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Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP , ABCA1 , LIPC , and SIDT2 . The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts ( P =5.9×10 −18 in the conjoint analysis). The SIDT2 /Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.

Background & Aims The etiology of nonalcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate kinase (L-PK or Pklr), in NAFLD by using patient samples and mouse models. Methods We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis. After treatment, we measured several metabolic phenotypes including obesity, insulin resistance, dyslipidemia, liver steatosis, and fibrosis. Liver tissues were used for gene expression and immunoblotting, and liver mitochondria bioenergetics was characterized. Results In both mice and humans, L-PK expression is up-regulated in males via testosterone and is strongly associated with NAFLD severity. In a steatosis model, L-PK silencing in male mice improved glucose tolerance, insulin sensitivity, and lactate/pyruvate tolerance compared with controls. Furthermore, these animals had reduced plasma cholesterol levels and intrahepatic triglyceride accumulation. Conversely, L-PK overexpression in male mice resulted in augmented disease phenotypes. In contrast, female mice overexpressing L-PK were unaffected. Mechanistically, L-PK altered mitochondrial pyruvate flux and its incorporation into citrate, and this, in turn, increased liver triglycerides via up-regulated de novo lipogenesis and increased PNPLA3 levels accompanied by mitochondrial dysfunction. Also, L-PK increased plasma cholesterol levels via increased PCSK9 levels. On the other hand, L-PK silencing reduced de novo lipogenesis and PNPLA3 and PCSK9 levels and improved mitochondrial function. Finally, in fibrosis model, we demonstrate that L-PK silencing in male mice reduced both liver steatosis and fibrosis, accompanied by reduced de novo lipogenesis and improved mitochondrial function. Conclusions L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Because NAFLD/nonalcoholic steatohepatitis exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics., Graphical abstract

The efficacy of anti-obesity drugs usually does not consider the high degree of interindividual variability in responses to the drug which could affect the decision to withdraw the drug early due to ineffectiveness or to continue therapy according to specific expectations of success. The aim of this study was to analyze body weight loss in kilograms during the first month (1 mo-BWLkg) of treatment with 30 mg phentermine and development of tolerance to phentermine, on its 6-month efficacy. One hundred sixty-six subjects with obesity were individually or jointly analyzed in the study. Subjects with 1 mo-BWLkg of kg < 3 kg who developed early tolerance did not achieve relevant BWR% (≥5%) at month 6, while the rest of the subgroups achieved increasing and progressive BWR%, according to their 1 mo-BWLkg range and time of onset of tolerance. The 1 mo-BWLkg and development of tolerance to phentermine could be useful to predict the expected 6-month efficacy trends in obese patients treated with 30 mg phentermine.

Dietary fiber (DF) is a major substrate for the gut microbiota that contributes to metabolic health. Recent studies have shown that diet–metabolic phenotype effect might be related to individual gut microbial profiles or enterotypes. Thus, the aim of this study was to examine whether microbial enterotypes modify the association between DF intake and metabolic traits. This cross-sectional study included 204 children (6–12 years old) and 75 adults (18–60 years old). Habitual DF intake was estimated with a Food Frequency Questionnaire and biochemical, clinical and anthropometric data were obtained. Gut microbiota was assessed through 16S sequencing and participants were stratified by enterotypes. Correlations adjusting for age and sex were performed to test the associations between dietary fiber components intake and metabolic traits. In children and adults from the Prevotella enterotype, a nominal negative correlation of hemicellulose intake with insulin and HOMA-IR levels was observed (p &lt, 0.05), while in individuals of the other enterotypes, these associations were not observed. Interestingly, the latter effect was not related to the fecal short-chain-fatty acids profile. Our results contribute to understanding the enterotype influence on the diet–phenotype interaction, which ultimate could provide evidence for their use as potential biomarkers for future precision nutrition strategies.

Summary Changes in the human gut microbiome are associated with obesity and metabolic syndrome, but the role of the gut virome in both diseases remains largely unknown. We characterized the gut dsDNA virome of 28 school-aged children with healthy normal-weight (NW, n = 10), obesity (O, n = 10), and obesity with metabolic syndrome (OMS, n = 8), using metagenomic sequencing of virus-like particles (VLPs) from fecal samples. The virome classification confirmed the bacteriophages' dominance, mainly composed of Caudovirales. Notably, phage richness and diversity of individuals with O and OMS tended to increase, while the VLP abundance remained the same among all groups. Of the 4,611 phage contigs composing the phageome, 48 contigs were highly prevalent in ≥80% of individuals, suggesting high inter-individual phage diversity. The abundance of several contigs correlated with gut bacterial taxa; and with anthropometric and biochemical parameters altered in O and OMS. To our knowledge, this gut phageome represents one of the largest datasets and suggests disease-specific phage alterations., Graphical Abstract, Highlights • The VLP abundance remained the same between normal weight and obesity groups • Increased phage richness and diversity is linked to the disease • Bacteriophages dominated the gut virome with high inter-individual diversity • Differential phage abundances and prevalences are associated with the disease, Biological sciences; Physiology; Microbiology; Virology; Endocrinology; Omics.

