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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.

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.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a demyelinating autoimmune disease of the central nervous system, more prevalent in individuals of non-European ancestry. Few studies have analyzed genetic risk factors in NMOSD, and HLA class II gene variation has been associated NMOSD risk in various populations including Mexicans. Thymopoietin (TMPO) has not been tested as a candidate gene for NMOSD or other autoimmune disease, however, experimental evidence suggests this gene may be involved in negative selection of autoreactive T cells and autoimmunity. We thus investigated whether the missense TMPO variant rs17028450 (Arg630Cys, frequent in Latin America) is associated with NMOSD, and whether this variant shows an interaction with HLA-class II rs9272219, previously associated with NMOSD risk. A total of 119 Mexican NMOSD patients, 1208 controls and 357 Native Mexican individuals were included. The HLA rs9272219 “T” risk allele frequency ranged from 21 to 68%, while the rs17028450 “T” minor allele frequency was as high as 18% in Native Mexican groups. Both rs9272219 and rs17028450 were significantly associated with NMOSD risk under additive models (OR = 2.48; p = 8 × 10–10 and OR = 1.59; p = 0.0075, respectively), and a significant interaction between both variants was identified with logistic regression models (p = 0.048). Individuals bearing both risk alleles had an estimated 3.9-fold increased risk of NMOSD. To our knowledge, this is the first study reporting an association of TMPO gene variation with an autoimmune disorder and the interaction of specific susceptibility gene variants, that may contribute to the genetic architecture of NMOSD in admixed Latin American populations.

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.

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

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.

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.

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.

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)

espanolAntecedentes: la concurrencia de trastornos por uso de sustancias (TUS) es alta en personas con enfermedades psiquiatricas; Mas importante aun, las personas con ambos trastornos (diagnostico dual) tienen sintomas mas graves. Se han propuesto trastornos psiquiatricos para compartir una susceptibilidad genetica con los TUS. Para explorar esta susceptibilidad genetica compartida, analizamos si alguna de las puntuaciones de riesgo poligenico (PRS) para los trastornos psiquiatricos podria estar asociada al diagnostico dual en pacientes con esquizofrenia (SCZ) o trastorno bipolar (BD). Metodos: Se incluyeron 192 individuos de ascendencia mexicana: 72 con SCZ, 53 con BD y 67 controles no relacionados sin trastornos psiquiatricos. Derivamos calculos de PRS para trastornos del espectro autista, trastorno de deficit de atencion / hiperactivo, BD, depresion mayor y SCZ utilizando estadisticas resumidas de asociacion de genoma previamente publicadas. Resultados: Encontramos que el diagnostico dual tenia una susceptibilidad genetica compartida con el trastorno depresivo mayor (MDD) y SCZ; Ademas, en individuos con BD, PRS podria predecir el diagnostico dual para MDD. Conclusiones: Nuestros resultados refuerzan la nocion de que las personas con diagnostico dual tienen una mayor susceptibilidad genetica a desarrollar ambos trastornos. Sin embargo, se requieren analisis de muestras de mayor tamano para aclarar aun mas como predecir riesgos a traves de PRS dentro de diferentes poblaciones. EnglishBackground: Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). Methods: We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. Results: We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. Conclusions: Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations. (REV INVEST CLIN. 2019;71:321-9)

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

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.

ObjectiveLarge-scale genome-wide association studies have uncovered genetic variants associated with depression; however, most of this work has been limited to adults of European ancestry. We investigate the ability of depression polygenic risk scores (PRS) to predict both lifetime and past year major depressive disorder (MDD) diagnosis and the experience of a major depressive episode (MDE) in a sample of adolescents with admixed ancestry from Mexico City, and explore whether adverse life events moderate these relations.MethodsThe study sample consisted of adolescents (N = 1,152) aged 12–17 from Mexico City who were interviewed and genotyped as part of a general population survey on adolescent mental health. PRS for depression were derived using summary statistics from a large-scale discovery genome-wide association study (GWAS) conducted on depressive symptoms that included over 800,000 individuals of European ancestry (Howard et al., 2019).ResultsHigher depression PRS were associated with a higher likelihood of both past year MDD and MDE and lifetime MDE, accounting for 1.5%-2.5% of the variance in these outcomes. Adversity did not moderate the relationship between depression PRS and lifetime or past year MDD or MDE.LimitationsThis study is cross-sectional. As such, a few participants might have experience MDD/MDE after the interview. In addition, our sample comprised only Mexican youth and thus it may not generalize to other populations.ConclusionOur results indicate that depression PRS derived from a European ancestry GWAS are associated with MDD and MDE risk among Mexican adolescents and have the potential to aid in the identification of youth who may be genetically prone to developing depressive symptoms.

