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.

The role of SLC16A11 variations in diabetes mellitus.

PURPOSE OF REVIEW: The aim of this study was to summarize the existing evidence that proves the association between an ethnic-specific SLC16A11 risk haplotype and type 2 diabetes found in the Latin American population. RECENT FINDINGS: The association has been replicated in consortia studies, especially in early-onset type 2 diabetes. No association has been found with gestational diabetes. Mild obesity-related diabetes is the most common T2D subphenotype found in patients with the risk haplotype. The SLC16A11 risk haplotype is associated with decreased insulin action, higher acute insulin secretory response to an intravenous glucose bolus and higher serum alanine aminotransferase levels. SUMMARY: The study of underrepresented populations in large genomic databases is a valuable resource to gain new knowledge about the pathophysiology of complex traits, especially if these groups have suffered repeated selection process caused by famine, migrations and war. This is the case of diabetes, obesity and lipid disorders in Latin American countries. Here, we summarize the existing evidence of a proof-of concept finding: the association between the SLC16A11 ethnic-specific risk haplotype and T2D.

A novel nonsense mutation in the insulin receptor gene in a patient with HAIR-AN syndrome and endometrial cancer.

Severe insulin resistance can be caused by rare genetic defects in the insulin receptor known as insulin receptoropathies. These genetic defects cause a wide spectrum of clinical manifestations ranging from mild syndromes to lethal disorders. Among those is the HAIR-AN an extreme subtype of polycystic ovary syndrome (PCOS). We present a case of a 29-year-old woman with amenorrhea, severe insulin resistance, hirsutism, and acanthosis nigricans who also developed endometrial cancer. She was found to carry a novel heterozygous nonsense mutation insulin receptor gene (INSR). The mutation was inherited from the mother. Levels of insulin receptor and AKT were measured using Western-Blot from peripheral blood mononuclear cells and were both decreased. Thus, we conclude that the identified mutation in the insulin receptor gene and lead to decreased activity of the downstream signaling of the insulin pathway.

Salir adelante: subjetividades políticas en primera infancia y familias en el destierro / Moving forward: Political subjectivities in early childhood and families in exile / Seguindo em frente: subjetividades políticas na primeira infância e famílias em situação de desterro

Resumen (analítico) Se presentan resultados de una investigación que problematiza el proceso de construcción de subjetividades políticas de niños y niñas de primera infancia cuyas familias han vivido el conflicto armado colombiano. Epistémica y metodológicamente se empleó la hermenéutica ontológica política, enfatizando las narrativas colectivas y generativas de 19 niñas, 25 niños, 23 madres, 7 padres, 15 maestras y 1 maestro, en dos Centros de Desarrollo Infantil en Bogotá y Pereira. Se encontró que salir adelante -como metáfora que da cuenta de las subjetividades de los niños y las niñas- involucra una opción por las relaciones, romper la homogeneización, prácticas de resistencia y re-existencia y constitución de subjetividades e identidades políticas. Se concluye que los niños y las niñas tienen disposiciones relacionales como sujetos políticos desde sus primeros años.

Abstract (analytical) The article presents the results of a research study that aimed to comprehend and strengthen the political subjectivities of children in early childhood whose families come from the context of armed conflict. Epistemically and methodologically, the research used political and performative ontological hermeneutics. It had an emphasis on the collective and generative narratives of 19 girls, 25 boys, 23 mothers, 7 fathers, 15 female teacher and 1 male teacher in two child care centers in Bogotá and Pereira. The results showed that "moving forward", as a metaphor that refers to children's subjectivities, involves an option for relationships, eliminates homogenization, and prompts resistance and re-existence practices, as well as the constitution of political subjectivities and identities. Participants concluded that the children's lives deserve to be lived because of their condition of humanity.

