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There are reports of different clinical statuses in carriers of intermediate alleles (IAs) of CAG trinucleotide repeats in the HTT gene, from individuals affected by a clinical picture indistinguishable from Huntington's disease (HD) to those without manifestations. Therefore, the possible clinical significance of these alleles has been widely debated.The aim of this study was to describe general and clinical features and discard HD phenocopies by molecular assessment in a case series of IA carriers on the HTT gene of a laboratory sample from a neurological center in Mexico.We selected individuals who had previously been tested for the HTT gene expansion, which resulted in IAs. Clinical information was obtained from medical records, and molecular analysis of the JPH3, PRNP, and TBP genes was performed only in IA carriers with clinical manifestations. In addition, two patients with IA and acanthocytes were evaluated by whole-exome sequencing. The scientific and ethical committees of the National Institute of Neurology and Neurosurgery Manuel Velasco Suárez (NINNMVS) approved this study.From 1994 to 2019, the Genetics Department of the NINNMVS confirmed 34 individuals with IAs, 15 of whom belonged to 11 families with HD (IA-HD) and 19 of whom had no family history of HD (IA-non-HD). We found a high proportion of manifestations of the HD phenotypic spectrum in the IA-non-HD subgroup. In addition, among the 20 samples of IA carriers with manifestations molecularly evaluated, we identified two unrelated subjects with CAG/CTG repeat expansions on the JPH3 gene, confirming HD-like 2 (HDL2), and one patient with the homozygous pathogenic c.3232GT variant (p.Glu1078Ter) in the VPS13A gene, demonstrating choreoacanthocytosis.Our results show the most extensive series of subjects with IAs and clinical manifestations. In addition, we identify three HD phenocopies, two HDL2 cases, and one choreoacanthocytosis case. Therefore, we emphasize evaluating other HD phenocopies in IA carriers with clinical manifestations whose family background is not associated with HD.

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.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.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.

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

Background Dilated cardiomyopathy (DCM) is a major cause of nonischemic heart failure and death in young adults. Next generation sequencing (NGS) has become part of the diagnostic workup in idiopathic and familial DCM. More than 50 DCM genes have been identified, revealing great molecular heterogeneity and variable diagnostic yield. Interpretation of variant pathogenicity is challenging particularly in underrepresented populations, as pathogenic variant databases include studies mainly from European/Caucasian populations. To date, no studies on genomic diagnosis of DCM have been conducted in Mexico. Methods We recruited 55 unrelated DCM patients, 22 familial (F‐DCM), and 33 idiopathic (I‐DCM), and performed site‐directed NGS seeking causal mutations. Diagnostic yield was defined as the proportion of individuals with at least one pathogenic (P) or likely pathogenic (LP) variant in DCM genes. Results Overall diagnostic yield was 47.3%, and higher in F‐DCM (63.6%) than in I‐DCM (36.4%, p = 0.047). Overall, NGS disclosed 41 variants of clinical interest (61.0% novel), 27 were classified as P/LP and 14 of unknown clinical significance. Of P/LP variants, 10 were A‐band region TTN truncating variants, five were found in DSP (18.5%), five in MYH7 (18.5%), two in LMNA (7.4%), and one in RBM20, ABCC9, FKTN, ACTA1, and TNNT2. NGS findings suggested autosomal recessive inheritance in three families, two with DSP loss of function mutations in affected individuals. The increasing number of mutation reports in DCM, increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of DCM‐related proteins, the recent refinement ACMG/ClinGen Guidelines, and co‐segregation analysis in DCM families helped increase the diagnostic yield. Conclusion This is the first NGS study performed in a group of Mexican DCM patients, contributing to understand the mutational spectrum and complexity of DCM molecular diagnosis., Molecular diagnosis in dilated cardiomyopathy (DCM) is challenging, particularly in underrepresented populations. We obtained a relatively high diagnostic yield in familial DCM (63.6%) and in idiopathic DCM (47.3%) in a group of Mexican patients. The increasing number of reports of mutations in DCM patients, the increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of some DCM‐related proteins, the refinement ACMG/ClinGen Guidelines and co‐segregation analysis helped achieve this higher diagnostic yield.