Background Elevations of circulating branched-chain amino acids (BCAA) are observed in humans with obesity and metabolic comorbidities, such as insulin resistance. Although it has been described that microbial metabolism contributes to the circulating pool of these amino acids, studies are still scarce, particularly in pediatric populations. Thus, we aimed to explore whether in early adolescents, gut microbiome was associated to circulating BCAA and in this way to insulin resistance. Methods Shotgun sequencing was performed in DNA from fecal samples of 23 early adolescents (10–12 years old) and amino acid targeted metabolomics analysis was performed by LC–MS/MS in serum samples. By using the HUMAnN2 algorithm we explored microbiome functional profiles to identify whether bacterial metabolism contributed to serum BCAA levels and insulin resistance markers. Results We identified that abundance of genes encoding bacterial BCAA inward transporters were negatively correlated with circulating BCAA and HOMA-IR (P 0.01). Interestingly, Faecalibacterium prausnitzii contributed to approximately ~ 70% of bacterial BCAA transporters gene count. Moreover, Faecalibacterium prausnitzii abundance was also negatively correlated with circulating BCAA (P = 0.001) and with HOMA-IR (P = 0.018), after adjusting for age, sex and body adiposity. Finally, the association between Faecalibacterium genus and BCAA levels was replicated over an extended data set (N = 124). Conclusions We provide evidence that gut bacterial BCAA transport genes, mainly encoded by Faecalibacterium prausnitzii, are associated with lower circulating BCAA and lower insulin resistance. Based on the later, we propose that the relationship between Faecalibacterium prausnitzii and insulin resistance, could be through modulation of BCAA.

A weekly conference series paired with lectures entitled "Microbiome-MX: exploring the Microbiota and Microbiome Research in Mexico" was organized to provide a multidisciplinary overview of the most recent research done in Mexico using high-throughput sequencing. Scientists and postgraduate students from several disciplines such as microbiology, bioinformatics, virology, immunology, nutrition, and medical genomics gathered to discuss state of the art in each of their respective subjects of expertise, as well as advances, applications and new opportunities on microbiota/microbiome research. In particular, high-throughput sequencing is a crucial tool to understand the challenges of a megadiverse developing country as Mexico, and moreover to know the scientific capital and capabilities available for collaboration. The conference series addressed three main topics important for Mexico: i) the complex role of microbiota in health and prevalent diseases such as obesity, diabetes, inflammatory bowel disease, tuberculosis, HIV, autoimmune diseases and gastric cancer; ii) the use of local, traditional and prehispanic products as pre/probiotics to modulate the microbiota and improve human health; and iii) the impact of the microbiota in shaping the biodiversity of economically important terrestrial and marine ecosystems. Herein, we summarize the contributions that Mexican microbiota/microbiome research is making to the global trends, describing the highlights of the conferences and lectures, rather than a review of the state-of-the-art of this research. This meeting report also presents the efforts of a multidisciplinary group of scientist to encourage collaborations and bringing this research field closer for younger generations.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite notable anthropometric variability with ancestry proportions, and a high burden of growth stunting and overweight/obesity in Hispanic/Latino populations. This address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults, to identify and fine-map common genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,769) and validated our findings in 9 additional studies (HISLA Stage 2, n=9,336). We conducted a trans-ethnic GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one novel BMI locus, as well two novel BMI signals and another novel height signal, each within established anthropometric loci. In our trans-ethnic meta- analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI. We replicated >60 established anthropometric loci in Hispanic/Latino populations at genome-wide significance—representing up to 30% of previously-reported index SNP anthropometric associations. Trans-ethnic meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our novel findings demonstrate that future studies may also benefit from leveraging differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

The effect of microbiota composition and its health on bone tissue is a novel field for research. However, their associations with bone mineral density (BMD) have not been established in postmenopausal women. The present study investigates the relation of diet, the microbiota composition, and the serum metabolic profile in postmenopausal women with normal-BMD or with low-BMD. Ninety-two Mexican postmenopausal women were classified into normal-BMD (n = 34) and low-BMD (n = 58). The V4 hypervariable region was sequenced using the Miseq platform. Serum vitamin D was determined by chemiluminescence immunoassay. Serum concentrations of acyl-carnitines and amino acids were determined by electrospray tandem mass spectrometry. Diet was assessed by a food frequency questionnaire. The low-BMD group had fewer observed species, higher abundance of &gamma, Proteobacteria, lower consumption of lycopene, and lower concentrations of leucine, valine, and tyrosine compared with the normal-BMD group. These amino acids correlated positively with the abundance of Bacteroides. Lycopene consumption positively correlated with Oscillospira and negatively correlated with Pantoea genus abundance. Finally, the intestinal microbiota of women with vitamin D deficiency was related to Erysipelotrichaceae and Veillonellaceae abundance compared to the vitamin D non-deficient group. Associations mediated by the gut microbiota between diet and circulating metabolites with low-BMD were identified.

