RESUMO
Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.
Assuntos
Bancos de Espécimes Biológicos , Genética Médica , Genoma Humano , Genômica , Hispânico ou Latino , Humanos , Glicemia/genética , Glicemia/metabolismo , Estatura/genética , Índice de Massa Corporal , Interação Gene-Ambiente , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/classificação , Hispânico ou Latino/genética , Homozigoto , México , Fenótipo , Triglicerídeos/sangue , Triglicerídeos/genética , Reino Unido , Genoma Humano/genéticaRESUMO
Dipeptidyl peptidase 4 (DPP4) regulates various physiological pathways and has a pivotal role in glucose homeostasis. The objective of this study was to verify the association of a haplotype constituted by two single nucleotide polymorphisms (rs2268894 and rs6741949) in the DPP4 gene with type 2 diabetes mellitus (T2DM) and fasting glycemia-related variables in a sample of Brazilian older adults, taking serum levels and enzymatic activity of DPP4 into account. Clinical, biochemical, and anthropometric characteristics as well as DPP4 serum levels and enzymatic activity were determined in 800 elderly (≥60 years old) individuals. Assessment of polymorphic sites was performed by real-time PCR whereas haplotypes were inferred from genotypic frequencies. Statistical analyses compared measures and proportions according to T2DM diagnosis and DPP4 haplotypic groups. The most common haplotype consisted of the T-rs2268894/G-rs6741949 string, which was 20% more frequent among non-diabetics. Considering non-diabetic patients alone, carriers of the T/G haplotype had significantly lower levels of blood glucose, insulin, HOMA-IR index, and DPP4 activity. Among diabetic patients, the T/G haplotype was associated with lower DPP4 levels whereas glycemic scores were not affected by allelic variants. Our results suggested that the genetic architecture of DPP4 affects the glycemic profile and DPP4 serum levels and activity among elderly individuals according to the presence or absence of T2DM, with a possible implication of the T/G haplotype to the risk of T2DM onset.
Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Dipeptidil Peptidase 4/genética , Idoso , Glicemia/análise , Glicemia/genética , Brasil , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Haplótipos , Humanos , Insulina , Pessoa de Meia-IdadeRESUMO
Butaphosphan is an organic phosphorus compound used in several species for the prevention of rapid catabolic states, however, the mechanism of action remains unclear. This study aimed at determining the effects of butaphosphan on energy metabolism of mice receiving a normal or hypercaloric diet (HCD) and submitted or not to food restriction. Two experiments were conducted: (1) during nine weeks, animals were fed with HCD (n = 28) ad libitum, and at the 10th week, were submitted to food restriction and received butaphosphan (n = 14) or saline injections (n = 14) (twice a day, for seven days) and; (2) during nine weeks, animals were fed with a control diet (n = 14) or HCD (n = 14) ad libitum, and at the 10th week, all animals were submitted to food restriction and received butaphosphan or saline injections (twice a day, for seven days). In food restriction, butaphosphan preserved epididymal white adipose tissue (WAT) mass, increased glucose, NEFA, and the HOMA index. In mice fed HCD and submitted to food restriction, the butaphosphan preserved epididymal WAT mass. Control diet influences on PI3K, GCK, and Irs1 mRNA expression. In conclusion, butaphosphan increased blood glucose and reduced fat mobilization in overweight mice submitted to caloric restriction, and these effects are influenced by diet.
