Mexican Biobank advances population and medical genomics of diverse ancestries.

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.

A haplotype in the dipeptidyl peptidase 4 gene impacts glycemic-related traits of Brazilian older adults.

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.

Butaphosphan Effects on Glucose Metabolism Involve Insulin Signaling and Depends on Nutritional Plan.

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.

Prevalencia de alteraciones del metabolismo glucídico en familiares de primer grado de pacientes diabéticos tipo 2 / Prevalence of glucidic metabolism alterations in first- degree relatives of type 2 diabetic patients

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)

The Relationship of Single Nucleotide Polymorphisms in the TRPV1 Gene with Lipid Profile, Glucose, and Blood Pressure in Mexican Population.

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.

Genomic ancestry and glycemic control in adolescents with type 1 diabetes: A multicenter study in Brazil.

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.

Polymorphism of the THOC5 of the transcription/export multiprotein complex and its correlation with the lipid and metabolic profile in middle-aged women.

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.

[Association of the TCF7L2 (RS7903146) genotype with adiposity and metabolic markers in the Chilean adult population]. / Asociación del polimorfismo rs7903146, del gen TCF7L2, con marcadores de adiposidad y metabólicos en población chilena - resultados del estudio GENADIO.

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.

Asociación del polimorfismo rs7903146, del gen TCF7L2, con marcadores de adiposidad y metabólicos en población chilena - resultados del estudio GENADIO / Association of the TCF7L2 (RS7903146) genotype with adiposity and metabolic markers in the Chilean adult population

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.

Altered Glycemic Control Associated With Polymorphisms in the SLC22A1 (OCT1) Gene in a Mexican Population With Type 2 Diabetes Mellitus Treated With Metformin: A Cohort Study.

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.

Genetic susceptibility to pre diabetes mellitus and related association with obesity and physical fitness components in Mexican-Mestizos.

Pre diabetes mellitus (pre-DM) is considered an early-reversible condition that can progress to Type 2 diabetes mellitus (T2DM) which is the main cause of death for adult Mexican population. Gene variants influencing fasting glucose levels may constitute helpful tool for prevention purposes in pre-DM condition. Physically active Mexican-Mestizo adults (n=565) were genotyped for 6 single nucleotide polymorphisms (SNPs) (ADIPOQ rs2241766, ACSL1 rs9997745, LIPC rs1800588, PPARA rs1800206, PPARG rs1801282 and PPARGC1A rs8192678) related to lipid and carbohydrate metabolism. Fasting glucose was measured and values classified as pre-DM (≥100mg/dL) or normal fasting glucose. Logistic models were used to test associations between pre-DM condition and SNPs, and interaction with Body Mass Index (BMI) and physical fitness components. The A allele of ASCL1 rs9997745 conferred increased risk (OR=3.39, p=0.001) of pre-DM which is modulated by BMI. The A allele of the PPARGC1A rs8192678 showed significant SNP*BMI (OR=1.10, p=0.008) interaction effect for pre-DM risk, meaning that obese subjects showed higher pre-DM risk but normal weight subjects showed lower risk. The effect increased with age and was attenuated by higher cardiorespiratory values. We found that both ACSL1 rs9997745 and PPARGC1A rs8192678 are associated with pre-DM, and that BMI significantly modified their association.

CYP2C9*3 gene variant contributes independently to glycaemic control in patients with type 2 diabetes treated with glibenclamide.