Low HDL-C is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Moreover, few lipid-associated variants have been tested for coronary artery disease (CAD) in Hispanic populations. Here, we performed a GWAS for HDL-C levels in 2,183 Mexican individuals, identifying 7 loci, including three with genome-wide significance and containing the candidate genes CETP, ABCA1 and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels for the first time, and this association was replicated in 3 independent cohorts (P=5.5×10−21 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C and ApoB levels and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant is functional. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel (HMDP) are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. In conclusion, this is the first study assessing genetic variants contributing to HDL-C levels and coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10–6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10–10). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America. Fil: Romero Hidalgo, Sandra. Instituto Nacional de Medicina Genómica; México Fil: Flores Rivera, José. Instituto Nacional de Neurología y Neurocirugía; México Fil: Rivas Alonso, Verónica. Instituto Nacional de Neurología y Neurocirugía; México Fil: Barquera, Rodrigo. Max Planck Institute For The Science Of Human History; Alemania. Instituto Nacional de Antropología e Historia; México Fil: Villarreal Molina, María Teresa. Instituto Nacional de Medicina Genómica; México Fil: Antuna Puente, Bárbara. Instituto Nacional de Medicina Genómica; México Fil: Macias Kauffer, Luis Rodrigo. Universidad Nacional Autónoma de México; México Fil: Villalobos Comparán, Marisela. Instituto Nacional de Medicina Genómica; México Fil: Ortiz Maldonado, Jair. Instituto Nacional de Neurología y Neurocirugía; México Fil: Yu, Neng. American Red Cross; Estados Unidos Fil: Lebedeva, Tatiana V.. American Red Cross; Estados Unidos Fil: Alosco, Sharon M.. American Red Cross; Estados Unidos Fil: García Rodríguez, Juan Daniel. Instituto Nacional de Medicina Genómica; México Fil: González Torres, Carolina. Instituto Nacional de Medicina Genómica; México Fil: Rosas Madrigal, Sandra. Instituto Nacional de Medicina Genómica; México Fil: Ordoñez, Graciela. Neuroimmunología, Instituto Nacional de Neurología y Neurocirugía; México Fil: Guerrero Camacho, Jorge Luis. Instituto Nacional de Neurología y Neurocirugía; México Fil: Treviño Frenk, Irene. American British Cowdray Medical Center; México. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Escamilla Tilch, Monica. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: García Lechuga, Maricela. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Tovar Méndez, Víctor Hugo. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Pacheco Ubaldo, Hanna. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: Acuña Alonzo, Victor. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: Bortolini, María Cátira. Universidade Federal do Rio Grande do Sul; Brasil Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; Perú Fil: Bedoya Berrío, Gabriel. Universidad de Antioquia; Colombia Fil: Rothhammer, Francisco. Universidad de Tarapacá; Chile Fil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentina Fil: Ruiz Linares, Andrés. Colegio Universitario de Londres; Reino Unido Fil: Canizales Quinteros, Samuel. Universidad Nacional Autónoma de México; México Fil: Yunis, Edmond. Dana Farber Cancer Institute; Estados Unidos Fil: Granados, Julio. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Corona, Teresa. Instituto Nacional de Neurología y Neurocirugía; México

Changes in the composition of the human gut microbiome are recognized to have a significant association with obesity and metabolic syndrome. Mexico leads worldwide childhood-obesity rankings representing an epidemic problem for public health. To this date, it is still unclear how the gut phageome, the bacteriophage component of the virome, influences childhood obesity and obesity with metabolic syndrome. We characterized the gut phageome of 28 school-age children with healthy normal-weight (NW), obese (O), and obese with metabolic syndrome (OMS) profiles, using metagenomic sequencing of virus-like particles (VLPs) from fecal samples. Viromes derived from VLPs were mainly dominated by Caudovirales, and only Inoviridae family was significantly increased in obesity. The three groups showed a similar number of VLPs, while a significant increase in phage richness and diversity was found in obesity groups compared NW. Few phage contigs dominated the phageome composition in NW, being increased in obesity groups. Interestingly, the majority of the phageome was shared among all individuals, establishing a core and common phageome, which abundances correlated with anthropometric and biochemical traits and bacteria previously associated with obesity and metabolic syndrome. We also established a healthy core phageome shared in >80% of NW samples, with a decreased prevalence in the O and OMS groups. Our data support that changes in the gut phageome may contribute to obesity and metabolic syndrome development via bacterial dysbiosis. We consider the phageome characterization provides the basis for novel diagnostic and therapeutic strategies for managing obesity and preventing metabolic syndrome development in obese children through potential phage manipulation. To the best of our knowledge, this study represents the most in-depth sequenced dataset of human bacteriophages, demonstrating for the first time that alterations of the gut phageome characterize obesity.

Background In the last decade, increasing evidence has shown that changes in human gut microbiota are associated with diseases, such as obesity. The excreted/secreted proteins (secretome) of the gut microbiota affect the microbial composition, altering its colonization and persistence. Furthermore, it influences microbiota-host interactions by triggering inflammatory reactions and modulating the host's immune response. The metatranscriptome is essential to elucidate which genes are expressed under diseases. In this regard, little is known about the expressed secretome in the microbiome. Here, we use a metatranscriptomic approach to delineate the secretome of the gut microbiome of Mexican children with normal weight (NW) obesity (O) and obesity with metabolic syndrome (OMS). Additionally, we performed the 16S rRNA profiling of the gut microbiota. Results Out of the 115,712 metatranscriptome genes that codified for proteins, 30,024 (26%) were predicted to be secreted, constituting the Secrebiome of the gut microbiome. The 16S profiling confirmed an increased abundance in Firmicutes and decreased in Bacteroidetes in the obesity groups, and a significantly higher richness and diversity than the normal weight group. We found novel biomarkers for obesity with metabolic syndrome such as increased Coriobacteraceae, Collinsela, and Collinsella aerofaciens; Erysipelotrichaceae, Catenibacterium and Catenibacterium sp., and decreased Parabacteroides distasonis, which correlated with clinical and anthropometric parameters associated to obesity and metabolic syndrome. Related to the Secrebiome, 16 genes, homologous to F. prausniitzi, were overexpressed for the obese and 15 genes homologous to Bacteroides, were overexpressed in the obesity with metabolic syndrome. Furthermore, a significant enrichment of CAZy enzymes was found in the Secrebiome. Additionally, significant differences in the antigenic density of the Secrebiome were found between normal weight and obesity groups. Conclusions These findings show, for the first time, the role of the Secrebiome in the functional human-microbiota interaction. Our results highlight the importance of metatranscriptomics to provide novel information about the gut microbiome’s functions that could help us understand the impact of the Secrebiome on the homeostasis of its human host. Furthermore, the metatranscriptome and 16S profiling confirmed the importance of treating obesity and obesity with metabolic syndrome as separate conditions to better understand the interplay between microbiome and disease.