Assuntos
Glicemia/efeitos dos fármacos , Butilaminas/farmacologia , Dieta , Metabolismo Energético/efeitos dos fármacos , Insulina/metabolismo , Ácidos Fosfínicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/genética , Glicemia/metabolismo , Restrição Calórica , Ingestão de Energia , Ácidos Graxos não Esterificados/sangue , Expressão Gênica , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sobrepeso/metabolismoRESUMO
Introducción: La diabetes mellitus se considera un síndrome heterogéneo con etiología compleja en el que influyen factores genéticos y ambientales. Objetivo: Identificar la presencia de alteraciones del metabolismo glucídico y factores de riesgo aterogénicos en familiares de primera línea de pacientes diabéticos tipo 2. Métodos: Se realizó un estudio descriptivo de corte transversal que incluyó a 120 pacientes adultos, hijos de pacientes diabéticos, en los que no se encontraban antecedentes de alteraciones del metabolismo glucídico, pertenecientes al Policlínico Universitario Héroes del Moncada, del municipio Plaza de la Revolución. Se estudiaron variables sociodemográficas, variables clínicas y relacionadas con los estilos de vida como la tensión arterial, el índice de masa corporal, colesterol, triglicéridos, glucemias (ayunas y posprandial), hábito de fumar, actividad física y hábitos dietéticos. Resultados: Los pacientes tenían una edad promedio de 54,42 años y predominó el sexo femenino. Se detectaron alteraciones del metabolismo glucídico en 28,3 por ciento de los cuales 23,3 por ciento se consideraron prediabéticos y 5 por ciento diabéticos. Los factores de riesgo que predominaron fueron la dieta inadecuada, obesidad abdominal, hipercolesterolemia e hipertrigliceridemia que fueron más evidentes en los pacientes diagnosticados como diabéticos. Conclusiones: Los familiares de primer grado de pacientes diabéticos pueden presentar una alta prevalencia de alteraciones del metabolismo glucídico y factores de riesgo aterogénicos, aún sin sintomatología evidente, lo que refuerza la necesidad de realizar un diagnóstico temprano para evitar la progresión de la enfermedad(AU)
Introduction: Diabetes mellitus is considered a heterogeneous syndrome with a complex etiology, influenced by genetic and environmental factors. Objective: To identify the presence of alterations of the glucidic metabolism and atherogenic risk factors in first- degree relatives of type 2 diabetic patients. Methods: A descriptive cross-sectional study was carried out at Heroes del Moncada University Polyclinic, in Plaza de la Revolution municipality. The study included 120 adult patients, descendants of diabetic patients. They had no history of alterations of the glucidic metabolism. Sociodemographic, clinical variables were studied, and those related to lifestyles such as blood pressure, body mass index, cholesterol, triglycerides, (fasting and postprandial) glycaemia, smoking, physical activity and dietary habits. Results: These patients had average age of 54.42 years and the female sex predominated. Alterations of the glucidic metabolism were detected in 28.3 percent, 23.3 percent of them were considered pre-diabetic and 5 percent diabetic. The predominant risk factors were inadequate diet, abdominal obesity, hypercholesterolemia, and hypertriglyceridemia, which was much evident in patients diagnosed as diabetic. Conclusions: The first-degree relatives of diabetic patients may present high prevalence of alterations of glucidic metabolism and atherogenic risk factors, even with no evident symptoms, which reinforces the need of early diagnosis to avoid the progression of the disease(AU)
Assuntos
Humanos , Masculino , Feminino , Glicemia/genética , Glicemia/metabolismo , Família , Epidemiologia Descritiva , Estudos Transversais , Risco à Saúde Humana , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 2/genéticaRESUMO
Aim: We analyzed the frequencies of the rs222749 G>A, rs222747 G>C, rs224534 G>A, and rs8065080 C > T polymorphisms in the TRPV1 gene and their relationships with biomarkers in a Mexican population. Materials and Methods: We included 195 students from two Mexican universities (72.3% female and 27.7% male, mean age, 20.8 ± 3.3 years). The biomarkers analyzed were lipid profile, glucose levels, blood pressure (BP), and body mass index. DNA was obtained from leukocytes by the dodecyltrimethylammonium bromide and cetyltrimethylammonium bromide method and polymorphisms were determined with TaqMan single nucleotide polymorphism (SNP) genotyping assays. Results: Alterations in lipid profile were total cholesterol ≥200 mg/dL in 9.7% of participants, triglycerides (TG) ≥150 mg/dL in 9.2%, high-density lipoprotein (HDL) <35 mg/dL in 6.7%, and low-density lipoprotein (LDL) ≥130 mg/dL in 6.2% of participants. Moreover, 8.2% of the subjects had BP values consistent with hypertension. The most frequent alleles were rs222749G (89.2%), rs222747G (69.2%), rs224534G (59.7%), and rs8065080T (62.3%). An analysis of the associations between the genotypic data and the biomarkers showed that the rs222749GA and rs224534GA genotypes were associated with higher diastolic and systolic BP values, respectively; the rs222747CC genotype was associated with lower LDL levels; the rs224534AA genotype was associated with higher HDL levels and lower triglycerides and LDL. The GGGC/GCAT and GGGT/GCAT haplotypes were associated with higher systolic BP. Conclusions: This study suggests a possible association between TRPV1 gene polymorphisms and BP and lipid profiles in a Mexican population.