Understanding the genetic structure of Native American populations is important to clarify their diversity, demographic history, and to identify genetic factors relevant for biomedical traits. Here, we show a demographic history reconstruction from 12 Native American whole genomes belonging to six distinct ethnic groups representing the three main described genetic clusters of Mexico (Northern, Southern, and Maya). Effective population size estimates of all Native American groups remained below 2,000 individuals for up to 10,000 years ago. The proportion of missense variants predicted as damaging is higher for undescribed (~ 30%) than for previously reported variants (~ 15%). Several variants previously associated with biological traits are highly frequent in the Native American genomes. These findings suggest that the demographic and adaptive processes that occurred in these groups shaped their genetic architecture and could have implications in biological processes of the Native Americans and Mestizos of today., People of Mexico have diverse historical and genetic background. Here, Romero-Hidalgo and colleagues sequence whole genomes of Native Americans of Mexico, and show demographic history and genetic variation shared among subgroups of Native Americans.

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

Background One of the most prevalent chronic diseases among elderly population is the Metabolic Syndrome (MetS). The aim of this study was to assess the prevalence of MetS and associated factors among Mexican elderly people. Subjects Cross-sectional survey carried out in Mexico (2007). A random sample (n = 516) of the elderly population (≥65 years; 277 female, 239 male) was interviewed. Anthropometric and analytical measurements, and a general questionnaire incorporating questions related to socio-demographic and life-style factors were used. MetS definition AHA/NHLBI/IDF was applied. Results The prevalence of MetS in the elderly (≥65 years) was of 72.9% (75.7% men; 70.4% women). Participants with values above MetS cut-off points were 92.4% (hypertension), 77.8% (hypertriglyceridemia), 77.1% (low HDL-cholesterol), 71.1% (hyperglycaemia), and 65.4% (central obesity). People with MetS showed higher values of anthropometric and biochemical variables than those without MetS, except for the height, cholesterol and creatinine. Mid-high education level (9–12 years), no smokers and former smokers, and Central-Western inhabitants of Mexico were associated with MetS components. BMI status was the main determinant of MetS prevalence and MetS components. Conclusion The reported prevalence of MetS among the elderly Mexican population was higher than those previously obtained in the geographical area, showing a major public health problem in Mexican elders.

Background The aim of this study was to explore whether interactions between FTO rs9939609 and ABCA1 rs9282541 affect BMI and waist circumference (WC), and could explain previously reported population differences in FTO-obesity and FTO-BMI associations in the Mexican and European populations. Methods A total of 3938 adults and 636 school-aged children from Central Mexico were genotyped for both polymorphisms. Subcutaneous and visceral adipose tissue biopsies from 22 class III obesity patients were analyzed for FTO and ABCA1 mRNA expression. Generalized linear models were used to test for associations and gene-gene interactions affecting BMI, WC and FTO expression. Results FTO and ABCA1 risk alleles were not individually associated with higher BMI or WC. However, in the absence of the ABCA1 risk allele, the FTO risk variant was significantly associated with higher BMI (P = 0.043) and marginally associated with higher WC (P = 0.067), as reported in Europeans. The gene-gene interaction affecting BMI and WC was statistically significant only in adults. FTO mRNA expression in subcutaneous abdominal adipose tissue according to ABCA1 genotype was consistent with these findings. Conclusions This is the first report showing evidence of FTO and ABCA1 gene variant interactions affecting BMI, which may explain previously reported population differences. Further studies are needed to confirm this interaction. Electronic supplementary material The online version of this article (doi:10.1186/s12881-017-0410-y) contains supplementary material, which is available to authorized users.

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.

There is a great deal of evidence that points to the association of the tumor necrosis factor-alpha ( TNF- α) gene as a common genetic factor in the pathogenesis of diseases that are caused by inflammatory and/or autoimmune etiologies. Two single nucleotide polymorphisms (SNPs) identified in the TNF -α promoter region have been associated with disease susceptibility and severity. We investigated whether −308G/A and −238G/A TNF-α polymorphisms were associated with asthma, systemic lupus erythematosus (SLE), and juvenile rheumatoid arthritis (JRA) in a pediatric Mexican population. In a case-control study of 725 patients (asthma: 226, JRA: 171, and SLE: 328) and 400 control subjects, the participants were analyzed using the allelic discrimination technique. The genotype distribution of both TNF -α polymorphisms was in Hardy-Weinberg equilibrium in each group. However, there were significant differences in the allele frequency of TNF -α-308A between the patients and the healthy controls. This allele was detected in 2.9% of the controls, 6.0% of asthmatic and JRA patients ( p = 0.002 and p = 0.0086), and 6.7% of SLE patients ( p = 0.00049); statistical significance was maintained after ancestry stratification (asthma: p = 0.0143, JRA: p = 0.0083, and SLE: p = 0.0026). Stratification by gender showed that the risk for the −308A allele in asthma and JRA was greater in females (OR = 4.16, p = 0.0008 and OR = 4.4, p = 0.0002, respectively). The TNF -α -238A allele showed an association only with JRA in males (OR = 2.89, p = 0.004). These results support the concept that the TNF-α gene is a genetic risk factor for asthma, SLE, and JRA in the pediatric Mexican population.

Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.

OBJECTIVE—The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic β-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population. RESEARCH DESIGN AND METHODS—The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20–69 years (121 with onset ≤45 years), and 202 nondiabetic control subjects aged >50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics. RESULTS—R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis ≤45 years) (OR 3.776, P = 3.3 × 10−6). Both associations remained significant after adjusting for admixture (P = 0.0008 and P = 8.1 × 10−6, respectively). Similar trends were observed in the independent study group, and the combined analysis of both populations showed a highly significant association of the R230C variant with type 2 diabetes, particularly with that of early onset (P = 7.6 × 10−6 and 9.4 × 10−8, respectively). CONCLUSIONS—The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disease characterized by progressive cerebellar ataxia and macular degeneration causing progressive blindness. It accounts for 1 to 11.6 % of spinocerebellar ataxias (SCAs) cases worldwide and for 7.4 % of SCA7 cases in Mexico. We identified a cluster of SCA7 families who resided in a circumscribed area of Veracruz and investigated whether the high incidence of the disease in this region was due to a founder effect. A total of 181 individuals from 20 families were studied. Four microsatellite markers and one SNP flanking the ATNX7 gene were genotyped and the ancestral origin and local ancestry analysis of the SCA7 mutation were evaluated. Ninety individuals from 19 families had the SCA7 mutation; all were found to share a common haplotype, suggesting that the mutation in these families originated from a common ancestor. Ancestral origin and local ancestry analysis of SCA7 showed that the chromosomal segment containing the mutation was of European origin. We here present evidence strongly suggesting that the high frequency of SCA7 in Veracruz is due to a founder effect and that the mutation is most likely of European origin with greatest resemblance to the Finnish population.

The patatin like phospholipase domain-containing (PNPLA3) I148M variant is the strongest genetic factor associated with elevated alanine transaminase (ALT) levels in different populations, particularly in Hispanics who have the highest 148M risk allele frequency reported to date. It has been suggested that Indigenous ancestry is associated with higher ALT levels in Mexicans. The aim of the present study was to assess the frequency of the PNPLA3 148M risk allele in Mexican indigenous and Mestizo individuals, and to examine its association with serum ALT levels. The study included a total of 1624 Mexican individuals: 919 Indigenous subjects from five different native groups and 705 Mexican Mestizo individuals (141 cases with ALT levels ≥40 U/L and 564 controls with ALT

Background Several studies have identified multiple obesity-associated loci mainly in European populations. However, their contribution to obesity in other ethnicities such as Mexicans is largely unknown. The aim of this study was to examine 26 obesity-associated single-nucleotide polymorphisms (SNP) in a sample of Mexican mestizos. Methods 9 SNPs in biological candidate genes showing replications (PPARG, ADRB3, ADRB2, LEPR, GNB3, UCP3, ADIPOQ, UCP2, and NR3C1), and 17 SNPs in or near genes associated with obesity in first, second and third wave GWAS (INSIG2, FTO, MC4R, TMEM18, FAIM2/BCDIN3, BDNF, SH2B1, GNPDA2, NEGR1, KCTD15, SEC16B/RASAL2, NPC1, SFRF10/ETV5, MAF, PRL, MTCH2, and PTER) were genotyped in 1,156 unrelated Mexican-Mestizos including 683 cases (441 obese class I/II and 242 obese class III) and 473 normal-weight controls. In a second stage we selected 12 of the SNPs showing nominal associations with obesity, to seek associations with quantitative obesity-related traits in 3 cohorts including 1,218 Mexican Mestizo children, 945 Mexican Mestizo adults, and 543 Indigenous Mexican adults. Results After adjusting for age, sex and admixture, significant associations with obesity were found for 6 genes in the case-control study (ADIPOQ, FTO, TMEM18, INSIG2, FAIM2/BCDIN3 and BDNF). In addition, SH2B1 was associated only with class I/II obesity and MC4R only with class III obesity. SNPs located at or near FAIM2/BCDIN3, TMEM18, INSIG2, GNPDA2 and SEC16B/RASAL2 were significantly associated with BMI and/or WC in the combined analysis of Mexican-mestizo children and adults, and FTO locus was significantly associated with increased BMI in Indigenous Mexican populations. Conclusions Our findings replicate the association of 8 obesity-related SNPs with obesity risk in Mexican adults, and confirm the role of some of these SNPs in BMI in Mexican adults and children.