Resumo (analítico) São apresentados resultados de uma investigação orientada para entender e fortalecer subjetividades políticas em meninos e meninas da primeira infância cujas famílias são originárias do conflito armado. Utilizou-se a hermenêutica ontológica política ou performativa, epistemológica e metodológica, com ênfase nas narrativas coletivas e generativas de 19 meninas, 25 meninos, 23 mães, 7 pais, 15 professores e uma professora, em dois centros de desenvolvimento infantil em Bogotá e Pereira. Verificou-se que avançar como uma metáfora responsável pelas subjetividades de meninos e meninas envolve uma opção de relacionamento, rompendo com a homogeneização, práticas de resistência e reexistência e constituição de subjetividades e identidades políticas. Conclui-se que a vida de meninos e meninas merece ser vivida em virtude de sua condição humana.

Critical role of acute hypoxemia on the cognitive impairment after severe COVID-19 pneumonia: a multivariate causality model analysis.

BACKGROUND: A high proportion of coronavirus disease 2019 (COVID-19) survivors may develop long-term cognitive impairment. We aimed to develop a multivariate causal model exposing the links between COVID-19-associated biomarkers, illness-related variables, and their effects on cognitive performance. METHODS: In this prospective study, we assess the potential drivers for the development of cognitive impairment in patients with severe COVID-19 pneumonia aged ≥ 18 years at 6-month follow-up after hospital discharge, using the Montreal Cognitive Assessment (MoCA). Patients with pre-existing cognitive impairment were excluded. Laboratory results at hospital admission were clustered by principal component analysis (PCA) and included in a path analysis model evaluating the causal relationship between age, comorbidities, hypoxemia, invasive mechanical ventilation (IMV) requirement, in-hospital delirium, and cognitive performance. RESULTS: We studied 92 patients: 54 (58.7%) men and 38 (41.3%) women, with median age of 50 years (interquartile range 42-55), among whom 50 (54.4%) tested positive for cognitive impairment at 6-month follow-up. Path analysis revealed a direct link between the thrombo-inflammatory component of PCA (C-reactive protein, fibrinogen, and neutrophils) and hypoxemia severity at hospital admission. Our model showed that low PaO2/FiO2 ratio values, unlike the thrombo-inflammatory component, had a direct effect on cognitive performance, independent from age, in-hospital delirium, and invasive mechanical ventilation. CONCLUSION: In this study, biomarkers of thrombo-inflammation in COVID-19 and low PaO2/FiO2 had a negative effect on cognitive performance 6 months after hospital discharge. These results highlight the critical role of hypoxemia as a driver for impaired cognition in the mid-term.

Factores de riesgo en pacientes con fisura de labio y paladar en México. Estudio en 209 pacientes / Risk factors associated with cleft lip and palate in Mexico. A 209 patient analysis

Introducción y objetivo: El labio hendido (con o sin paladar hendido asociado) y el paladar hendido aislado afectan a 1 de cada 600 recién nacidos en el mundo. Su etiología es multifactorial e intervienen factores de medioambiente, sociodemográficos y genéticos.El objetivo del presente estudio es establecer una relación entre los distintos tipos de fisuras labio-palatinas y diversos factores de riesgo asociados a su prevalencia en México.Material y método.Estudiamos 209 pacientes de diferentes edades con diagnóstico de labio y paladar hendido, atendidos en hospitales generales públicos y privados de las regiones del norte, centro y sur de la república mexicana. Obtuvimos los datos de los pacientes a través de entrevistas a madres o tutores en los menores de edad y por entrevista directa a los mayores de edad.Resultados.El 47.8% fueron mujeres. La edad promedio fue de 8.9 ± 7.3 años. Del total, 163 (78%) tenían diagnóstico de fisura labio-palatina, y 46 (22%) de fisura de labio o paladar aislados. La edad de la madre al momento del embarazo infuyó en la mayor prevalencia de la fisura labio-palatina. Los antecedentes familiares de fisuras labio-palatinas también determinaron mayor porcentaje de pacientes con labio + paladar hendido que con el padecimiento aislado (41.1% frente a 26.1% respectivamente).Conclusiones.Consideramos que, dado que la edad de la madre al momento del embarazo es un factor directamente asociado a la prevalencia de la fisura labio-palatina, los estudios derivados de Salud Pública son fundamentales, particularmente aquellos que tratan sobre el embarazo de alto riesgo (madre adolescente y madre de edad avanzada). (AU)

