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Major depressive disorder (MDD) and type 2 diabetes (T2D) are complex disorders whose comorbidity can be due to hypercortisolism and may be explained by dysfunction of the corticotropin-releasing hormone receptor 1 (CRHR1) and cortisol feedback within the hypothalamic-pituitary-adrenal axis (HPA axis). To investigate the role of the CRHR1 gene in familial T2D, MDD, and MDD-T2D comorbidity, we tested 152 CRHR1 single-nucleotide-polymorphisms (SNPs), via 2-point parametric linkage and linkage disequilibrium (LD; i.e., association) analyses using 4 models, in 212 peninsular families with T2D and MDD. We detected linkage/LD/association to/with MDD and T2D with 122 (116 novel) SNPs. MDD and T2D had 4 and 3 disorder-specific novel risk LD blocks, respectively, whose risk variants reciprocally confirm one another. Comorbidity was conferred by 3 novel independent SNPs. In silico analyses reported novel functional changes, including the binding site of glucocorticoid receptor-alpha [GR-α] on CRHR1 for transcription regulation. This is the first report of CRHR1 pleiotropic linkage/LD/association with peninsular familial MDD and T2D. CRHR1 contribution to MDD is stronger than to T2D and may antecede T2D onset. Our findings suggest a new molecular-based clinical entity of MDD-T2D and should be replicated in other ethnic groups.
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The metabolome offers a dynamic, comprehensive, and precise picture of the phenotype. Current high-throughput technologies have allowed the discovery of relevant metabolites that characterize a wide variety of human phenotypes with respect to health, disease, drug monitoring, and even aging. Metabolomics, parallel to genomics, has led to the discovery of biomarkers and has aided in the understanding of a diversity of molecular mechanisms, highlighting its application in precision medicine. This review focuses on the metabolomics that can be applied to improve human health, as well as its trends and impacts in metabolic and neurodegenerative diseases, cancer, longevity, the exposome, liquid biopsy development, and pharmacometabolomics. The identification of distinct metabolomic profiles will help in the discovery and improvement of clinical strategies to treat human disease. In the years to come, metabolomics will become a tool routinely applied to diagnose and monitor health and disease, aging, or drug development. Biomedical applications of metabolomics can already be foreseen to monitor the progression of metabolic diseases, such as obesity and diabetes, using branched-chain amino acids, acylcarnitines, certain phospholipids, and genomics; these can assess disease severity and predict a potential treatment. Future endeavors should focus on determining the applicability and clinical utility of metabolomic-derived markers and their appropriate implementation in large-scale clinical settings.
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The TCF7L2 protein is a key transcriptional effector of the Wnt/ß-catenin signaling pathway, regulating gene expression. It was initially identified in cancer research and embryologic developmental studies. Later, the TCF7L2 gene was linked to type 2 diabetes (T2D), implicating TCF7L2 and Wnt-signaling in metabolic disorders and homeostasis. In fact, TCF7L2-T2D variants confer the greatest relative risk for T2D, unquestionably predicting conversion to T2D in individuals with impaired glucose tolerance. We aim to describe the relevance of TCF7L2 in other human disorders. The TCF7L2-single nucleotide polymorphisms (SNPs) and T2D-risk association have been replicated in numerous follow-up studies, and research has now been performed in several other diseases. In this article, we discuss common TCF7L2-T2D variants within the framework of their association with human diseases. The TCF7L2 functional regions need to be further investigated because the molecular and cellular mechanisms through which TCF7L2 contributes to risk associations with different diseases are still not fully elucidated. In this review, we show the association of common TCF7L2-T2D variants with many types of diseases. However, the role of rare genetic variations in the TCF7L2 gene in distinct diseases and ethnic groups has not been explored, and understanding their impact on specific phenotypes will be of clinical relevance. This offers an excellent opportunity to gain a clearer picture of the role that the TCF7L2 gene plays in the pathophysiology of human diseases. The potential pleiotropic role of TCF7L2 may underlie a possible pathway for comorbidity in human disorders.