Obesity prevalence has increased in the last decades worldwide leading to metabolic complications, such as type 2 diabetes, steatosis, cardiovascular disease, among others; its development is influenced by genetic factors and environmental factors, such as intestinal microbiome. In Mexico, 33.3% of the adults present this disease. Obesity is defined as an excessive adipose tissue accumulation, provoking its dysfunction. Adipose tissue remodeling, which involves angiogenesis, hypoxia and inflammation, is implicated in the developing of obesity and metabolic modifications. Bariatric surgery is the most used and successful intervention to control morbid obesity, leading a maintained loss of weight and remission of some of its comorbidities as type 2 diabetes. Here, we review some of the molecular aspects of the metabolic changes provoked by bariatric surgery and its impact in weight loss and comorbidities remission. In summary, this article reviews the genetic aspects, microbiome and molecular facts (adipose tissue remodeling) that are involved in obesity development. In addition, some of the molecular aspects about bariatric surgery are described and the mechanisms that are regulated to control obesity and its comorbidities.

BACKGROUND: Gut microbiota, by influencing multiple metabolic processes in the host, is an important determinant of human health and disease. However, gut dysbiosis associated with metabolic complications shows inconsistent patterns. This is likely driven by factors shaping gut microbial composition that have largely been under-evaluated, at a population level, in school-age children, especially from developing countries. RESULTS: Through characterization, by 16S sequencing, of the largest gut microbial population-based school-aged children cohort in Latin America (ORSMEC, N = 926, aged 6–12 y), we identified associations of 14 clinical and environmental covariates (P(FDR)

Background. The gene for patatin-like phospholipase domain containing 3 (PNPLA3) is associated with non-alcoholic fatty liver disease (NAFLD) development. We previously found that Mexican indigenous population had the highest frequency reported of the PNPLA3 148M risk allele. Further, we observed a relationship between M148M genotype with elevated ALT levels in individuals with normal weight, overweight and obese. We sought to investigate whether PNPLA3 polymorphism is associated with NAFLD development in Mexicans. Material and methods. We enrolled 189 Mexican patients with NAFLD and 201 healthy controls. Anthropometric, metabolic, and biochemical variables were measured, and rs738409 (Ile148Met substitution) polymorphism was genotyped by sequencing. Results. Logistic regression analysis, using a recessive model, suggested that PNPLA3 polymorphism in Mexican population is significantly associated (OR = 1.711, 95% CI: 1.014-2.886; P = 0.044) with NAFLD. Conclusions: The PNPLA3 gene is associated with NAFLD in Mexican population. More studies are required to explain the high prevalence of PNPLA3 polymorphism in Mexican-Americans, Mexican-Indians, and Mexican-Mestizos.

Non-alcoholic fatty liver disease (NAFLD) is the accumulation of extra fat in liver cells not caused by alcohol. Elevated transaminase levels are common indicators of liver disease, including NAFLD. Previously, we demonstrated that PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) are associated with elevated transaminase levels in overweight/obese Mexican adults. We investigated the association between 288 SNPs identified in genome-wide association studies and risk of elevated transaminase levels in an admixed Mexican-Mestizo sample of 178 cases of NAFLD and 454 healthy controls. The rs2896019, rs12483959, and rs3810622 SNPs in PNPLA3 and rs1227756 in COL13A1 were associated with elevated alanine aminotransferase (ALT, ≥40 IU/L). A polygenic risk score (PRS) based on six SNPs in the ADIPOQ, COL13A1, PNPLA3, and SAMM50 genes was also associated with elevated ALT. Individuals carrying 9–12 risk alleles had 65.8% and 48.5% higher ALT and aspartate aminotransferase (AST) levels, respectively, than those with 1–4 risk alleles. The PRS showed the greatest risk of elevated ALT levels, with a higher level of significance than the individual variants. Our findings suggest a significant association between variants in COL13A1, ADIPOQ, SAMM50, and PNPLA3, and risk of NAFLD/elevated transaminase levels in Mexican adults with an admixed ancestry. This is the first study to examine high-density single nucleotide screening for genetic variations in a Mexican-Mestizo population. The extent of the effect of these variations on the development and progression of NAFLD in Latino populations requires further analysis.

Host gene variants selected by diet adaptation have been associated with the microbiome. Poole et al. (Cell Host Microbe 2019;25;553-564.E7) reported that AMY1 copy number, associated with obesity, also impacts microbiome composition and function. Complex genetics-diet-microbiome interactions and their effect on obesity could eventually translate into personalized nutrition.