Background and objective: Cleft lip and palate are associated with several factors including demographic and genetic factors among others. The estimated prevalence of the disease is 1-600 worldwide.Our aim is to study the relationship between the prevalence of cleft lip and palate and several factors associated to the disease in Mexico.Methods.A total of 209 patients with cleft lip and palate (isolated or combined) were included. Patients were referred from both public and private hospitals. Data were collected through direct interview and questionnaire with patientes´ mother or parent.Results.In our study, 47.8% patients were female. Mean age was 8.9 ± 7.3 years old; 163 patients (78%) had a combined cleft-lip and palate, and 46 (22%) had an isolated cleft lip or palate. Mother´s age was directly associated with the prevalence of cleft lip and palate. The history of facial clefts in the family was also directly related to the presence of a combined cleft, in contrast to an isolated cleft. (41.1% vs 26.1% respectively).Conclusions.In our study, both cleft lip and palate were directly related to the age of the mother. Thus, we believe that future studies should address the importance of preventive measures and treatment in the woman with a high-risk pregnancy (such as adolescent teens with pregnancy and elderly women). (AU)

Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes.

BACKGROUND: Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. METHODS: We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. RESULTS: Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. CONCLUSIONS: Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.

Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia.

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

Serial femtosecond crystallography on in vivo-grown crystals drives elucidation of mosquitocidal Cyt1Aa bioactivation cascade.

Cyt1Aa is the one of four crystalline protoxins produced by mosquitocidal bacterium Bacillus thuringiensis israelensis (Bti) that has been shown to delay the evolution of insect resistance in the field. Limiting our understanding of Bti efficacy and the path to improved toxicity and spectrum has been ignorance of how Cyt1Aa crystallizes in vivo and of its mechanism of toxicity. Here, we use serial femtosecond crystallography to determine the Cyt1Aa protoxin structure from sub-micron-sized crystals produced in Bti. Structures determined under various pH/redox conditions illuminate the role played by previously uncharacterized disulfide-bridge and domain-swapped interfaces from crystal formation in Bti to dissolution in the larval mosquito midgut. Biochemical, toxicological and biophysical methods enable the deconvolution of key steps in the Cyt1Aa bioactivation cascade. We additionally show that the size, shape, production yield, pH sensitivity and toxicity of Cyt1Aa crystals grown in Bti can be controlled by single atom substitution.

Use of PCSK9 Inhibitor in a Mexican Boy with Compound Heterozygous Familial Hypercholesterolemia: A Case Report.

We report on the case of an 8-year-old Mexican male, with a 3-year-old clinical diagnosis of familial hypercholesterolemia, and the difficulties encountered in his treatment while in our care. His treatment started with a regimen consisting of ezetimibe/simvastatin, cholestyramine, and a dietary plan of 1600 calories, with a limited intake of 200 mg of cholesterol per day. Problems arose when the patient's low-density lipoprotein cholesterol (LDL) levels did not meet ideal targets, which prompted the use of LDL cholesterol apheresis (not available in Mexico) for 6 months. As a last resort, PCSK9 inhibitors were administered but the LDL levels remained in the 600 mg/dL range. AmbryGenetics conducted a genetic test employing the Sanger method. The results suggested that there were 2 different mutations for each allele of the same LDL receptor gene (c.249delTinsGG and p.(Cys109Arg)), located in exons 3 and 4, respectively. We identified compound heterozygous mutations in our index case, with him having both the p.C109R mutation (from the maternal lineage), as well as a c.249delTinsGG mutation (from the paternal lineage). The p.C109R mutation has been previously reported, not only in Mexico, but in European regions (Germany, Czech Republic, Ireland, Italy) as well. Functional studies indicated a residual enzymatic activity of 15% to 30% for heterozygotes. To date, the variant c.249delTinsGG has not been reported. This case study illustrates the fact that in Mexico there are limited options available for treatment in such a scenario. As medical professionals, we are limited by the tools at our disposal.