WHAT IS KNOWN AND OBJECTIVE: Glibenclamide is a prescribed glucose-lowering medication for diabetes, but there are interindividual variations in the therapeutic response. In this cross-sectional study, the aim was to explore the association of genetic variants in CYP2C9, ABCC8, KCNJ11 and TCF7L2 with good glycaemic control in Mexican type 2 diabetes (T2D) treated with glibenclamide. METHODS: Patients with T2D receiving treatment with glibenclamide or glibenclamide plus metformin were included. Patients with A1C ≤ 7% were considered to have good glycaemic control, whereas patients with A1C ≥ 8% were considered having poor glycaemic control. Genotyping was performed by real-time PCR using TaqMan probes for the genetic variants. Association was performed by calculating OR with 95% confidence intervals (95% CI). For the multivariate analysis, a multiple logistic regression was performed including the confounding variables age, exercised, BMI, glibenclamide dose, time with T2D and concomitant metformin. RESULTS AND DISCUSSION: Four hundred and four patients were included in the study, median age of the participants was 50 years (IQR 11.0), the median time with disease was 6 years (IQR 8.0), 118 (29.2%) were men, and 243 (60.1%) received glibenclamide in combination with metformin. CYP2C9*3 variant was associated with good glycaemic control (OR = 2.747 [95% CI, 1.194-6.324]), whereas the variants, CYP2C9*2, TCF7L2 rs7903146 and rs12255372, ABCC8 rs757110 and KCNJ11 rs5219, were not. In the multivariate analysis, the CYP2C9*3 variant maintained its association (OR = 2.779 [95% CI, 1.142-6.763]). WHAT IS NEW AND CONCLUSION: The findings suggest that CYP2C9*3 genetic variant independently contributes to good glycaemic control of patients with type 2 diabetes treated with glibenclamide.

Bariatric surgery and gene expression in the gut.

PURPOSE OF REVIEW: The current review provides an overview of recent literature on new findings related to bariatric surgery and gut gene expression. RECENT FINDINGS: Bariatric surgery modulates the expression of intestinal genes. Experimental and clinical investigations have demonstrated the association of gut rearrangement with changes in intestinal expression of genes related to glucose metabolism. Recent data suggest that bariatric surgery also affects expression of genes belonging to other pathways, including nutrient transporters and metabolism of vitamin B12, decreasing pathway-encoding genes that may contribute to vitamin B12 deficiency in the postoperative period. SUMMARY: Bariatric surgery is an effective intervention strategy against severe obesity, resulting in sustained weight loss and reduction of comorbidities. Nutritional genomic changes appear in response to bariatric surgery, possibly due to adaptive gut response. Improved understanding of the molecular pathways modulated by this intervention may facilitate weight and comorbidities management.

Evaluating the transferability of 15 European-derived fasting plasma glucose SNPs in Mexican children and adolescents.

Genome wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) that are associated with fasting plasma glucose (FPG) in adult European populations. The contribution of these SNPs to FPG in non-Europeans and children is unclear. We studied the association of 15 GWAS SNPs and a genotype score (GS) with FPG and 7 metabolic traits in 1,421 Mexican children and adolescents from Mexico City. Genotyping of the 15 SNPs was performed using TaqMan Open Array. We used multivariate linear regression models adjusted for age, sex, body mass index standard deviation score, and recruitment center. We identified significant associations between 3 SNPs (G6PC2 (rs560887), GCKR (rs1260326), MTNR1B (rs10830963)), the GS and FPG level. The FPG risk alleles of 11 out of the 15 SNPs (73.3%) displayed significant or non-significant beta values for FPG directionally consistent with those reported in adult European GWAS. The risk allele frequencies for 11 of 15 (73.3%) SNPs differed significantly in Mexican children and adolescents compared to European adults from the 1000G Project, but no significant enrichment in FPG risk alleles was observed in the Mexican population. Our data support a partial transferability of European GWAS FPG association signals in children and adolescents from the admixed Mexican population.

Símdrome de Silver-Russell (hemihipertrofia) y cor triatriatum en un neonato / Silver-Russell syndrome (hemihypertrophy) and cor triatriatum in a newborn

Tanto el síndrome de hemihipertrofia como el cor triatriatum son patologías sumamente infrecuentes. La hemihipertrofia se define como el sobrecrecimiento completo o parcial de uno de los hemicuerpos. El cor triatriatum es una cardiopatía congénita caracterizada por una membrana que divide la aurícula izquierda en dos cámaras; si esta membrana tiene un orificio restrictivo, provoca obstrucción al pasaje sanguíneo desde las venas pulmonares hacia el ventrículo izquierdo, lo que genera hipertensión y edema pulmonar. En este contexto, el ductus arterioso permeable puede actuar como vía de descompresión del circuito pulmonar al permitir el pasaje sanguíneo desde la arteria pulmonar hacia la aorta. Presentamos a un paciente con diagnóstico de síndrome de Silver-Rusell (hemihipertrofia), cor triatriatum y ductus arterioso con flujo invertido. Hasta donde conocemos, esta asociación de patologías infrecuentes y forma de presentación no se han descrito anteriormente.