Background and aims Non-alcoholic fatty liver disease (NAFLD) and elevated alanine transaminase (ALT) levels are common in obese Hispanic adults and children. Recently, a PNPLA3 gene variant (I148M) was strongly associated with NAFLD and higher ALT levels in obese adults, including Hispanics. The aims of this study were to estimate the frequency of elevated ALT levels, and to address the influence of obesity and PNPLA3/I148M on ALT levels in a general population sample of Mexican school-aged children. Methods A total of 1037 non-related Mexican children aged 6 to 12 years were genotyped for the I148M variant. Anthropometric, clinical and metabolic parameters were collected from all participants. Results Elevated ALT levels (> 35 U/L) were more frequent in obese (26.9%) and overweight (9.3%) than in normal weight children (2.2%). The M148M genotype was significantly associated with elevated ALT levels in this population (OR = 3.7, 95% CI 2.3–5.9; P = 3.7 × 10− 8), and children carrying the M148M genotype showed significantly lower HDL cholesterol levels and BMI z-core (P = 0.036 and 0.015, respectively). On stratifying by BMI percentile, this genotype conferred a much greater risk of elevated ALT levels in normal weight (OR = 19.9, 95% CI 2.5–157.7; P = 0.005) than overweight and obese children (OR = 3.4, 95% CI 1.3–8.9; P = 0.014 and OR = 3.1, 95% CI 1.7–5.5; P = 1.4 x10− 4, respectively). Conclusions The I148M PNPLA3 variant is strongly associated with elevated ALT levels in normal weight and overweight/obese Mexican children. Thus, the M148M genotype may be considered as an important risk factor for liver damage in this population.

BACKGROUND: Common variants rs6232 and rs6235 in the PCSK1 gene have been associated with obesity in European populations. We aimed to evaluate the contribution of these variants to obesity and related traits in Mexican children and adults. METHODOLOGY/PRINCIPAL FINDINGS: Rs6232 and rs6235 were genotyped in 2382 individuals, 1206 children and 1176 adults. Minor allele frequencies were 0.78% for rs6232 and 19.99% for rs6235. Rs6232 was significantly associated with childhood obesity and adult class III obesity (OR = 3.01 95%CI 1.64-5.53; P = 4 × 10⁻⁴ in the combined analysis). In addition, this SNP was significantly associated with lower fasting glucose levels (P = 0.01) and with increased insulin levels and HOMA-B (P = 0.05 and 0.01, respectively) only in non-obese children. In contrast, rs6235 showed no significant association with obesity or with glucose homeostasis parameters in any group. CONCLUSION/SIGNIFICANCE: Although rs6232 is rare in the Mexican population, it should be considered as an important risk factor for extreme forms of obesity.

The R230C variant of the ATP-binding cassette transporter A1 (ABCA1) gene has been consistently associated with decreased HDL-cholesterol (HDL-C) concentrations in several studies in the Mexican mestizo population. However, information on how diet composition modifies the effect of the ABCA1-R230C variant on HDL-C concentrations is very scarce. The aim of the present study was to analyze whether the effect of ABCA1-R230C on HDL-C concentrations is modulated by dietary factors in a nationwide population sample of 3591 adults from the National Health and Nutrition Survey conducted by the State’s Employees’ Social Security and Social Services Institute. All participants answered a validated questionnaire to assess health status and weekly food consumption. Fasting blood samples were drawn for biochemical analysis and DNA extraction, and the ABCA1-R230C variant was genotyped using TaqMan assays. Statistical analyses consisted of simple linear and multiple regression modeling adjusting for age, BMI, smoking, and alcohol consumption. The overall C risk allele frequency was 9.3% and the variant was significantly associated with low HDL-C concentrations in both sexes. A significant negative correlation between carbohydrate consumption and HDL-C concentrations was observed in women bearing the R230C variant (P = 0.021) and a significant gene-diet interaction was found only in premenopausal women (P = 0.037). In conclusion, the effect of the ABCA1-R230C gene variant on HDL-C concentrations is modulated by carbohydrate intake in premenopausal women. This finding may help design optimized dietary interventions according to sex and ABCA1-R230C genotype. J. Nutr. doi: 10.3945/jn.111.152421.