Development and validation of a predictive model for incident type 2 diabetes in middle-aged Mexican adults: the metabolic syndrome cohort.

BACKGROUND: Type 2 diabetes mellitus (T2D) is a leading cause of morbidity and mortality in Mexico. Here, we aimed to report incidence rates (IR) of type 2 diabetes in middle-aged apparently-healthy Mexican adults, identify risk factors associated to ID and develop a predictive model for ID in a high-risk population. METHODS: Prospective 3-year observational cohort, comprised of apparently-healthy adults from urban settings of central Mexico in whom demographic, anthropometric and biochemical data was collected. We evaluated risk factors for ID using Cox proportional hazard regression and developed predictive models for ID. RESULTS: We included 7636 participants of whom 6144 completed follow-up. We observed 331 ID cases (IR: 21.9 per 1000 person-years, 95%CI 21.37-22.47). Risk factors for ID included family history of diabetes, age, abdominal obesity, waist-height ratio, impaired fasting glucose (IFG), HOMA2-IR and metabolic syndrome. Early-onset ID was also high (IR 14.77 per 1000 person-years, 95%CI 14.21-15.35), and risk factors included HOMA-IR and IFG. Our ID predictive model included age, hypertriglyceridemia, IFG, hypertension and abdominal obesity as predictors (Dxy = 0.487, c-statistic = 0.741) and had higher predictive accuracy compared to FINDRISC and Cambridge risk scores. CONCLUSIONS: ID in apparently healthy middle-aged Mexican adults is currently at an alarming rate. The constructed models can be implemented to predict diabetes risk and represent the largest prospective effort for the study metabolic diseases in Latin-American population.

Toxicity of Bacillus thuringiensis-Derived Pesticidal Proteins Cry1Ab and Cry1Ba against Asian Citrus Psyllid, Diaphorina citri (Hemiptera).

The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera), is an important pest of citriculture. The ACP vectors a bacterium that causes huanglongbing (HLB), a devastating and incurable disease of citrus. The bacterium Bacillus thuringiensis (Bt) produces multiple toxins with activity against a diverse range of insects. In efforts to provide additional control methods for the ACP vector of HLB, we identified pesticidal proteins derived from Bt for toxicity against ACP. The trypsin proteolytic profiles of strain-derived toxins were characterized. Strain IBL-00200, one of six strains with toxins shown to have basal activity against ACP was selected for liquid chromatography-mass spectrometry (LC-MS/MS) identification of the individual Cry toxins expressed. Toxicity assays with individual toxins derived from IBL-00200 were then performed. The activated form of the Cry toxins Cry1Ab and Cry1Ba were toxic to ACP with LC50 values of approximately 120 µg/mL. Disruption of the midgut epithelium was associated with the toxicity of both the IBL-00200-derived toxin mixture, and with Cry1Ba. With further optimization of the efficacy of Cry1Ab and Cry1Ba, these toxins may have practical utility against ACP. Bt toxins with activity against ACP may provide an additional tool for management of ACP and the associated HLB disease, thereby providing a more sustainable and environmentally benign approach than repeated application of broad-spectrum insecticides.

Prevalence of germline mutations in the TP53 gene in patients with early-onset breast cancer in the Mexican population.