Hemihypertrophy syndrome and cor triatriatum are extremely rare pathologies. Hemihypertrophy is defined as complete or partial overgrowth of one of the hemibodies. Cor triatriatum is a congenital heart disease characterized by a membrane which separates the left atrium into two chambers; if that membrane has a restrictive hole, it causes obstruction to blood passage from the pulmonary veins into the left ventricle causing hypertension and pulmonary edema. In this context, the patent ductus arteriosus can act as a means of decompression of the pulmonary circuit, because it allows the blood passage from the pulmonary artery to the aorta. We report a patient with Silver-Rusell syndrome (hemihypertrophy), cor triatriatum and ductus arteriosus with reverse flow. To our knowledge, this association of rare pathologies and this clinical presentation have not been described previously.

Símdrome de Silver-Russell (hemihipertrofia) y cor triatriatum en un neonato / Silver-Russell syndrome (hemihypertrophy) and cor triatriatum in a newborn

Tanto el síndrome de hemihipertrofia como el cor triatriatum son patologías sumamente infrecuentes. La hemihipertrofia se define como el sobrecrecimiento completo o parcial de uno de los hemicuerpos. El cor triatriatum es una cardiopatía congénita caracterizada por una membrana que divide la aurícula izquierda en dos cámaras; si esta membrana tiene un orificio restrictivo, provoca obstrucción al pasaje sanguíneo desde las venas pulmonares hacia el ventrículo izquierdo, lo que genera hipertensión y edema pulmonar. En este contexto, el ductus arterioso permeable puede actuar como vía de descompresión del circuito pulmonar al permitir el pasaje sanguíneo desde la arteria pulmonar hacia la aorta. Presentamos a un paciente con diagnóstico de síndrome de Silver-Rusell (hemihipertrofia), cor triatriatum y ductus arterioso con flujo invertido. Hasta donde conocemos, esta asociación de patologías infrecuentes y forma de presentación no se han descrito anteriormente.(AU)

Hemihypertrophy syndrome and cor triatriatum are extremely rare pathologies. Hemihypertrophy is defined as complete or partial overgrowth of one of the hemibodies. Cor triatriatum is a congenital heart disease characterized by a membrane which separates the left atrium into two chambers; if that membrane has a restrictive hole, it causes obstruction to blood passage from the pulmonary veins into the left ventricle causing hypertension and pulmonary edema. In this context, the patent ductus arteriosus can act as a means of decompression of the pulmonary circuit, because it allows the blood passage from the pulmonary artery to the aorta. We report a patient with Silver-Rusell syndrome (hemihypertrophy), cor triatriatum and ductus arteriosus with reverse flow. To our knowledge, this association of rare pathologies and this clinical presentation have not been described previously.(AU)

FTO gene variants are not associated with polycystic ovary syndrome in women from Southern Brazil.

BACKGROUND AND AIMS: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, presenting polygenic traits as well as determined by environmental factors. Given the overlap between PCOS and obesity, we assessed the frequencies of SNPs rs9939609 and rs8050136 in intron 1 of the FTO gene and their haplotypes in women with PCOS and healthy controls with regular cycles from Southern Brazil and investigated their relationship with metabolic traits and endocrine parameters. SUBJECTS AND METHODS: The sample comprised 298 women (199 with PCOS and 99 non-hirsute women with regular ovulatory cycles). FTO genotyping was done by real-time PCR. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using PHASE 2.1.1 software. RESULTS: The distribution of rs9939609 (PCOS: 32.6% TT, 45.9% TA, 21.5% AA; controls: 33.3% TT, 49.0% TA, 17.7% AA) and rs8050136 (PCOS: 21.7% AA, 43.3% AC, 35.0% CC; controls: 14.9% AA, 48.9% AC, 36.2% CC) was similar between groups. The mean age of participants was 22.7±7.1years. Women with PCOS had significantly higher BMI, waist circumference, total testosterone, and FAI vs. controls. In the PCOS group, no differences between genotypes and haplotypes were found for clinical variables. The presence of at least one risk allele for polymorphisms rs9939609 and rs8050136 was associated with higher fasting glucose levels. CONCLUSION: Our findings indicate that neither the FTO rs9939609 and rs8050136 polymorphisms nor its haplotypes are related to PCOS, but suggest an association between the presence of risk alleles of SNPs rs9939609 and rs8050136 in FTO and glucose levels in women from Southern Brazil.