Assuntos
Pressão Sanguínea/genética , Lipídeos/genética , Canais de Cátion TRPV/genética , Adulto , Alelos , Glicemia/genética , Índice de Massa Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Glucose/genética , Haplótipos , Humanos , Hipertensão , Lipídeos/sangue , Masculino , México/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA/métodos , Canais de Cátion TRPV/metabolismo , Triglicerídeos/sangue , Adulto JovemRESUMO
OBJECTIVE: To determine the influence of genomic ancestry (GA) and self-reportedcolor-race (SRCR) on glycemic control in adolescents with type 1 diabetes (T1D) in an admixed population. RESEARCH DESIGN AND METHODS: This multicenter nationwide study was conducted in 14 public clinics in 10 Brazilian cities. We estimated global and individual African, European, and Native Amerindian GA proportions using a panel of 46 AIM-INDEL markers. From 1760 patients, 367 were adolescents (20.9%): 184 female (50.1%), aged 16.4 ± 1.9 years, age at diagnosis 8.9 ± 4.3 years, duration of diabetes 8.1 ± 4.3 years, years of study 10.9 ± 2.5 and HbA1c of 9.6 ± 2.4%. RESULTS: Patients SRCR as White: 176 (48.0%), Brown: 159 (43.3%), Black: 19(5.2%), Asians: 5 (1.4%) and Amerindians: 8 (2.2%). The percentage of European GA prevailed in all groups: White (71.1), Brown (58.8), Black (49.6), Amerindians (46.1), and Asians (60.5). Univariate correlation was noted between A1c and African GA, r = 0.11, P = .03; years of study, r = -0.12 P = .010, and having both private and public health care insurance (r = -0.20, P < .001). After adjustments, the multivariate logistic analysis showed that SRCR or GA did not influence glycemic control. CONCLUSIONS: A high percentage of European GA was noted in our patients, even in those who self-reported as non-White, confirming the highly admixed ethnicity of the Brazilian population. Better glycemic control was associated with having both types of health care; however, there was no association between glycemic control with GA or SRCR. Future prospective studies with other admixed populations are necessary to confirm our findings.
Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 1 , Controle Glicêmico , Grupos Raciais/genética , Adolescente , Idade de Início , Glicemia/metabolismo , Brasil/epidemiologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/genética , Etnicidade/genética , Etnicidade/estatística & dados numéricos , Feminino , Predisposição Genética para Doença/etnologia , Genética Populacional , Genômica , Controle Glicêmico/estatística & dados numéricos , Humanos , Masculino , Estudos Prospectivos , Grupos Raciais/estatística & dados numéricosRESUMO
The transcription/export complex (TREX) is formed by a core called THO. These are necessary for the transcription and packaging of messenger RNA and its subsequent nuclear exportation. Studies have correlated THO-specific polymorphisms with abnormalities of HDL-C metabolism. To correlate lipid and metabolic parameters with the genetic variants of the rs8135828 polymorphism of the THOC5 gene in middle-aged women. DNA was extracted from the whole blood of 183 women aged 40-65 and tested for the rs8135828 polymorphism of the THOC5 gene using real-time PCR. HDL-C, LDL-C, triglyceride, and total cholesterol levels, as well as other metabolic parameters, were correlated with the polymorphism genotypes: GG, AG, and AA. Mean age of women was 50.6 ± 6.3 years, 54.6% were postmenopausal and 16.4% had the metabolic syndrome. GG was the most frequently determined genotype (62.3%). There were no differences in lipid levels according to genotypes; although there was a trend for lower HDL-C levels for the AA and AG + AA genotypes. Those with the AG and AG + AA genotypes displayed significantly higher glucose levels (p = .02 and p = .002, respectively); with a trend toward a higher metabolic syndrome prevalence and increased abdominal perimeters in both variants (AG and AG + AA). The AG genotype was related to higher glucose levels but not with abnormal lipid parameters. There is a need for more research in this regard.