BACKGROUND: Heterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. An important issue related to BC in the Mexican population is the average age at diagnosis, which is approximately 11 years younger than that of patients in the United States (U.S.) and Europe. The aim of this study was to determine the prevalence of germline mutations in TP53 among young Mexican BC patients. METHODS: We searched for germline mutations in the TP53 gene using targeted next-generation sequencing (NGS) in 78 BC patients younger than 45 years old (yo) who tested negative for BRCA1/2 mutations. A group of 509 Mexican women aged 45yo or older without personal or family BC history (parents/grandparents) was used as a control. RESULTS: We identified five patients with pathogenic variants in the TP53 gene, equivalent to 6.4% (5/78). Among patients diagnosed at age 36 or younger, 9.4% (5/55) had pathogenic TP53 mutations. Three of these variants were missense mutations (c.844C > T, c.517G > A, and c.604C > T), and the other two mutations were frameshifts (c.291delC and c.273dupC) and had not been reported previously. We also identified a variant of uncertain clinical significance (VUS), c.672G > A, which causes a putative splice donor site mutation. All patients with TP53 mutations had high-grade and HER2-positive tumors. None of the 509 patients in the healthy control group had mutations in TP53. CONCLUSIONS: Among Mexican BC patients diagnosed at a young age, we identified a high proportion with germline mutations in the TP53 gene. All patients with the TP53 mutations had a family history suggestive of LFS. To establish the clinical significance of the VUS found, additional studies are needed. Pathogenic variants of TP53 may explain a substantial fraction of BC in young women in the Mexican population. Importantly, none of these mutations or other pathological variants in TP53 were found in the healthy control group.

The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-size adipocytes.

Objective A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk. Design Cross-sectional study. Methods We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic-hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies. Results Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (ß = -0.164, P = 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P = 0.02) and of 7.34 U/L in gamma-glutamyltransferase (GGT) (P = 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P < 0.001). Conclusions Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.

DYSLIPIDEMIA IN MEXICO, A CALL FOR ACTION.

The purpose of this manuscript is to highlight the peculiarities of the Mexican population regarding the clinical expression, genetics, and treatment of lipid disorders. Furthermore, it is a call for action to address the existing gaps in care and research of dyslipidemias. The Mexican Mestizos are highly susceptible to metabolic disorders (i.e., low high-density lipoprotein cholesterol concentrations, hypertriglyceridemia, abdominal obesity, and type 2 diabetes); these conditions are associated with ethnic-specific genetic variants. On the other hand, despite the high prevalence of dyslipidemia in Mexican adults, there is a lack of awareness of these conditions. The public is not informed about the need for screening and the potential benefit of the lipid-lowering treatments. Underdiagnosis and undertreatment are two of the main challenges to be solved. Dyslipidemias are not among the priorities of the health systems for the prevention of cardiovascular disease; access to laboratory resources and medications is insufficient in primary care units despite the proven cost-benefit of the treatment of lipid disorders. Evidence-based public policies are needed to change the practice and allocation of assets to be capable of preventing cardiovascular diseases. Treatment of dyslipidemia should have a prominent role in any effort to decrease the number of preventable deaths caused by non-communicable diseases.

Mexican Carriers of the HNF1A p.E508K Variant Do Not Experience an Enhanced Response to Sulfonylureas.

OBJECTIVE: To assess whether an ethnic-specific variant (p.E508K) in the maturity-onset diabetes of the young (MODY) gene hepatocyte nuclear factor-1α (HNF1A) found in Mexicans is associated with higher sensitivity to sulfonylureas, as documented in patients with MODY3. RESEARCH DESIGN AND METHODS: We recruited 96 participants (46 variant carriers and 50 age- and sex-matched noncarriers). Response to glipizide (one 2.5-5.0-mg dose), metformin (four 500-mg doses), and an oral glucose challenge was evaluated using a previously validated protocol. Glucose and insulin levels and their areas under the curve (AUCs) were compared between groups. RESULTS: Carriers of the p.E508K variant had a lower maximum insulin peak during the glipizide challenge as compared with noncarriers with diabetes (P < 0.05). Also, carriers had a lower insulin response after the oral glucose challenge. Following an oral glucose tolerance test in the presence of metformin, carriers of the p.E508K variant with diabetes had a lower maximum insulin peak and total and incremental insulin AUC value as compared with noncarriers with diabetes (P < 0.05). A similar but nonsignificant trend was seen in participants without type 2 diabetes. CONCLUSIONS: Carriers of variant p.E508K in HNF1A have a reduced insulin response rather than the increased sensitivity to sulfonylureas seen in patients with MODY3.

The panorama of familial hypercholesterolemia in Latin America: a systematic review.

The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified.