Mexican Biobank advances population and medical genomics of diverse ancestries.

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.

Three approaches to assessing dietary quality in Mexican adolescents from 2006 to 2018 with data from national health and nutrition surveys.

OBJECTIVE: To assess trends in the dietary quality of Mexican adolescents from 2006 to 2018, both overall and by sociodemographic indicators, using adaptations of the EAT-Lancet Planetary Health (PH) recommendations, optimal intake estimated by the Global Burden of Disease (GBD) and 2015 Mexican Dietary Guidelines (MDG) in nationally representative samples. DESIGN: Using dietary data from a semi-quantitative FFQ, dietary quality indexes were constructed as adaptations of three dietary intake recommendations. Trends in adherence to recommendations were evaluated with multivariate quantile regression models with survey year as the main independent variable and adjusted for age, sex, energy intake, dwelling area, geographical region, household assets condition, and student/non-student status. P values and CI were Bonferroni-corrected. SETTING: Mexico. PARTICIPANTS: Non-pregnant or lactating adolescents aged 12-19 years (n 16 520). RESULTS: Adherence to the PH index was about 40 %, GBD was nearly 35 % and MDG was about 37 %. The lowest adherences were for added sugars, sugar-sweetened beverages, nuts and seeds, red meats, processed meats, and legumes (<28 %). No 2006-2018 trends in total adherence were found in any index. Nevertheless, negative adherence trends were identified for poultry (ß = -2·4), and saturated fats (ß = -0·93), and positive for unsaturated oils (ß = 1·23), in the PH. In MDG, relevant trends were found for plain water (ß = 1·63) and foods rich in fats (ß = -1·24). CONCLUSIONS: Mexican adolescents have demonstrated poor dietary quality by these three approaches. Therefore, this population has a high-risk profile for diet-associated chronic diseases. Further research and appropriate public policies are needed.

Association between life-course leisure-time physical activity and prostate cancer.

OBJECTIVE: To evaluate the association between life-course leisure-time physical activity (PA) and prostate cancer (PC) among males living in Mexico City. Materials and meth-ods. Information from 394 incident PC cases and 794 popula-tion controls matched by age (± 5 years), was analyzed. Using leisure-time PA information at different life stages, life-course PA patterns were constructed. The association between PA and PC was estimated using an unconditional logistic regres-sion model. RESULTS: Three life-course PA patterns were identified: low PA (71.0%), moderate PA (22.0%), and high PA (7.0%); this last pattern was characterized by higher levels and consistent PA practice. Compared with inactive males, those in the high PA pattern (OR: 0.50; 95%CI: 0.26-0.93) had significantly lower PC odds. CONCLUSION: Intense and regular PA could reduce the possibility of PC. These results are in accordance with PA World Health Organization rec-ommendations.

Clinical and metabolomic predictors of regression to normoglycemia in a population at intermediate cardiometabolic risk.