Assuntos
Glicemia/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Proteínas Nucleares/genética , Triglicerídeos/metabolismo , Adulto , Glicemia/genética , Colesterol/metabolismo , Feminino , Genótipo , Humanos , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Projetos Piloto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Type 2 diabetes etiology has a strong genetic component. More than 20 genetic variants have been associated with diabetes and other metabolic markers. However, the polymorphism rs7903146 of the TCF7L2 gene has shown the strongest association. AIM: To investigate the association of TCF7L2 (rs7903146) genotype with adiposity and metabolic markers in the Chilean adult population. MATERIAL AND METHODS: The association of TCF7L2 (rs7093146) with adiposity and metabolic markers was studied in 301 participants. The outcomes of the study were adiposity markers (body weight, body mass index (BMI), fat mass and waist circumference) and metabolic markers (blood glucose, insulin, HOMA-IR, lipid profile, high sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT) and leptin). RESULTS: There was an association between the polymorphism TCF7L2 genotype and fasting blood glucose. The latter increased by 4.86 mg/dl per each copy of the risk allele [(95% confidence intervals (CI): 0.48; 9.24), p = 0.03] in the unadjusted adjusted model. However, this association was slightly attenuated in the fully adjusted model [4.38 mg/dl (95% IC: 0.16; 8.60), p = 0.04)]. There were no associations between the TCF7L2 genotype and any other metabolic or adiposity outcome. CONCLUSIONS: These findings confirm the association between the TCF7L2 (rs7903146) and fasting glucose in the Chilean population. However, further studies are needed to confirm the association between the TCF7L2 and diabetes risk in the Chilean population.
Assuntos
Adiposidade/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adiposidade/etnologia , Adulto , Alelos , Antropometria , Glicemia/genética , Chile , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Genótipo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Valores de Referência , Fatores de Risco , Adulto JovemRESUMO
Background: Type 2 diabetes etiology has a strong genetic component. More than 20 genetic variants have been associated with diabetes and other metabolic markers. However, the polymorphism rs7903146 of the TCF7L2 gene has shown the strongest association. Aim: To investigate the association of TCF7L2 (rs7903146) genotype with adiposity and metabolic markers in the Chilean adult population. Material and Methods: The association of TCF7L2 (rs7093146) with adiposity and metabolic markers was studied in 301 participants. The outcomes of the study were adiposity markers (body weight, body mass index (BMI), fat mass and waist circumference) and metabolic markers (blood glucose, insulin, HOMA-IR, lipid profile, high sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT) and leptin). Results: There was an association between the polymorphism TCF7L2 genotype and fasting blood glucose. The latter increased by 4.86 mg/dl per each copy of the risk allele [(95% confidence intervals (CI): 0.48; 9.24), p = 0.03] in the unadjusted adjusted model. However, this association was slightly attenuated in the fully adjusted model [4.38 mg/dl (95% IC: 0.16; 8.60), p = 0.04)]. There were no associations between the TCF7L2 genotype and any other metabolic or adiposity outcome. Conclusions: These findings confirm the association between the TCF7L2 (rs7903146) and fasting glucose in the Chilean population. However, further studies are needed to confirm the association between the TCF7L2 and diabetes risk in the Chilean population.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Polimorfismo de Nucleotídeo Único , Diabetes Mellitus Tipo 2/genética , Adiposidade/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Valores de Referência , Glicemia/genética , Marcadores Genéticos , Modelos Lineares , Chile , Antropometria , Estado Nutricional , Estudos Transversais , Fatores de Risco , Diabetes Mellitus Tipo 2/metabolismo , Alelos , Adiposidade/etnologia , Estudos de Associação Genética , Frequência do Gene , GenótipoRESUMO
The organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion transporter MATE1, encoded by the SLC22A1, SLC22A2, and SLC47A1 genes, respectively, are responsible for the absorption of metformin in enterocytes, hepatocytes, and kidney cells. The aim of this study was to evaluate whether genetic variations in the SLC22A1, SLC22A2, and SLC47A1 genes could be associated with an altered response to metformin in patients with type 2 diabetes mellitus. A cohort study was conducted in 308 individuals with a diagnosis of type 2 diabetes mellitus of less than 3 years and who had metformin monotherapy. Three measurements of blood glycated hemoglobin (HbA1c ) were obtained at the beginning of the study and after 6 and 12 months. Five polymorphisms were analyzed in the SLC22A1 (rs622342, rs628031, rs594709), SLC22A2 (rs316019), and SLC47A1 (rs2289669) genes by real-time polymerase chain reaction. The results showed a significant association among genotypes CC-rs622342 (ß = 1.36; P < .001), AA-rs628031 (ß = 0.98; P = .032), and GG-rs594709 (ß = 1.21; P = .016) in the SLC22A1 gene with an increase in HbA1c levels during the follow-up period. Additionally, a significant association was found in the CGA and CAG haplotypes with an increase in HbA1c levels compared to the highest-frequency haplotype (AGA). In conclusion, the genetic variation in the SLC22A1 gene was significantly related to the variation of the HbA1c levels, an important indicator of glycemic control in diabetic patients. This information may contribute to identifying patients with an altered response to metformin before starting their therapy.