Estrogen receptor αlpha gene (ESR1) PvuII and XbaI polymorphisms are associated to metabolic and proinflammatory factors in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that involves multiple factors. Although the etiology of PCOS is unknown, there is an involvement of sex steroid hormones in the pathophysiology of this syndrome. Therefore, polymorphisms in genes involved in the action of estrogen may contribute to a woman's susceptibility to PCOS. AIM: This study aimed to evaluate the association between the polymorphisms PvuII and XbaI in the estrogen receptor alpha (ESR1) gene and the occurrence of PCOS. The study also aimed to assess the influence of these polymorphisms on the metabolic and inflammatory profiles of women with PCOS. MATERIAL AND METHODS: This case-control study included 99 women with PCOS, diagnosed according to the Rotterdam criteria, and 104 age-matched healthy women. The polymorphisms were evaluated using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: No association between the ESR1 gene polymorphisms and the presence of PCOS was observed. However, we found associations between the PvuII polymorphism and C-reactive protein levels, testosterone levels, family history of diabetes, and waist circumference. The XbaI polymorphism was associated with fasting glucose and a family history of hypertension. CONCLUSION: These polymorphisms are not associated with PCOS development, but they are involved in the phenotype of complications of the syndrome. Therefore, prior knowledge of these genomic variants might contribute to taking preventive measures that could delay the metabolic and reproductive complications commonly seen in women with PCOS.

Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

Recovery of insulin sensitivity and Slc2a4 mRNA expression depend on T3 hormone during refeeding.

OBJECTIVE: GLUT4 protein, encoded by the Slc2a4 gene, plays a key role in muscle glucose uptake, and its expression decreases in muscles under insulin resistance. Slc2a4/GLUT4 decreases with fasting and rapidly increases with refeeding and the same occurs to plasma glucose, amino acids, insulin and T3. Thus, they might be potential regulators of the Slc2a4 gene, which makes them promising targets for strategies to improve GLUT4 expression. Herein, we investigate the role of metabolic-hormonal parameters triggered by refeeding upon the Slc2a4 expression. MATERIALS/METHODS: Plasma glucose/insulin/T3, and gastrocnemius Slc2a4 mRNA contents were measured in rats studied at the end of 48-h fasting, and subsequently at: i) 2-4h after spontaneous refeeding; ii) 2-4h after T3 injection, without refeeding; and iii) 0.5-2h after intravenous infusion of insulin, insulin+glucose and insulin+amino acids, without refeeding. RESULTS: Refeeding increased plasma glucose/insulin/T3 and muscle Slc2a4 mRNA, reverting insulin resistance. Post-fasting infusions surprisingly induced a further Slc2a4 mRNA decrease (~20%, P<0.05 vs. fasting), but T3 injection induced a ~2-fold increase in Slc2a4 mRNA, 2-4h later (P<0.001). Moreover, T3 increased glycemia and insulinemia to the 2h-refed rats levels, suggesting that T3 elevation is a key factor to the mechanisms of metabolic balance during refeeding. CONCLUSIONS: Refeeding induces a rapid increase in muscle Slc2a4 expression, not associated with increased plasma glucose, insulin or amino acids, but highly correlated to increased plasma T3 concentration. This result points out T3 hormone as a powerful Slc2a4 enhancer, an effect that may be acutely explored in situations of insulin resistance.