BACKGROUND: Impaired fasting glucose (IFG) is a prevalent and potentially reversible intermediate stage leading to type 2 diabetes that increases risk for cardiometabolic complications. The identification of clinical and molecular factors associated with the reversal, or regression, from IFG to a normoglycemia state would enable more efficient cardiovascular risk reduction strategies. The aim of this study was to identify clinical and biological predictors of regression to normoglycemia in a non-European population characterized by high rates of type 2 diabetes. METHODS: We conducted a prospective, population-based study among 9637 Mexican individuals using clinical features and plasma metabolites. Among them, 491 subjects were classified as IFG, defined as fasting glucose between 100 and 125 mg/dL at baseline. Regression to normoglycemia was defined by fasting glucose less than 100 mg/dL in the follow-up visit. Plasma metabolites were profiled by Nuclear Magnetic Resonance. Multivariable cox regression models were used to examine the associations of clinical and metabolomic factors with regression to normoglycemia. We assessed the predictive capability of models that included clinical factors alone and models that included clinical factors and prioritized metabolites. RESULTS: During a median follow-up period of 2.5 years, 22.6% of participants (n = 111) regressed to normoglycemia, and 29.5% progressed to type 2 diabetes (n = 145). The multivariate adjusted relative risk of regression to normoglycemia was 1.10 (95% confidence interval [CI] 1.25 to 1.32) per 10 years of age increase, 0.94 (95% CI 0.91-0.98) per 1 SD increase in BMI, and 0.91 (95% CI 0.88-0.95) per 1 SD increase in fasting glucose. A model including information from age, fasting glucose, and BMI showed a good prediction of regression to normoglycemia (AUC = 0.73 (95% CI 0.66-0.78). The improvement after adding information from prioritized metabolites (TG in large HDL, albumin, and citrate) was non-significant (AUC = 0.74 (95% CI 0.68-0.80), p value = 0.485). CONCLUSION: In individuals with IFG, information from three clinical variables easily obtained in the clinical setting showed a good prediction of regression to normoglycemia beyond metabolomic features. Our findings can serve to inform and design future cardiovascular prevention strategies.

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

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

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

A panel of 32 AIMs suitable for population stratification correction and global ancestry estimation in Mexican mestizos.

BACKGROUND: Association studies are useful to unravel the genetic basis of common human diseases. However, the presence of undetected population structure can lead to both false positive results and failures to detect genuine associations. Even when most of the approaches to deal with population stratification require genome-wide data, the use of a well-selected panel of ancestry informative markers (AIMs) may appropriately correct for population stratification. Few panels of AIMs have been developed for Latino populations and most contain a high number of markers (> 100 AIMs). For some association studies such as candidate gene approaches, it may be unfeasible to genotype a numerous set of markers to avoid false positive results. In such cases, methods that use fewer AIMs may be appropriate. RESULTS: We validated an accurate and cost-effective panel of AIMs, for use in population stratification correction of association studies and global ancestry estimation in Mexicans, as well as in populations having large proportions of both European and Native American ancestries. Based on genome-wide data from 1953 Mexican individuals, we performed a PCA and SNP weights were calculated to select subsets of unlinked AIMs within percentiles 0.10 and 0.90, ensuring that all chromosomes were represented. Correlations between PC1 calculated using genome-wide data versus each subset of AIMs (16, 32, 48 and 64) were r2 = 0.923, 0.959, 0.972 and 0.978, respectively. When evaluating PCs performance as population stratification adjustment covariates, no correlation was found between P values obtained from uncorrected and genome-wide corrected association analyses (r2 = 0.141), highlighting that population stratification correction is compulsory for association analyses in admixed populations. In contrast, high correlations were found when adjusting for both PC1 and PC2 for either subset of AIMs (r2 > 0.900). After multiple validations, including an independent sample, we selected a minimal panel of 32 AIMs, which are highly informative of the major ancestral components of Mexican mestizos, namely European and Native American ancestries. Finally, the correlation between the global ancestry proportions calculated using genome-wide data and our panel of 32 AIMs was r2 = 0.972. CONCLUSIONS: Our panel of 32 AIMs accurately estimated global ancestry and corrected for population stratification in association studies in Mexican individuals.

Survival After Ischemic and Hemorrhagic Stroke: A 4-Year Follow-Up at a Mexican Hospital.

BACKGROUND: Overall, 75.2% of deaths from stroke occur in low- and middle-income countries. Mexico is a middle-income country with little information about the prognosis of early and late postischemic and hemorrhagic stroke. OBJECTIVE: To evaluate the factors associated with post-stroke survival in the Mexican population. METHODS: Observational study of consecutive stroke cases involving a first-ever hemorrhagic or ischemic stroke, with patients who received care at the National Institute of Neurology and Neurosurgery, in Mexico City, between 2009 and 2012. Patients were followed for up to 4 years after the index event. Exploratory analysis of survival was carried out with Kaplan-Meier and log-rank tests. Factors associated with survival time were determined using Cox models. RESULTS: A total of 300 out of 544 (55.15%) patients had a hemorrhagic stroke, 135 of 544 (24.82%) patients died during the entire follow-up period, and 56 of 544 (10.29%) died in the first 30 days post-stroke (early mortality). Early mortality after stroke was associated with age ≥ 65 years (Adjusted Hazard Ratio - AHR = 2.07, P = .02) and ≥ 2 in-hospital medical complications (AHR = 46.13, P < .01). Late mortality was associated with age ≥ 65 years (AHR = 3.43, P < .01), ≥2 in-hospital medical complications (AHR = 2.55, P < .01), high comorbidity (AHR = 5.43, P < .01), and recurrence (AHR = 1.90, P = .01). CONCLUSIONS: Patients with hemorrhagic and ischemic stroke who presented in-hospital medical complications, high comorbidity, and were over 65 years old had higher rates of early and late mortality.

Frequency of the T307A, N680S, and -29G>A single-nucleotide polymorphisms in the follicle-stimulating hormone receptor in Mexican subjects of Hispanic ancestry.

BACKGROUND: FSHR SNPs may influence the ovarian sensitivity to endogenous and exogenous FSH stimulation. Given the paucity of data on the FSHR c.919A > G, c.2039A > G and - 29G > A SNPs in Hispanic population, we here analyzed their frequency distribution in Mexican mestizo women. METHODS: Samples from 224 Mexican mestizo women enrolled in an IVF program as well as a genotype database from 8182 Mexican mestizo subjects, were analyzed for FSHR SNPs at positions c.919, c.2039 and - 29G > A. Association between the genetic variants and reproductive outcomes was assessed. RESULTS: The c.919 and c.2039 SNPs were in strong linkage disequilibrium and their corresponding genotype frequencies in the IVF group were: AA 46.8%, AG 44.2%, and GG 8.9%, and AA 41.9%, AG 48.2% and GG 9.8%, respectively. For the -29G > A SNP, genotype frequencies were 27% (GG), 50% (GA) and 23% (AA). In normal oocyte donors with the c.2039 GG genotype, the number of oocytes recovered after ovarian stimulation (COS) were significantly (p < 0.01) lower than in those bearing other genotypes in this or the -29G > A SNP. Analysis of the large scale database revealed that both allelic and genotype frequencies for the three SNPs were very similar to those detected in the IVF cohort (p ≥ 0.38) and that female carriers of the c.2039 G allele tended to present lower number of pregnancies than women bearing the AA genotype; this trend was stronger when women with more Native American ancestry was separately analyzed (OR = 2.0, C.I. 95% 1.03-3.90, p = 0.04). There were no differences or trends in the number of pregnancies among the different genotypes of the -29G > A SNP. CONCLUSIONS: The frequency of the GG/GG combination genotype for the c.919 and c.2039 SNPs in Mexican hispanics is among the lowest reported. The GG genotype is associated with decreased number of oocytes recovered in response to COS as well as to lower pregnancy rates in Hispanic women from the general population. The absence of any effect of the -29AA genotype on the response to COS, indicates that there is no need to perform this particular genotype testing in Hispanic women with the purpose of providing an individually-tailored COS protocol.

Prenatal exposure to persistent organic compounds and their association with anogenital distance in infants.

RESEARCH QUESTION: What is the association between prenatal exposure to persistent organic pollutants, separately and combined, and anogenital distance (in-utero endocrine disruption marker). DESIGN: A cohort study conducted in Sonora, Mexico. Blood concentrations of polychlorobiphenyls (PCB) 28, 74, 118, 138/158, 153, 170, 180 and the isomers of dichlorodiphenyltrichloroethane (DDT) and its metabolites were determined in women in the third trimester of pregnancy; three variants of anogenital distance were measured on five occasions during the first year of life of their infants: 82 girls (402 observations) and 74 boys (356 observations). RESULTS: Boys had negative and significant associations between anogenital distance/height and the concentrations of PCB 28 (beta = - 0.005;P = 0.006), PCB 74 (beta = - 0.003;P = 0.013), and PCB 170 (beta = - 0.005;P = 0.001) when analysed individually. Negative and significant associations were also found using statistical models applied to mixtures of compounds. The latter associations were sometimes larger in magnitude and significance, suggesting a possible potentiation of the compounds. No associations were observed between anogenital distance and DDT in either sex or with PCB in girls. CONCLUSIONS: The decreased anogenital distance associated with prenatal exposure to the persistent organic pollutants, observed consistently in different analyses, suggests an under-masculinizing effect of these environmental pollutants in boys.

Determinants of folate and vitamin B12 plasma levels in the French E3N-EPIC cohort.

PURPOSE: Impaired B vitamin status has been identified as a risk factor for major chronic diseases. This study aims at examining the determinants of plasma folate and vitamin B12 concentrations, considering lifestyle factors and MTHFR polymorphisms. METHODS: A total of 988 women aged 40-65 years from the French E3N cohort were investigated. Intakes of folate and vitamin B12 were assessed using food frequency questionnaires, and plasma concentrations were measured by microbiological assay. Dietary scores were computed to summarize folate and vitamin B12 dietary sources. MTHFR-C677T and MTHFR-A1298C were determined by Kaspar assay. Pearson's partial correlation coefficients and multivariable linear regression models were used to assess correlations between main determinants and plasma folate and vitamin B12 levels. RESULTS: The partial correlation coefficient between dietary intakes and plasma folate was 0.19 (p value <0.001) and 0.08 (p value = 0.008) for vitamin B12. Dietary scores were the main determinant of B vitamin plasma concentrations with a percent change per unit increase of 12.64% (p value <0.001) for folate and 7.6% (p value <0.001) for vitamin B12. Homozygous (T/T) or heterozygous (C/T) women for MTHFR-C677T had lower plasma folate concentrations [C/T: -6.48% (p value = 0.038) and T/T: -15.89% (p value <0.001)] compared to women carrying the C/C genotype. Other determinants of B vitamin plasma concentration include: smoking status for folate, and age and hormone replacement therapy for vitamin B12. CONCLUSIONS: We confirmed previous findings on the role of diet as main determinant of folate and vitamin B12 plasma concentrations. However, the impact of genetic polymorphisms and lifestyle factors on plasma B vitamin concentrations should not be neglected.

Prenatal Docosahexaenoic Acid Supplementation Does Not Affect Nonfasting Serum Lipid and Glucose Concentrations of Offspring at 4 Years of Age in a Follow-Up of a Randomized Controlled Clinical Trial in Mexico.

BACKGROUND: Docosahexaenoic acid (DHA) has regulatory effects on lipid and glucose metabolism. Differences in DHA availability during specific developmental windows may program metabolic changes. OBJECTIVE: We investigated the effects of maternal DHA supplementation during pregnancy on the nonfasting serum lipid and glucose concentrations of offspring at 4 y of age. METHODS: We used data from the Prenatal Omega-3 Fatty Acid Supplementation, Growth, and Development trial, a double-blind randomized controlled trial conducted in Mexico. Pregnant women were supplemented daily with 400 mg DHA or placebo from 18-22 wk of gestation to delivery. The primary outcomes of the trial were offspring growth and neurological development. Nonfasting blood samples were obtained from the offspring at 4 y of age. We analyzed serum total, HDL, non-HDL, and LDL cholesterol; the total-to-HDL cholesterol ratio; apolipoprotein B (apoB); triglycerides; glucose; and insulin as secondary outcomes and compared their concentrations between treatment groups. RESULTS: Data from 524 offspring were available. The women were compliant with the intervention based on pill counts and changes in cord blood and breast milk DHA concentrations. None of the between-group differences (DHA compared with placebo), adjusted for maternal height and time since last food intake, were significant (P range 0.27-0.83). Means (95% CIs) were as follows: total cholesterol (TC), 1.73 mg/dL (-2.63, 6.09 mg/dL); HDL cholesterol, 0.66 mg/dL (-1.07, 2.39 mg/dL); non-HDL cholesterol, 1.77 mg/dL (-1.83, 5.37 mg/dL); LDL cholesterol, 1.62 mg/dL (-2.21, 5.45 mg/dL); TC:HDL ratio, 0.01 (-0.09, 0.11); apoB, -0.15 mg/dL (-2.78, 2.48 mg/dL); triglycerides, 0.21 mg/dL (-10.93, 10.52 mg/dL); glucose, -0.67 mg/dL (-2.46, 1.11 mg/dL); and insulin, 0.62 µU/mL (-0.88, 2.11 µU/mL). CONCLUSION: Prenatal DHA supplementation does not affect nonfasting serum lipid and glucose concentrations of offspring at 4 y of age. This trial was registered at clinicaltrials.gov as NCT00646360.