SummaryBackground Childhood obesity is a serious public health problem in Mexico. Adult gut microbiota composition has been linked to obesity, but few studies have addressed the role of gut microbiota in childhood obesity. Objectives The aim of this study is to compare gut microbiota composition in obese and normal-weight children and to associate gut microbiota profiles with amino acid serum levels and obesity-related metabolic traits. Methods Microbial taxa relative abundance was determined by 16S rRNA sequencing in 67 normal-weight and 71 obese children aged 6–12 years. Serum amino acid levels were measured by mass spectrometry. Associations between microbiota composition, metabolic parameters and amino acid serum levels were tested. Results No significant differences in phyla abundances or Firmicutes/Bacteroidetes ratios were observed between normal-weight and obese children. However, Bacteroides eggerthii abundance was significantly higher in obese children and correlated positively with body fat percentage and negatively with insoluble fibre intake. Additionally, Bacteroides plebeius and unclassified Christensenellaceae abundances were significantly higher in normal-weight children. Abundance of both these species correlated negatively with phenylalanine serum levels, a metabolite also found to be associated with obesity in Mexican children. Conclusions The study identified bacterial species associated with obesity, metabolic complications and amino acid serum levels in Mexican children.

Aim To identify associations among allelic variants of the genes FTO, ABCA1, ADRB3, and PPARG with anthropometric and biochemical traits, metabolic diseases (obesity, T2D or metabolic syndrome) in an adult population from Northwest Mexico. Methods Blood samples were collected from 846 subjects including 266 normal weight subjects, 285 with obesity, and 295 with T2D. Of the 846 persons in the study, 365 presented metabolic syndrome diagnostic criteria. Anthropometric and biochemical traits were recorded and 4 single nucleotide polymorphisms (SNPs): FTO rs9939609 A-allele, ABCA1 rs9282541 A-allele, ADRB3 rs4994 G-allele, and PPARG rs1801282 G-allele were genotyped by real-time PCR. Results FTO rs9939609 A-allele was significantly associated with obesity (p: 8.3 × 10−4), and metabolic syndrome (p: 0.001), but no individual SNPs were significantly associated with T2D. Finally, the cumulative risk of the four SNPs was significantly associated with obesity (p: 1.95 × 10−4). Conclusion Associations in FTO, ABCA, ADRB3, and PPARG SNPs presented in this study with obesity and metabolic syndrome could represent a risk for developing metabolic diseases in Northwest Mexican adult subjects.

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

The genetic risk of developing type 2 diabetes (T2D) increases in parallel with the proportion of Native American ancestry. Mestizo Mexicans have a 70% Native Amerindian genetic background. The T130I polymorphism in the HNF4A gene has been associated with early-onset T2D in mestizo Mexicans. Thus, the aim of the present study was to evaluate the frequency and relationship of the T130I variant in the HNF4A gene with risk factors for developing T2D in eleven indigenous groups from Mexico. In two groups, all exons of the HNF4A gene were directly sequenced; in the remaining the T130I polymorphism was analyzed by restriction fragment length polymorphism. Ancestry informative markers were assessed to confirm the Amerindian component. An additional analysis of EHH was carried out. Interestingly, HNF4A gene screening revealed only the presence of the T130I polymorphism. The range frequency of the risk allele (T) in the indigenous groups was from 2.7 to 16%. Genotypic frequencies (T130I/I130I) were higher and significantly different from those of all of the populations included in the HapMap Project (P

Risk of hyperuricemia is modified by genetic and environmental factors. Our aim was to identify factors associated with serum uric acid levels and hyperuricemia in Mexicans. A pilot Genome-wide association study GWAS was performed in a subgroup of participants (n = 411) from the Health Workers Cohort Study (HWCS). Single nucleotide polymorphisms (SNPs) associated with serum uric acid levels were validated in all the HWCS participants (n = 1939) and replicated in independent children (n = 1080) and adult (n = 1073) case-control studies. The meta-analysis of the whole HWCS and replication samples identified three SLC2A9 SNPs: rs1014290 (p = 2.3 &times, 10&minus, 64), rs3775948 (p = 8.2 &times, 64) and rs11722228 (p = 1.1 &times, 17), and an ABCG2 missense SNP, rs2231142 (p = 1.0 &times, 18). Among the non-genetic factors identified, the visceral adiposity index, smoking, the metabolic syndrome and its components (waist circumference, blood pressure, glucose and hyperlipidemia) were associated with increased serum uric acid levels and hyperuricemia (p &lt, 0.05). Among the female HWCS participants, the odds ratio for hyperuricemia was 1.24 (95% CI, 1.01&ndash, 1.53) per unit increase in soft drink consumption. As reported in other studies, our findings indicate that diet, adiposity and genetic variation contribute to the elevated prevalence of hyperuricemia in Mexico.

Background: Serum uric acid (SUA) is a heritable trait associated with cardiovascular risk factors and coronary artery disease (CAD). Genome wide association studies (GWAS) have identified several genes associated with SUA, mainly in European populations. However, to date there are few GWAS in Latino populations, and the role of SUA-associated single nucleotide polymorphisms (SNPs) in cardiovascular disease has not been studied in the Mexican population. Methods: We performed genome-wide SUA association study in 2153 Mexican children and adults, evaluated whether genetic effects were modified by sex and obesity, and used a Mendelian randomization approach in an independent cohort to study the role of SUA modifying genetic variants in premature CAD. Results: Only two loci were associated with SUA levels: SLC2A9 (β = −0.47 mg/dl, P = 1.57 × 10−42 for lead SNP rs7678287) and ABCG2 (β = 0.23 mg/dl, P = 2.42 × 10−10 for lead SNP rs2231142). No significant interaction between SLC2A9 rs7678287 and ABCG2 rs2231142 genotypes and obesity was observed. However, a significant ABCG2 rs2231142 genotype*sex interaction (P = 0.001) was observed in adults but not in children. Although SUA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (eGFR), only ABCG2 rs2231142 was associated with decreased eGFR in the premature CAD group. Conclusions: SUA elevation was independently associated with premature CAD, metabolic syndrome and decreased eGFR in the Mexican population. However, a Mendelian randomization approach using the lead SUA-associated SNPs (SLC2A9 and ABCG2) did not support a causal role of elevated SUA levels for premature CAD. Fil: Macias Kauffer, Luis R.. Instituto Nacional de Medicina Genómica Mexico; México. Universidad Nacional Autónoma de México; México Fil: Villamil Ramírez, Hugo. Instituto Nacional de Medicina Genómica Mexico; México Fil: León Mimila, Paola. Instituto Nacional de Medicina Genómica Mexico; México Fil: Jacobo Albavera, Leonor. Inmegen; México Fil: Posadas Romero, Carlos. Instituto Nacional de Cardiologia Ignacio Chavez; México Fil: Posadas Sánchez, Rosalinda. Instituto Nacional de Cardiologia Ignacio Chavez; México Fil: López Contreras, Blanca E.. Instituto Nacional de Medicina Genómica Mexico; México Fil: Morán Ramos, Sofía. Instituto Nacional de Medicina Genómica Mexico; México Fil: Romero Hidalgo, Sandra. Inmegen; México Fil: Acuña Alonzo, Víctor. Colegio Universitario de Londres; Reino Unido Fil: del Río Navarro, Blanca E.. Hospital Infantil de Mexico Federico Gomez; México Fil: Bortolini, Maria Cátira. Universidade Federal do Rio Grande do Sul; Brasil Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; Perú Fil: Bedoya, Gabriel. Universidad de Antioquia; Colombia Fil: Rothhammer, Francisco. Universidad de Chile; Chile Fil: González José, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentina Fil: Ruiz-Linares, Andres. Fudan University; China. Anthropologie Bio-culturelle, Droit, Éthique & Fil: Stephens, Christopher R.. Universidad Nacional Autónoma de México. Instituto de Ciencias Nucleares; México Fil: Velazquez Cruz, Rafael. Instituto Nacional de Medicina Genómica Mexico; México Fil: Fernández del Valle Laisequilla, Cecilia. Productos Medix; México Fil: Reyes-García, Juan G.. INSTITUTO POLITÉCNICO NACIONAL (IPN); Fil: Barranco Garduño, Lina M.. Instituto Nacional de Enfermedades Respiratorias; México Fil: Carrasco-Portugal, Miriam del C.. Instituto Nacional de Enfermedades Respiratorias; México Fil: Flores-Murrieta, Francisco J.. Instituto Nacional de Enfermedades Respiratorias; México. INSTITUTO POLITÉCNICO NACIONAL (IPN); Fil: Vargas Alarcón, Gilberto. Instituto Nacional de Cardiologia Ignacio Chavez; México Fil: Aguilar Salinas, Carlos A.. Escuela de Medicina y Ciencias de la Salud Tecsalud; México. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Villarreal Molina, Teresa. Inmegen; México Fil: Canizales Quinteros, Samuel. Instituto Nacional de Medicina Genómica Mexico; México

We report the genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human apolipoprotein E*3-Leiden and cholesteryl ester transfer protein and fed a "Western" diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors are involved. Moreover, genome-wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. Conclusion: The pathways showed substantial overlap between our mouse model and the human disease.

Aims Trimethylamine N-oxide (TMAO), choline and betaine serum levels have been associated with metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). These associations could be mediated by insulin resistance. However, the relationships among these metabolites, insulin resistance and NAFLD have not been thoroughly investigated. Moreover, it has recently been suggested that TMAO could play a role in NAFLD by altering bile acid metabolism. We examined the association between circulating TMAO, choline and betaine levels and NAFLD in obese subjects. Methods Serum TMAO, choline, betaine and bile acid levels were measured in 357 Mexican obese patients with different grades of NAFLD as determined by liver histology. Associations of NAFLD with TMAO, choline and betaine levels were tested. Moreover, association of TMAO levels with non-alcoholic steatohepatitis (NASH) was tested separately in patients with and without T2D. Results TMAO and choline levels were significantly associated with NAFLD histologic features and NASH risk. While increased serum TMAO levels were significantly associated with NASH in patients with T2D, in non-T2D subjects this association lost significance after adjusting for sex, BMI and HOMA2-IR. Moreover, circulating secondary bile acids were associated both with increased TMAO levels and NASH. Conclusions In obese patients, circulating TMAO levels were associated with NASH mainly in the presence of T2D. Functional studies are required to evaluate the role of insulin resistance and T2D in this association, both highly prevalent in NASH patients.