Objective Osteoporosis is a complex health disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics with metabolic and environmental factors. The tumor necrosis factor receptor superfamily, member 11b ( TNFRSF11B ) gene , has been investigated in relation to BMD. Three polymorphisms in/nearby TNFRSF11B have been associated with BMD variations in some populations. The aim of this study was to investigate the possible association among three SNPs of TNFRSF11B and their haplotypes with the presence of BMD variations in postmenopausal Mexican Mestizo women. Subjects and methods One thousand unrelated postmenopausal women of Mexican-Mestizo ethnic origin, who attended the outpatient clinic for routine, general medical evaluation, were invited and 750 women accepted to participate in the study. A structured questionnaire for risk factors was applied and BMD was measured in total hip and lumbar spine by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Three single-nucleotide polymorphisms in TNFRSF11B gene were studied: rs4355801, rs2073618, and rs6993813. Real-time PCR allelic discrimination was used for genotyping. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r 2 , and haplotype analysis was conducted. Results Of the subjects, 31% had osteoporosis, 45.1% had osteopenia, and 23.9% had normal BMD. Genotype and allele distributions showed no significant differences; however, A – G – T haplotype was associated with variations in femoral neck BMD ( P = 0.022). Conclusions In our study population, analysis of the haplotypes of TNFRSF11B is a better genetic marker for variations in BMD.

The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults.We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. HDL subclass distribution was analyzed in a subgroup of 81 age, gender and BMI-matched children.Individuals carrying the C230 allele showed a significantly lower HDL-C levels (P=2.9x10(-8)), and higher TC/HDL-C ratio, BMI, BMI z-score and percent fat mass (P=0.001, 0.049, 0.032 and 0.039, respectively). HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (P0.05). Moreover, the proportion of HDL(2b) was lower, while the proportion of HDL(3a) and HDL(3b) particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (P0.05).Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children.

The aim of this study was to investigate the attitudes toward cancer predictive genetic testing in a group of non-high-risk women and men and to analyze the factors that may influence their intention to use these tests. We studied a sample of 859 outpatient women and men attending the four tertiary care hospitals of the ISSSTE (Institute of Social Security and Services for Government Employees) in Mexico City. Subjects between the ages of 30 and 74 years with no present or past history of cancer were asked to answer a questionnaire through face-to-face interview. Two different questionnaires were designed, one for women and the other for men, regarding genetic testing of a high-risk gene for breast and prostate cancer, respectively. Descriptive statistics and univariate comparisons were carried out using chi-square test, Wilcoxon's signed rank test, and Friedman test. Multivariate analysis was performed using logistic regression technique. Results showed that the majority of women attended clinics for regular check-ups and for performing screening tests to detect breast cancer, and men did not follow this pattern regarding prostate cancer. Women were more motivated to get genetic testing, more aware about its benefits, and more concerned about having cancer than men.

Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low-HDL cholesterol but not in high-HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.

Coronary artery disease and diabetes mellitus are among the primary mortality and morbidity causes in Mexico. Genetic factors play a fundamental role in the development of these entities. In the past few years due to the recognition and study of families with monogenic forms of diabetes and dislipidemias associated with development of atherosclerosis, several genes and loci have been associated with these conditions through genetic linkage studies. These studies have provided evidence of the genetic heterogeneity that exists and the type of genes involved in different ethnic groups. The study of Mexican families with early-onset diabetes and combined familial hyperlipidemia showed the participation of different genetic loci associated with these conditions in the Mexican population. These findings show the value of gene mapping strategies in the identification of the genetic component in these entities in our population.

BackgroundVNN1 gene expression levels and the G-137T polymorphism have been associated with high density lipoprotein cholesterol (HDL-C) levels in Mexican American adults. We aim to evaluate the contribution of VNN1 gene expression and the G-137T variant to HDL-C levels and other metabolic traits in Mexican prepubertal children.Methodology/principal findingsVNN1 mRNA expression levels were quantified in peripheral blood leukocytes from 224 unrelated Mexican-Mestizo children aged 6-8 years (107 boys and 117 girls) and were genotyped for the G-137T variant (rs4897612). To account for population stratification, a panel of 10 ancestry informative markers was analyzed. After adjustment for admixture, the TT genotype was significantly associated with lower VNN1 mRNA expression levels (P = 2.9 × 10(-5)), decreased HDL-C levels (β = -6.19, P = 0.028) and with higher body mass index (BMI) z-score (β = 0.48, P = 0.024) in the total sample. In addition, VNN1 expression showed a positive correlation with HDL-C levels (r = 0.220; P = 0.017) and a negative correlation with BMI z-score (r = -0.225; P = 0.015) only in girls.Conclusion/significanceOur data suggest that VNN1 gene expression and the G-137T variant are associated with HDL-C levels in Mexican children, particularly in prepubertal girls.