Metabolic Syndrome and Mammographic Density in Premenopausal Chilean Women.

BACKGROUND: Metabolic syndrome (MetS) has been previously associated with an increased risk of breast cancer in postmenopausal women. Mammographic density (MD) is a marker of breast cancer risk. There is little evidence of an association between MetS and MD in premenopausal women. METHODS: Through a cross-sectional study, we evaluated 364 premenopausal Chilean women in which we measured anthropometric, blood pressure, and metabolic markers. MetS and its components were defined according to the National Cholesterol Education Program Adult Treatment Plan III criteria. We estimated MD by absolute dense volume (ADV, cm3), nondense volume (NDV, cm3), and percentage of dense volume (PDV, %). The relationship between MetS and MD was assessed by linear regression models. RESULTS: After adjusting for sociodemographic and gyneco-obstetrics variables, nonsignificant association was found between MetS and ADV (log ß = 0.10; 95%CI: -0.01, 0.21). However, abdominal obesity, high triglycerides, and number of components of MetS were directly related to higher ADV (P < 0.05). CONCLUSION: Our results showed no association between MetS and ADV; nevertheless, abdominal obesity and triglycerides were related to higher ADV. If MD could be modifiable through nutritional factors, it would open new perspectives for the prevention of breast cancer through obesity prevention strategies at population level.

[Oxidative stress, lung function and exposure to air pollutants in Mexican schoolchildren with and without asthma]. / Estrés oxidativo, función pulmonar y exposición a contaminantes atmosféricos en escolares mexicanos con y sin asma.

OBJECTIVE.: To assess the association between the air pollutants exposure on markers of oxidative stress and lung function in schoolchildren with and without asthma from Salamanca and Leon Guanajuato, Mexico. MATERIALS AND METHODS: We realized determinations of oxidative stress biomarkers and lung function tests in 314 schoolchildren. Information of air pollutants (O3, SO2, CO, PM2.5 and PM10) were obtained from monitoring stations and multiple linear regression models were run to assess the association. RESULTS: An increase of 0.09 pmol in conjugated dienes was observed by exposure to PM10 lag 1 in asthmatics from Salamanca (p<0.05). The exposure to O3 during the same day increased the concentration of Lipohydroperoxides in 4.38 nmol in asthmatics of Salamanca, as well as in 2.31 nmol by exposure to PM10 lag 2 (p<0.05). The forced vital capacity decreased by 138 and 203 ml in children without asthma, respectively, due to exposure to carbon monoxide (p<0.05). CONCLUSIONS: Exposure to air pollutants increase oxidative stress and decreased lung function in schoolchildren, with and without asthma.

OBJETIVO: Evaluar la asociación entre la exposición a contaminantes atmosféricos y marcadores de estrés oxidativo, por un lado, y la función pulmonar, por el otro, en escolares, con y sin asma, de las ciudades de Salamanca y León, en Guanajuato, México. MATERIAL Y MÉTODOS: Se realizaron determinaciones de marcadores de estrés oxidativo y pruebas de función pulmonar en 314 escolares, y se obtuvo información sobre contaminantes atmosféricos (ozono, dióxido de azufre, monóxido de carbono y partículas menores de 2.5 µm y menores de 10 µm) de las estaciones de monitoreo correspondientes. Para evaluar la asociación se corrieron modelos de regresión lineal múltiple. RESULTADOS: Con un día de retraso a la exposición a partículas menores de 10 µm (PM10), se observó un incremento de 0.09 pmol en los dienos conjugados entre niños asmáticos de Salamanca (p<0.05). La exposición a ozono durante el mismo día incrementó la concentración de lipo-hidroperóxidos en 4.38 nmol entre asmáticos de Salamanca, así como en 2.31 nmol por la exposición a PM10 para dos días de retraso (p<0.05). La capacidad vital forzada disminuyó 138 y 203 ml en niños sin asma, respectivamente, por la exposición a monóxido de carbono (p<0.05). CONCLUSIONES: La exposición a contaminantes atmosféricos incrementa el estrés oxidativo y disminuye la función pulmonar en escolares con y sin asma.

Temporal Trends in Mortality from Ischemic and Hemorrhagic Stroke in Mexico, 1980-2012.

BACKGROUND: Over the past decades, the decline in mortality from stroke has been more pronounced in high-income countries than in low- and middle-income countries. We evaluated changes in temporal stroke mortality trends in Mexico according to sex and type of stroke. METHODS: We assessed stroke mortality from Mexico's National Health Information System for the period from 1980 to 2012. We analyzed age-adjusted mortality rates by sex, type of stroke, and age group. The annual percentage change and the average annual percentage change (AAPC) in the slopes of the age-adjusted mortality trends were determined using joinpoint regression models. RESULTS: The age-adjusted mortality rates due to stroke decreased between 1980 and 2012, from 44.55 to 33.47 per 100,000 inhabitants, and the AAPC (95% confidence interval [CI]) was -.9 (-1.0 to -.7). The AAPC for females was -1.1 (-1.5 to -.7) and that for males was -.7 (-.9 to -.6). People older than 65 years showed the highest mortality throughout the period. Between 1980 and 2012, the AAPC (95% CI) for ischemic stroke was -3.8 (-4.8 to -2.8) and was -.5 (-.8 to -.2) for hemorrhagic stroke. For the same period, the AAPC for intracerebral hemorrhage (ICH) was -.7 (-1.6 to .2) and that for subarachnoid hemorrhage (SAH) was 1.6 (.4-2.8). CONCLUSIONS: The age-adjusted mortality rates of all strokes combined, ischemic stroke, hemorrhagic stroke, and ICH, decreased between 1980 and 2012 in Mexico. However, the increase in SAH mortality makes it necessary to explore the risk factors and clinical management of this type of stroke.

Genome-wide association study of colorectal cancer in Hispanics.

Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10(-8) Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10(-6)) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47-2.36); P = 2.5×10(-7)], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21-1.55); P = 4.0×10(-7)), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36-2.01); P = 4.1×10(-7)) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37-2.08); P=7.8×10(-7)]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10(-5)) and 11q12.2 (P = 6.8×10(-5)), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations.

Effects of antioxidant supplements and nutrients on patients with asthma and allergies.