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Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Diabetes Mellitus Tipo 2/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genéticaRESUMO
TCF7L2 is the most potent locus for type 2 diabetes (T2D) risk and the first locus to have been robustly reported by genomic linkage studies. TCF7L2 is a transcription factor that forms a basic part of the Wnt signaling pathway. This gene has highly conserved sequence regions that correspond to functional domains. The association of TCF7L2 with T2D is one of the most powerful genetically discovered in studies of complex diseases, as it has been consistently replicated in multiple populations with diverse genetic origins. The mechanisms over which TCF7L2 exerts its effect on T2D are still not well understood. In this article, we describe the main molecular mechanisms of how TCF7L2 is related to T2D. TCF7L2 variants associated with T2D risk exert an influence on the initial therapeutic success of the hypoglycemic oral agent sulfonylurea. Thus, it is important to know whether there are other TCF7L2 variants associated with T2D that can influence treatment with oral hypoglycemic agents. Resequencing of the TCF7L2 gene in diverse ethnic groups is required to reveal common and rare variations and their role in different pathologies and in adverse reactions to drugs. Identification of TCF7L2-susceptibility disease variants will permit, at a given moment, offering of therapies to patients according to their genotype.
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Diabetes Mellitus Tipo 2/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/fisiologia , Adipogenia/genética , Animais , Diabetes Mellitus Tipo 2/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Via de Sinalização Wnt/genéticaRESUMO
AIMS: Metabolomics have been used to evaluate the role of small molecules in human disease. However, the cost and complexity of the methodology and interpretation of findings have limited the transference of knowledge to clinical practice. Here, we apply a targeted metabolomics approach using samples blotted in filter paper to develop clinical-metabolomics models to detect kidney dysfunction in diabetic kidney disease (DKD). METHODS: We included healthy controls and subjects with type 2 diabetes (T2D) with and without DKD and investigated the association between metabolite concentrations in blood and urine with eGFR and albuminuria. We also evaluated performance of clinical, biochemical and metabolomic models to improve kidney dysfunction prediction in DKD. RESULTS: Using clinical-metabolomics models, we identified associations of decreased eGFR with body mass index (BMI), uric acid and C10:2 levels; albuminuria was associated to years of T2D duration, A1C, uric acid, creatinine, protein intake and serum C0, C10:2 and urinary C12:1 levels. DKD was associated with age, A1C, uric acid, BMI, serum C0, C10:2, C8:1 and urinary C12:1. Inclusion of metabolomics increased the predictive and informative capacity of models composed of clinical variables by decreasing Akaike's information criterion, and was replicated both in training and validation datasets. CONCLUSIONS: Targeted metabolomics using blotted samples in filter paper is a simple, low-cost approach to identify outcomes associated with DKD; the inclusion of metabolomics improves predictive capacity of clinical models to identify kidney dysfunction and DKD-related outcomes.
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Nefropatias Diabéticas/sangue , Metabolômica/métodos , Técnicas de Diagnóstico Molecular/métodos , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/urina , Feminino , Humanos , Masculino , Metaboloma , Metabolômica/normas , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular/normasRESUMO
Rigorous nutritional care during early life leads to healthy adulthood. Cardiovascular and metabolic disorders, the most prevalent clinical challenges worldwide, are epidemiologically linked to poor nutritional habits throughout life. We aimed to understand whether postnatal overnutrition (PO) initiated during lactation affects metabolic markers and vascular function later in life. To test this hypothetical effect, we studied a PO Wistar rat model based on adjusting litter size at the third day of age to three pups and eight for the control group (C). Systemic parameters such as body weight and food intake were significantly increased in adult rats, measured up to 36 weeks. Moreover, fat mass, triglycerides, insulin and systolic blood pressure were all significantly increased in the PO group. Furthermore, we assessed whether these alterations would affect morphological and functional parameters in isolated vessels. Consistent with systemic alterations of the vasculature, contraction of thoracic aortic rings, determined by dose-response curves to norepinephrine (NE), was significantly reduced in PO rats. Histological stains revealed that the relative area of collagen was higher and the elastic fiber density was lower in the distal rings of PO rats. Altogether, our results highlight the critical importance of having a healthy neonatal nutrition to prevent harmful metabolic and vascular alterations during adulthood.