Spontaneous cervico-cerebral artery dissection (CCAD) is a common condition found among young patients with ischemic stroke. We examined the possible association between the polymorphism of methylenetetrahydrofolate reductase (MTHFR)-C677T and the gene mutation in transforming growth factor beta receptor II (TGFBR2) in a cohort of CCAD patients. One-hundred CCAD cases (65 males; mean age: 38.08 ± 10.68 years) and 100 matching controls were included. Ancestry informative markers (AIMs) were used to increase internal validity of the genetic analysis. Genotypes of the C677T polymorphism in the MTHFR gene were determined by polymerase chain reaction and restriction fragment length polymorphism; direct sequencing was used for a mutation analysis of the TGFBR2 gene. Associations were evaluated using a multivariate statistics, and Hardy–Weinberg equilibrium was analyzed. We also incorporated our data into a meta-analysis of the MTHFR-C677T. Sixty-three patients presented with vertebral and 37 with carotid artery dissection. Ancestry markers found a call rate on each over 95 %. All AIMs did not deviate from Hardy–Weinberg equilibrium (p > 0.05). The homozygous TT genotype was more frequent in cases (OR 2.04, CI 95 % 1.53–2.72, p = 0.005), whereas no significant difference was found on heterozygous CT genotype. TGFBR2 mutation was not present in our samples. In the meta-analysis of MTHFR/C677T variant, a total 613 cases and 1547 controls were analyzed; we found a moderate association for the recessive model genotype (OR 2.04, CI 95 % 1.53–2.72; p = 0.342; Z = 4.83; I 2 = 11.3). This study supports a positive association between the MTHFR-C677T polymorphism and genetically confirmed Mexican mestizo CCAD patients.

Background and aim Abnormal cholesterol metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH) and fibrosis. miR-33 and miR-144 regulate adenosine triphosphate binding cassette transporter (ABCA1) and other target genes involved in cholesterol efflux, fatty acid oxidation and inflammation. We explored relationships between non-alcoholic fatty liver disease (NAFLD) and the hepatic expression of ABCA1/ABCG1, as well as other target genes regulated by miR-33 (carnitine O-octanoyltransferase, CROT and hydroxyacyl-CoA-dehydrogenase β-subunit, HADHB) and miR-144 (toll-like receptor-2, TLR2). Moreover, we evaluated whether the expression of these genes is correlated with miR-33a/b and miR-144 expression in Mexican individuals with morbid obesity. Methods Eighty-four morbidly obese subjects undergoing bariatric surgery were included in this study. Liver biopsies were obtained to measure hepatic triglyceride and free cholesterol contents, as well as ABCA1, ABCG1, CROT, HADHB, TLR2, miR-33a/b and miR-144 expression. Results Hepatic free cholesterol content was significantly increased in NASH as compared to non-NASH subjects, while ABCA1 and ABCG1 protein levels significantly decreased with NASH and fibrosis progression. The relative expression of miR-33a and miR-144 correlated inversely with ABCA1 but not with ABCG1 protein levels. Moreover, both miRNAs increased significantly in NASH individuals. miR-33 target genes CROT and HADHB correlated inversely with miR-33a. However, the expression of these genes was not associated with NASH. Conclusions miR-33a/144 and their target gene ABCA1 may contribute to the pathogenesis of NASH in morbidly obese subjects.

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10−10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10−8). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10−11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure., Author summary Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here we performed genome-wide association studies for eyebrow thickness in multiple ethnic groups, including Han Chinese, Uyghurs, Latin Americans, and Caucasians. We found solid evidence that novel genetic variants near the SOX2, FOXD1 and EDAR genes could affect eyebrow thickness. After fine mapping, we prioritized four variants for experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that the variants rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes. This represents a successful example of a combination of GWAS and CRISPR/Cas9 technology to demonstrate how non-coding variants with regulatory functions may play an important role in common diseases and traits. Finally, suitable statistical analyses suggest that, contrary to popular speculation, eyebrow thickness should not be subject to strong selection pressure, including sexual selection.

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10−8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development. Fil: Shaffer, John R.. University of Pittsburgh; Estados Unidos Fil: Li, Jinxi. University of Chinese Academy of Sciences; China Fil: Lee, Myoung Keun. University of Pittsburgh; Estados Unidos Fil: Roosenboom, Jasmien. University of Pittsburgh; Estados Unidos Fil: Orlova, Ekaterina. University of Pittsburgh; Estados Unidos Fil: Adhikari, Kaustabh. Colegio Universitario de Londres; Reino Unido Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; Perú Fil: Poletti, Giovanni. Universidad Peruana Cayetano Heredia; Perú Fil: Schuler Faccini, Lavinia. Universidade Federal do Rio Grande do Sul; Brasil Fil: Bortolini, Maria Catira. Universidade Federal do Rio Grande do Sul; Brasil Fil: Canizales Quinteros, Samuel. Universidad Nacional Autónoma de México; México Fil: Rothhammer, Francisco. Universidad de Tarapacá; Chile Fil: Bedoya, Gabriel. Universidad de Antioquia; Colombia Fil: González José, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentina Fil: Pfeffer, Paige E.. Saint Louis University; Estados Unidos Fil: Wollenschlaeger, Christopher A.. University of Pittsburgh; Estados Unidos Fil: Hecht, Jacqueline T.. University of Texas; Estados Unidos Fil: Wehby, George. University of Iowa; Estados Unidos Fil: Moreno, Lina M.. University of Iowa; Estados Unidos Fil: Ding, Anan. University of Chinese Academy of Sciences; China Fil: Jin, Li. University of Chinese Academy of Sciences; China. Fudan University; China Fil: Yang, Yajun. Fudan University; China Fil: Carlson, Jenna C.. University of Pittsburgh; Estados Unidos Fil: Leslie, Elizabeth J.. University of Pittsburgh; Estados Unidos Fil: Feingold, Eleanor. University of Pittsburgh; Estados Unidos Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Hinds, David A.. 899 West Evelyn Avenue; Estados Unidos Fil: Cox, Timothy C.. Seattle Children’s Research Institute; Estados Unidos. University of Washington; Estados Unidos. Monash University; Australia Fil: Wang, Sijia. University of Chinese Academy of Sciences; China. Fudan University; China Fil: Ruiz Linares, Andrés. Colegio Universitario de Londres; Reino Unido. Fudan University; China. Aix-Marseille University; Francia Fil: Weinberg, Seth M.. University of Pittsburgh; Estados Unidos

Background— Polymorphisms of methylenetetrahydrofolate reductase ( MTHFR ) have been associated with diastolic blood pressure, hypertension, and other cardiovascular diseases; however, results of these studies are still controversial. In this study, we sought to determine whether 2 functional variants (rs1801133 and rs13306560) within the MTHFR are associated with hypertension in Mexican-Mestizos. Methods and Results— We performed a case–control study with 1214 subjects including adults and children to test for the association of both single nucleotide polymorphisms with essential hypertension. The adult group included 764 participants (372 patients and 391 controls) and the group of children included 418 participants (209 patients and 209 controls). rs13306560 was associated with essential hypertension in adults (odds ratio, 4.281; 95% confidence interval, 1.841–9.955; P =0.0003) with a statistical power >0.8. In children, none of the polymorphisms was associated with essential hypertension. In addition, we assessed the effect of the rs13306560 polymorphism on the MTHFR promoter region by means of luciferase reporter gene assays using human umbilical vein endothelial cells. Cells transfected with the pMTHFRaLUC construct showed an ≈25% reduction in luciferase activity ( P =0.003). Furthermore, the promoter activity was reduced considerably by in vitro methylation of CpG sequences. Conclusions— Our data suggest that the rs13306560 polymorphism of the MTHFR may be part of the observed hypertension process in Mexican-Mestizo populations, but further studies are warranted. In addition, the allele A of the rs13306560 polymorphism as well as the in vitro methylation of CpGs reduced the promoter activity of the MTHFR regulatory region.

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near/in PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes associated with non-alcoholic fatty liver disease (NAFLD) mainly in individuals of European ancestry. The aim of the study was to test whether these genetic variants and a genetic risk score (GRS) are associated with elevated liver fat content and non-alcoholic steatohepatitis (NASH) in Mexicans with morbid obesity.130 morbidly obese Mexican individuals were genotyped for six SNPs in/near PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes. Hepatic fat content [triglyceride (HTG) and total cholesterol (HTC)] was quantified directly in liver biopsies and NASH was diagnosed by histology. A GRS was tested for association with liver fat content and NASH using logistic regression models. In addition, 95 ancestry-informative markers were genotyped to estimate population admixture proportions.After adjusting for age, sex and admixture, PNPLA3, LYPLAL1, GCKR and PPP1R3B polymorphisms were associated with higher HTG content (P0.05 for PNPLA3, LYPLAL1, GCKR polymorphisms and P = 0.086 for PPP1R3B). The GRS was significantly associated with higher HTG and HTC content (P = 1.0 × 10(-4) and 0.048, respectively), steatosis stage (P = 0.029), and higher ALT levels (P = 0.002). Subjects with GRS ≥ 6 showed a significantly increased risk of NASH (OR = 2.55, P = 0.045) compared to those with GRS ≤ 5. However, the GRS did not predict NASH status, as AUC of ROC curves was 0.56 (P = 0.219).NAFLD associated loci in Europeans and a GRS based on these loci contribute to the accumulation of hepatic lipids and NASH in morbidly obese Mexican individuals.

The obesity pandemic and the metabolic complications derived from it represent a major public health challenge worldwide. Although obesity is a multifactorial disease, research from the past decade suggests that the gut microbiota interacts with host genetics and diet, as well as with other environmental factors, and thus contributes to the development of obesity and related complications. Despite abundant research on animal models, substantial evidence from humans has only started to accumulate over the past few years. Thus, the aim of the present review is to discuss structural and functional characteristics of the gut microbiome in human obesity, challenges associated with multi-omic technologies, and advances in identifying microbial metabolites with a direct link to obesity and metabolic complications. To date, studies suggests that obesity is related to low microbial diversity and taxon depletion sometimes resulting from an interaction with host dietary habits and genotype. These findings support the idea that the depletion or absence of certain taxa leaves an empty niche, likely leading to compromised functionality and thus promoting dysbiosis. Although the role of altered gut microbiota as cause or consequence of obesity remains controversial, research on microbial genomes and metabolites points towards an increased extraction of energy from the diet in obesity and suggests that metabolites, such as trimethylamine-N-oxide or branched-chain amino acids, participate in metabolic complications. Future research should be focused on structural and functional levels to unravel the mechanism linking gut microbiota and obesity.

Childhood obesity is associated with a number of metabolic abnormalities leading to increased cardiovascular risk. Metabolites can be useful as early biomarkers and new targets to promote early intervention beginning in school age. Thus, we aimed to identify metabolomic profiles associated with obesity and obesity-related metabolic traits. We used data from the Obesity Research Study for Mexican children (ORSMEC) in Mexico City and included a case control (n = 1120), cross-sectional (n = 554) and a longitudinal study (n = 301) of 6–12-year-old children. Forty-two metabolites were measured using electrospray MS/MS and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical and biochemical parameters. Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity (OR = 1.57; 95%CI 1.45–1.69, P = 3.84 × 10−31) and serum triglycerides (TG) (β = 0.067, P = 4.5 × 10−21). These associations were validated in the cross-sectional study (P P = 0.016). This study shows that an amino acid signature significantly associated with childhood obesity, is an independent risk factor of future hypertriglyceridemia in children.