Asthma and allergic diseases have become a worldwide public health concern because of their increased prevalence. Despite decades of research on risk factors, the causes of these disorders are poorly understood. They are thought to develop through complex interactions between genetic and environmental factors. Because pulmonary and systemic oxidative stress increase inflammatory responses relevant to asthma and allergy, dietary or vitamin supplementation with antioxidants (a broad and varied category) has been proposed as an approach to reducing asthma incidence or morbidity. Meta-analyses of observational epidemiologic studies of variable methodological quality suggest associations of relatively low dietary intake of antioxidants and higher asthma and allergy prevalence. However, there have been few longitudinal studies of maternal or child dietary or vitamin/supplement antioxidant intake and asthma/allergy development. Moreover, there are no clinical trial data to support the use of dietary antioxidants or supplements to prevent asthma or allergy. A few small clinical trials suggest that specific antioxidants from diet or vitamin supplements might improve asthma control or lung function in asthmatic children or adults. Studies suggest that responses to antioxidants might be modified by life stage, genetic susceptibility, and environmental sources of oxidative stress. Large trials of antioxidant vitamin supplementation to prevent cancer suggest an increase in overall mortality with antioxidant vitamin supplementation, at least in populations with sufficient dietary antioxidant intake. This cautionary experience suggests that future trials to assess whether antioxidants reduce asthma incidence or improve asthma control should focus on supplementation of dietary sources of antioxidants. The potential benefits and risks of trials of vitamin supplements might be considered in special situations in which vulnerable populations have marked deficiency in dietary antioxidants, poor access to dietary antioxidants, and high exposure to environmental sources of oxidants.

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.

IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

Immunogenicity of RV1 and RV5 vaccines administered in standard and interchangeable mixed schedules: a randomized, double-blind, non-inferiority clinical trial in Mexican infants.

Introduction: Rotavirus-associated diarrheal diseases significantly burden healthcare systems, particularly affecting infants under five years. Both Rotarix™ (RV1) and RotaTeq™ (RV5) vaccines have been effective but have distinct application schedules and limited interchangeability data. This study aims to provide evidence on the immunogenicity, reactogenicity, and safety of mixed RV1-RV5 schedules compared to their standard counterparts. Methods: This randomized, double-blind study evaluated the non-inferiority in terms of immunogenicity of mixed rotavirus vaccine schedules compared to standard RV1 and RV5 schedules in a cohort of 1,498 healthy infants aged 6 to 10 weeks. Participants were randomly assigned to one of seven groups receiving various combinations of RV1, and RV5. Standard RV1 and RV5 schedules served as controls of immunogenicity, reactogenicity, and safety analysis. IgA antibody levels were measured from blood samples collected before the first dose and one month after the third dose. Non-inferiority was concluded if the reduction in seroresponse rate in the mixed schemes, compared to the standard highest responding scheme, did not exceed the non-inferiority margin of -0.10. Reactogenicity traits and adverse events were monitored for 30 days after each vaccination and analyzed on the entire cohort. Results: Out of the initial cohort, 1,365 infants completed the study. Immunogenicity analysis included 1,014 infants, considering IgA antibody titers ≥20 U/mL as seropositive. Mixed vaccine schedules demonstrated non-inferiority to standard schedules, with no significant differences in immunogenic response. Safety profiles were comparable across all groups, with no increased incidence of serious adverse events or intussusception. Conclusion: The study confirms that mixed rotavirus vaccine schedules are non-inferior to standard RV1 and RV5 regimens in terms of immunogenicity and safety. This finding supports the flexibility of rotavirus vaccination strategies, particularly in contexts of vaccine shortage or logistic constraints. These results contribute to the global effort to optimize rotavirus vaccination programs for broader and more effective pediatric coverage.Clinical trial registration: ClinicalTrials.gov, NCT02193061.

Ozone exposure, vitamin C intake, and genetic susceptibility of asthmatic children in Mexico City: a cohort study.

BACKGROUND: We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function (FEF(25-75)) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566). METHODS: 257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches. RESULTS: The change in FEF(25-75) per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was -91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF(25-75) of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF25-75 did not differ by vitamin C intake. CONCLUSIONS: Our results provide further evidence that asthmatic children predicted to have compromised antioxidant defense by virtue of genetic susceptibility combined with deficient antioxidant intake may be at increased risk of adverse effects of ozone on pulmonary function.