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Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Hipernutrição/fisiopatologia , Adiposidade , Animais , Animais Recém-Nascidos , Pressão Sanguínea , Peso Corporal , Modelos Animais de Doenças , Ingestão de Alimentos , Feminino , Insulina/sangue , Lactação , Tamanho da Ninhada de Vivíparos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Sístole , Triglicerídeos/sangue , Vasoconstritores/farmacologiaRESUMO
BACKGROUND: Genetic variations of the TCF7L2 gene are associated with the development of Type 2 diabetes (T2D). The associated mutations have demonstrated an adaptive role in some human populations, but no studies have determined the impact of evolutionary forces on genetic diversity in indigenous populations from Mexico. Here, we sequenced and analyzed the variation of the TCF7L2 gene in three Amerindian populations and compared the results with whole-exon-sequencing of Mestizo populations from Sigma and the 1000 Genomes Project to assess the roles of selection and recombination in diversity. RESULTS: The diversity in the indigenous populations was biased to intronic regions. Most of the variation was low frequency. Only mutations rs77961654 and rs61724286 were located on exon 15. We did not observe variation in intronic region 4-6 in any of the three indigenous populations. In addition, we identified peaks of selective sweeps in the mestizo samples from the Sigma Project within this region. By replicating the analysis of association with T2D between case-controls from the Sigma Project, we determined that T2D was most highly associated with the rs7903146 risk allele and to a lesser extent with the other six variants. All associated markers were located in intronic region 4-6, and their r(2) values of linkage disequilibrium were significantly higher in the Mexican population than in Africans from the 1000 Genomes Project. We observed reticulations in both the haplotypes network analysis from seven marker associates and the neighborNet tree based on 6061 markers in the TCF7L2 gene identified from all samples of the 1000 Genomes Project. Finally, we identified two recombination hotspots in the upstream region and 3' end of the TCF7L2 gene. CONCLUSIONS: The lack of diversity in intronic region 4-6 in Indigenous populations could be an effect of selective sweeps generated by the selection of neighboring rare variants at T2D-associated mutations. The survivors' variants make the intronic region 4-6 the area of the greatest population differentiation within the TCF7L2 gene. The abundance of selective peak sweeps in the downstream region of the TCF7L2 gene suggests that the TCF7L2 gene is part of a region that is in constant recombination between populations.
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Etnicidade/genética , Íntrons/genética , Polimorfismo Genético , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Diabetes Mellitus Tipo 2/genética , Éxons/genética , Humanos , México/etnologia , Mutação , Recombinação GenéticaRESUMO
Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention.
Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention.
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Calpaína/genética , HDL-Colesterol/sangue , Fibras na Dieta , Dislipidemias/sangue , Dislipidemias/genética , Variação Genética , Proteínas de Soja , Adulto , Diabetes Mellitus Tipo 2 , Dislipidemias/dietoterapia , Feminino , Genótipo , Humanos , Masculino , México , Estudos ProspectivosRESUMO
Several studies have identified nearly 40 different type 2 diabetes susceptibility loci, mainly in European populations, but few of them have been evaluated in the Mexican population. The aim of this study was to examine the extent to which 24 common genetic variants previously associated with type 2 diabetes are associated in Mexican Mestizos. Twenty-four single nucleotide polymorphisms (SNPs) in or near genes (KCNJ11, PPARG, TCF7L2, SLC30A8, HHEX, CDKN2A/2B, CDKAL1, IGF2BP2, ARHGEF11, JAZF1, CDC123/CAMK1D, FTO, TSPAN8/LGR5, KCNQ1, THADA, ADAMTS9, NOTCH2, NXPH1, RORA, UBQLNL, and RALGPS2) were genotyped in Mexican Mestizos. A case-control association study comprising 1,027 type 2 diabetic individuals and 990 control individuals was conducted. To account for population stratification, a panel of 104 ancestry-informative markers was analyzed. Association to type 2 diabetes was found for rs13266634 (SLC30A8), rs7923837 (HHEX), rs10811661 (CDKN2A/2B), rs4402960 (IGF2BP2), rs12779790 (CDC123/CAMK1D), and rs2237892 (KCNQ1). In addition, rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes. Lack of association for the rest of the variants may have resulted from insufficient power to detect smaller allele effects.
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Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/genética , Proteínas de Transporte de Cátions/genética , Quinase 5 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Canal de Potássio KCNQ1/genética , Masculino , México , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Fatores de Transcrição/genética , Transportador 8 de Zinco , tRNA MetiltransferasesRESUMO
Mexico is developing the basis for genomic medicine to improve healthcare of its population. The extensive study of genetic diversity and linkage disequilibrium structure of different populations has made it possible to develop tagging and imputation strategies to comprehensively analyze common genetic variation in association studies of complex diseases. We assessed the benefit of a Mexican haplotype map to improve identification of genes related to common diseases in the Mexican population. We evaluated genetic diversity, linkage disequilibrium patterns, and extent of haplotype sharing using genomewide data from Mexican Mestizos from regions with different histories of admixture and particular population dynamics. Ancestry was evaluated by including 1 Mexican Amerindian group and data from the HapMap. Our results provide evidence of genetic differences between Mexican subpopulations that should be considered in the design and analysis of association studies of complex diseases. In addition, these results support the notion that a haplotype map of the Mexican Mestizo population can reduce the number of tag SNPs required to characterize common genetic variation in this population. This is one of the first genomewide genotyping efforts of a recently admixed population in Latin America.