioeconomic burden. Nurturing preterm newborns is a critical medical issue because they have limited nutrient stores and it is difficult to establish enteral feeding, which leads to inadequate growth frequently associated with poor neurodevelopmental outcomes. Parenteral nutrition (PN) provides nutrients to preterm newborns, but its biochemical effects are not completely known. To study the effect of PN treatment on preterm newborns, an untargeted metabolomic 1H nuclear magnetic resonance (NMR) assay was performed on 107 urine samples from 34 hospitalized patients. Multivariate data (Principal Component Analysis, PCA, Orthogonal partial least squares discriminant analysis OPLS-DA, parallel factor analysis PARAFAC-2) and univariate analyses were used to identify the association of specific spectral data with different nutritional types (NTs) and gestational ages. Our results revealed changes in the metabolic profile related to the NT, with the tricarboxylic acid cycle and galactose metabolic pathways being the most impacted pathways. Low citrate and succinate levels, despite higher glucose relative urinary concentrations, seem to constitute the metabolic profile found in the studied critically ill preterm newborns who received PN, indicating an energetic dysfunction that must be taken into account for better nutritional management.
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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.
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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 JovemRESUMO
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.
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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 PúblicaRESUMO
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a demyelinating autoimmune disease of the central nervous system, more prevalent in individuals of non-European ancestry. Few studies have analyzed genetic risk factors in NMOSD, and HLA class II gene variation has been associated NMOSD risk in various populations including Mexicans. Thymopoietin (TMPO) has not been tested as a candidate gene for NMOSD or other autoimmune disease, however, experimental evidence suggests this gene may be involved in negative selection of autoreactive T cells and autoimmunity. We thus investigated whether the missense TMPO variant rs17028450 (Arg630Cys, frequent in Latin America) is associated with NMOSD, and whether this variant shows an interaction with HLA-class II rs9272219, previously associated with NMOSD risk. A total of 119 Mexican NMOSD patients, 1208 controls and 357 Native Mexican individuals were included. The HLA rs9272219 "T" risk allele frequency ranged from 21 to 68%, while the rs17028450 "T" minor allele frequency was as high as 18% in Native Mexican groups. Both rs9272219 and rs17028450 were significantly associated with NMOSD risk under additive models (OR = 2.48; p = 8 × 10-10 and OR = 1.59; p = 0.0075, respectively), and a significant interaction between both variants was identified with logistic regression models (p = 0.048). Individuals bearing both risk alleles had an estimated 3.9-fold increased risk of NMOSD. To our knowledge, this is the first study reporting an association of TMPO gene variation with an autoimmune disorder and the interaction of specific susceptibility gene variants, that may contribute to the genetic architecture of NMOSD in admixed Latin American populations.
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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.
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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/genéticaRESUMO
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.
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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 RiscoRESUMO
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.
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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.
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Indígena Americano ou Nativo do Alasca/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/epidemiologiaRESUMO
BACKGROUND: Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). METHODS: We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. RESULTS: We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. CONCLUSIONS: Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.
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Transtorno Bipolar/epidemiologia , Transtornos Mentais/epidemiologia , Esquizofrenia/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Transtorno Bipolar/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Diagnóstico Duplo (Psiquiatria) , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtornos Mentais/genética , México , Pessoa de Meia-Idade , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto JovemRESUMO
Background Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). Methods We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. Results We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. Conclusions Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Esquizofrenia/epidemiologia , Transtorno Bipolar/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Mentais/epidemiologia , Esquizofrenia/genética , Transtorno Bipolar/genética , Diagnóstico Duplo (Psiquiatria) , Transtornos Relacionados ao Uso de Substâncias/genética , Predisposição Genética para Doença , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/epidemiologia , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , MéxicoRESUMO
Risk of hyperuricemia is modified by genetic and environmental factors. Our aim was to identify factors associated with serum uric acid levels and hyperuricemia in Mexicans. A pilot Genome-wide association study GWAS was performed in a subgroup of participants (n = 411) from the Health Workers Cohort Study (HWCS). Single nucleotide polymorphisms (SNPs) associated with serum uric acid levels were validated in all the HWCS participants (n = 1939) and replicated in independent children (n = 1080) and adult (n = 1073) case-control studies. The meta-analysis of the whole HWCS and replication samples identified three SLC2A9 SNPs: rs1014290 (p = 2.3 × 10-64), rs3775948 (p = 8.2 × 10-64) and rs11722228 (p = 1.1 × 10-17); and an ABCG2 missense SNP, rs2231142 (p = 1.0 × 10-18). Among the non-genetic factors identified, the visceral adiposity index, smoking, the metabolic syndrome and its components (waist circumference, blood pressure, glucose and hyperlipidemia) were associated with increased serum uric acid levels and hyperuricemia (p < 0.05). Among the female HWCS participants, the odds ratio for hyperuricemia was 1.24 (95% CI, 1.01-1.53) per unit increase in soft drink consumption. As reported in other studies, our findings indicate that diet, adiposity and genetic variation contribute to the elevated prevalence of hyperuricemia in Mexico.
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Hiperuricemia , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Criança , Feminino , Estudo de Associação Genômica Ampla , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Hiperuricemia/sangue , Hiperuricemia/epidemiologia , Hiperuricemia/genética , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
BACKGROUND: Serum uric acid (SUA) is a heritable trait associated with cardiovascular risk factors and coronary artery disease (CAD). Genome wide association studies (GWAS) have identified several genes associated with SUA, mainly in European populations. However, to date there are few GWAS in Latino populations, and the role of SUA-associated single nucleotide polymorphisms (SNPs) in cardiovascular disease has not been studied in the Mexican population. METHODS: We performed genome-wide SUA association study in 2153 Mexican children and adults, evaluated whether genetic effects were modified by sex and obesity, and used a Mendelian randomization approach in an independent cohort to study the role of SUA modifying genetic variants in premature CAD. RESULTS: Only two loci were associated with SUA levels: SLC2A9 (ßâ¯=â¯-0.47â¯mg/dl, Pâ¯=â¯1.57â¯×â¯10-42 for lead SNP rs7678287) and ABCG2 (ßâ¯=â¯0.23â¯mg/dl, Pâ¯=â¯2.42â¯×â¯10-10 for lead SNP rs2231142). No significant interaction between SLC2A9 rs7678287 and ABCG2 rs2231142 genotypes and obesity was observed. However, a significant ABCG2 rs2231142 genotype*sex interaction (Pâ¯=â¯0.001) was observed in adults but not in children. Although SUA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (eGFR), only ABCG2 rs2231142 was associated with decreased eGFR in the premature CAD group. CONCLUSIONS: SUA elevation was independently associated with premature CAD, metabolic syndrome and decreased eGFR in the Mexican population. However, a Mendelian randomization approach using the lead SUA-associated SNPs (SLC2A9 and ABCG2) did not support a causal role of elevated SUA levels for premature CAD.
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Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Ácido Úrico/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , México/epidemiologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
Genome-wide association studies (GWAS) have identified copy number variants (CNVs) associated with obesity in chromosomal regions 1p31.1, 10q11.22, 11q11, 16p12.3, and recently 1p21.1, which contains the salivary amylase gene (AMY1). Recent evidence suggests this enzyme may influence gut microbiota composition through carbohydrate (mainly starch) degradation. The role of these CNVs in obesity has been scarcely explored in the Latino population, and thus the aim of our study was to evaluate the association of 1p31.1, 10q11.22, 11q11, 16p12.3 and 1p21.1 CNVs with obesity in 921 Mexican children, to replicate significant associations in 920 Mexican adults, and to analyze the association of AMY1 copy number with gut microbiota in 75 children and 45 adults. Of the five CNVs analyzed, 1q11 CNV was significantly associated with obesity in children, but not in adults. Only AMY1 CNV was significantly associated with obesity in both age groups. Moreover, gut microbiota analyses revealed a positive correlation between AMY1 copy number and Prevotella abundance. This genus has enzymes and gene clusters essential for complex polysaccharide degradation and utilization. To our knowledge, this is the first study to analyze the association of these five CNVs in the Mexican population and to report a correlation between AMY1 CN and gut microbiota in humans.
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Variações do Número de Cópias de DNA , Microbioma Gastrointestinal/genética , Predisposição Genética para Doença , Obesidade/genética , Prevotella , alfa-Amilases Salivares/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Obesidade/epidemiologia , Adulto JovemRESUMO
Non-alcoholic fatty liver disease (NAFLD) is the accumulation of extra fat in liver cells not caused by alcohol. Elevated transaminase levels are common indicators of liver disease, including NAFLD. Previously, we demonstrated that PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) are associated with elevated transaminase levels in overweight/obese Mexican adults. We investigated the association between 288 SNPs identified in genome-wide association studies and risk of elevated transaminase levels in an admixed Mexican-Mestizo sample of 178 cases of NAFLD and 454 healthy controls. The rs2896019, rs12483959, and rs3810622 SNPs in PNPLA3 and rs1227756 in COL13A1 were associated with elevated alanine aminotransferase (ALT, ≥40IU/L). A polygenic risk score (PRS) based on six SNPs in the ADIPOQ, COL13A1, PNPLA3, and SAMM50 genes was also associated with elevated ALT. Individuals carrying 9-12 risk alleles had 65.8% and 48.5% higher ALT and aspartate aminotransferase (AST) levels, respectively, than those with 1-4 risk alleles. The PRS showed the greatest risk of elevated ALT levels, with a higher level of significance than the individual variants. Our findings suggest a significant association between variants in COL13A1, ADIPOQ, SAMM50, and PNPLA3, and risk of NAFLD/elevated transaminase levels in Mexican adults with an admixed ancestry. This is the first study to examine high-density single nucleotide screening for genetic variations in a Mexican-Mestizo population. The extent of the effect of these variations on the development and progression of NAFLD in Latino populations requires further analysis.
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Adiponectina/genética , Alanina Transaminase/genética , Aspartato Aminotransferases/genética , Colágeno Tipo XIII/genética , Lipase/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Idoso , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Estudos de Casos e Controles , Etnicidade/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , México , Pessoa de Meia-Idade , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Herança Multifatorial/genética , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Childhood obesity is associated with a number of metabolic abnormalities leading to increased cardiovascular risk. Metabolites can be useful as early biomarkers and new targets to promote early intervention beginning in school age. Thus, we aimed to identify metabolomic profiles associated with obesity and obesity-related metabolic traits. We used data from the Obesity Research Study for Mexican children (ORSMEC) in Mexico City and included a case control (n = 1120), cross-sectional (n = 554) and a longitudinal study (n = 301) of 6-12-year-old children. Forty-two metabolites were measured using electrospray MS/MS and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical and biochemical parameters. Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity (OR = 1.57; 95%CI 1.45-1.69, P = 3.84 × 10-31) and serum triglycerides (TG) (ß = 0.067, P = 4.5 × 10-21). These associations were validated in the cross-sectional study (P < 0.0001). In the longitudinal cohort, the amino acid signature was associated with serum TG and with the risk of hypertriglyceridemia after 2 years (OR = 1.19; 95%CI 1.03-1.39, P = 0.016). This study shows that an amino acid signature significantly associated with childhood obesity, is an independent risk factor of future hypertriglyceridemia in children.
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Aminoácidos/metabolismo , Biomarcadores/metabolismo , Hipertrigliceridemia/diagnóstico , Metaboloma , Obesidade Infantil/complicações , Aminoácidos/análise , Antropometria , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Humanos , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/metabolismo , Estudos Longitudinais , Masculino , México/epidemiologia , Fatores de RiscoRESUMO
Obesity is a major public health concern in Mexico and worldwide. Although the estimated heritability is high, common variants identified by genome-wide association studies explain only a small proportion of this heritability. A combination of linkage and association strategies could be a more robust and powerful approach to identify other obesity-susceptibility variants. We thus sought to identify novel genetic variants associated with obesity-related traits in the Mexican population by combining these methods. We performed a genome-wide linkage scan for body mass index (BMI) and other obesity-related phenotypes in 16 Mexican families using the Sequential Oligogenic Linkage Analysis Routines Program. Associated single-nucleotide polymorphisms (SNPs) were tested for associations in an independent cohort. Two suggestive BMI-linkage peaks (logarithm of odds ⩾1.5) were observed at chromosomal regions 11q13 and 13q22. Only rs614080 in the 11q13 region was significantly associated with BMI and related traits in these families. This association was also significant in an independent cohort of Mexican adults. Moreover, this variant was significantly associated with GSTP1 gene expression levels in adipose tissue. In conclusion, the rs614080 SNP near the GSTP1 gene was significantly associated with BMI and GSTP1 expression levels in the Mexican population.
Assuntos
Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Cromossomos Humanos Par 11/química , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/patologiaRESUMO
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by mutations in the thymidine phosphorylase gene located on chromosome 22q13.32-ter, causing defective functioning of the enzyme. At present 87 sporadic or familial cases have been reported and 52 different mutations identified. We present herein the clinical, neuromuscular and molecular findings of two affected brothers from an indigenous Mexican family living in a very small village not far from Mexico City, both brothers being homozygous for a novel mutation (Leu133Pro) in exon 3 of the ECGF1 gene.
Assuntos
Encefalomiopatias Mitocondriais/genética , Mutação , Timidina Fosforilase/genética , Adulto , Feminino , Humanos , Masculino , México , Encefalomiopatias Mitocondriais/enzimologia , LinhagemRESUMO
OBJECTIVE: To evaluate the efficacy of PCR in the diagnosis of extrapulmonary tuberculosis (TB) and its impact in the management of patients in a tertiary-care center in Mexico City. METHOD: We conducted a retrospective study based on 40 clinical charts of patients to whom nested PCR was performed for the diagnosis of TB from June 1999 to December 2000. We reviewed the medical notes of 10 days before and 10 days after the PCR study to analyze its impact in the management of the patient. Also, we reviewed the rest of the chart to decide if the patient suffered from TB or not (gold standard). The categories of diagnosis were definitive case of TB, probable TB and no TB. We calculated the sensitivity, specificity, and predictive values. RESULTS: The PCR was positive in 45% of the cases. The sensitivity of PCR to diagnosis TB was 50%, specificity 59%, and the positive and negative predictive value were 35% and 72%, respectively. If just spinal fluid was included, the sensitivity and the negative predictive value increased to 75% and 63%, respectively. The PCR had an impact in the management of 13% of the patients. CONCLUSIONS: The PCR for the diagnosis of extrapulmonary TB has limited efficacy, which improves when the test is done in spinal fluid samples. The impact of the result of PCR in the clinical management of the patients was poor.