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25–44%; P −14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p −9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p −6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p −10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation.

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.

In order to summarized the polygenic background of psychiatric diseases, polygenic risk scores (PRS) have been developed. Recently, PRS have been use to predict patients with higher comorbidities in psychiatric diseases, like dual diagnosis. PRS are principally derived in analysis of Caucasian and Asian populations, we are not aware of how this PRS could be applied in populations with high admixture. In order to explored this, the present work has the aim to analyzed if previous calculated PRS for psychiatric diseases could predict dual diagnosis in Mexican population, and also, if PRS calculation could be influenced by Mexican Amerindian (MA) global ancestry. We performed PRS calculation, using PRSice, with summary genome-wide association statistics previously published for psychiatric diseases, and also, performed Nagelkerke correlation test in order to established if PRS are correlated with dual diagnosis. We found that dual diagnosis could be predicted by major depressive disorder polygenic risk score. Nevertheless, schizophrenia polygenic risk score is highly correlated with global MA ancestry, independently of the schizophrenia diagnosis. Our results reinforced the notion that PRS calculation could be deviated by the MA global ancestry, nevertheless analysis on larger sample sizes are required in order to clarified this issue.

Obesity is a major public health concern in Mexico and worldwide. Although the estimated heritability is high, common variants identified by genome-wide association studies explain only a small proportion of this heritability. A combination of linkage and association strategies could be a more robust and powerful approach to identify other obesity-susceptibility variants. We thus sought to identify novel genetic variants associated with obesity-related traits in the Mexican population by combining these methods. We performed a genome-wide linkage scan for body mass index (BMI) and other obesity-related phenotypes in 16 Mexican families using the Sequential Oligogenic Linkage Analysis Routines Program. Associated single-nucleotide polymorphisms (SNPs) were tested for associations in an independent cohort. Two suggestive BMI-linkage peaks (logarithm of odds ⩾1.5) were observed at chromosomal regions 11q13 and 13q22. Only rs614080 in the 11q13 region was significantly associated with BMI and related traits in these families. This association was also significant in an independent cohort of Mexican adults. Moreover, this variant was significantly associated with GSTP1 gene expression levels in adipose tissue. In conclusion, the rs614080 SNP near the GSTP1 gene was significantly associated with BMI and GSTP1 expression levels in the Mexican population.

Genome-wide association studies (GWAS) have identified copy number variants (CNVs) associated with obesity in chromosomal regions 1p31.1, 10q11.22, 11q11, 16p12.3, and recently 1p21.1, which contains the salivary amylase gene (AMY1). Recent evidence suggests this enzyme may influence gut microbiota composition through carbohydrate (mainly starch) degradation. The role of these CNVs in obesity has been scarcely explored in the Latino population, and thus the aim of our study was to evaluate the association of 1p31.1, 10q11.22, 11q11, 16p12.3 and 1p21.1 CNVs with obesity in 921 Mexican children, to replicate significant associations in 920 Mexican adults, and to analyze the association of AMY1 copy number with gut microbiota in 75 children and 45 adults. Of the five CNVs analyzed, 1q11 CNV was significantly associated with obesity in children, but not in adults. Only AMY1 CNV was significantly associated with obesity in both age groups. Moreover, gut microbiota analyses revealed a positive correlation between AMY1 copy number and Prevotella abundance. This genus has enzymes and gene clusters essential for complex polysaccharide degradation and utilization. To our knowledge, this is the first study to analyze the association of these five CNVs in the Mexican population and to report a correlation between AMY1 CN and gut microbiota in humans.