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BACKGROUND: Arsenic, cadmium, and lead are toxic elements that widely contaminate our environment. These toxicants are associated with acute and chronic health problems, and evidence suggests that minority communities, including Hispanic/Latino Americans, are disproportionately exposed. Few studies have assessed culturally specific predictors of exposure to understand the potential drivers of racial/ethnic exposure disparities. OBJECTIVE: We sought to evaluate acculturation measures as predictors of metal/metalloid (hereafter "metal") concentrations among Mexican American adults to illuminate potential exposure sources that may be targeted for interventions. METHODS: As part of a longitudinal cohort, 510 adults, aged 35 to 69 years, underwent baseline interview, physical examination, and urine sample collection. Self-reported acculturation was assessed across various domains using the Short Acculturation Scale for Hispanics (SASH). Multivariable linear regression was used to assess associations between acculturation and urinary concentrations of arsenic, cadmium, and lead. Ordinal logistic regression was utilized to assess associations between acculturation and a metal mixture score. Lastly, best subset selection was used to build a prediction model for each toxic metal with a combination of the acculturation predictors. RESULTS: After adjustment, immigration factors were positively associated with arsenic and lead concentrations. For lead alone, English language and American media and food preferences were associated with lower levels. Immigration and parental heritage from Mexico were positively associated with the metal mixture, while preferences for English language, media, and food were negatively associated. CONCLUSION: Acculturation-related predictors of exposure provide information about potential sources of toxic metals, including international travel, foods, and consumer products. The findings in this research study provide information to empower future efforts to identify and address specific acculturation-associated toxicant exposures in order to promote health equity through clinical guidance, patient education, and public policy.
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PURPOSE: The purpose of the study was to explore the feasibility of using commonly available technology, such as text messaging, for diabetes prevention in rural Mexican American communities during COVID-19. METHODS: Participants were selected from a diabetes prevention study funded by the National Institutes of Health that, prior to COVID-19, involved in-person group intervention sessions. Participants were predominantly female adults born in Mexico and Spanish-speaking. A subsample (n = 140) was divided into 3 cohorts: (1) 50 who completed the initial in-person intervention prior to the COVID-19 research pause, (2) 60 who needed additional support sessions to complete the intervention and thus received 10 text messages with links to relevant online diabetes prevention videos (TM+), and (3) 30 who received enhanced usual care involving health guidance offered during data collection (control). Repeated measures analysis of covariance was used to evaluate cohort differences at 24 months post baseline. RESULTS: No significant cohort differences were found for depression, eating self-efficacy, alcohol intake, fat avoidance, or sedentary behaviors. Differences in A1C showed both in-person and TM+ cohorts having lower mean A1C levels (5.5%) than the control cohort (5.7%). The TM+ cohort had lower body mass index than other cohorts and a lower diabetes conversion rate (22.2%) compared to the control cohort (28%). Participants indicated preferences for in-person/TM+ combination interventions. The strongest positive feedback was for the TM+ intervention cooking demonstration videos. CONCLUSIONS: Augmented text messaging combined with in-person sessions had similar outcomes to the all in-person strategy and thus has the potential for expanding the reach of diabetes prevention to many Mexican American communities.
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Diabetes Mellitus , Estado Pré-Diabético , Envio de Mensagens de Texto , Adulto , Feminino , Humanos , Masculino , COVID-19 , Diabetes Mellitus/prevenção & controle , Hemoglobinas Glicadas , Americanos Mexicanos , Estado Pré-Diabético/terapiaRESUMO
C-reactive protein (CRP) is a commonly used marker of low-grade inflammation as well as a marker of acute infection. CRP levels are elevated in those with diabetes and increased CRP concentrations are a risk factor for developing type 2 diabetes. Gut microbiome effects on metabolism and immune responses can impact chronic inflammation, including affecting CRP levels, that in turn can lead to the development and maintenance of dysglycemia. Using a high-sensitivity C-reactive protein (hsCRP) assay capable of detecting subtle changes in C-reactive protein, we show that higher hsCRP levels specifically correlate with worsening glycemia, reduced microbial richness and evenness, and with a reduction in the Firmicutes/Bacteroidota ratio. These data demonstrate a pivotal role for CRP not only in the context of worsening glycemia and changes to the gut microbiota, but also highlight CRP as a potential target for mitigating type 2 diabetes progression or as a therapeutic target that could be manipulated through the microbiome. Understanding these processes will provide insights into the etiology of type 2 diabetes in addition to opening doors leading to possible novel diagnostic strategies and therapeutics.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Microbiota , Humanos , Proteína C-Reativa , InflamaçãoRESUMO
Background: Differences in arsenic metabolism capacity may influence risk for type 2 diabetes, but the mechanistic drivers are unclear. We evaluated the associations between arsenic metabolism with overall diabetes prevalence and with static and dynamic measures of insulin resistance among Mexican Americans living in Starr County, Texas. Methods: We utilized data from cross-sectional studies conducted in Starr County, Texas, from 2010-2014. A Mendelian randomization approach was utilized to evaluate the associations between arsenic metabolism and type 2 diabetes prevalence using the intronic variant in the arsenic methylating gene, rs9527, as the instrumental variable for arsenic metabolism. To further assess mechanisms for diabetes pathogenesis, proportions of the urinary arsenic metabolites were employed to assess the association between arsenic metabolism and insulin resistance among participants without diabetes. Urinary biomarkers of arsenic metabolites were modeled as individual proportions of the total. Arsenic metabolism was evaluated both with a static outcome of insulin resistance, homeostatic measure of assessment (HOMA-IR), and a dynamic measure of insulin sensitivity, Matsuda Index. Results: Among 475 Mexican American participants from Starr County, higher metabolism capacity for arsenic is associated with higher diabetes prevalence driven by worse insulin resistance. Presence of the minor T allele of rs9527 is independently associated with an increase in the proportion of monomethylated arsenic (MMA%) and is associated with an odds ratio of 0.50 (95% CI: 0.24, 0.90) for type 2 diabetes. This association was conserved after potential covariate adjustment. Furthermore, among participants without type 2 diabetes, the highest quartile of MMA% was associated with 22% (95% CI: -33.5%, -9.07%) lower HOMA-IR and 56% (95% CI: 28.3%, 91.3%) higher Matsuda Index for insulin sensitivity. Conclusions: Arsenic metabolism capacity, indicated by a lower proportion of monomethylated arsenic, is associated with increased diabetes prevalence driven by an insulin resistant phenotype among Mexican Americans living in Starr County, Texas.
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BACKGROUND: Parkinson's disease is a heterogeneous neurodegenerative disorder with distinctive gut microbiome patterns suggesting that interventions targeting the gut microbiota may prevent, slow, or reverse disease progression and severity. OBJECTIVE: Because secretory IgA (SIgA) plays a key role in shaping the gut microbiota, characterization of the IgA-Biome of individuals classified into either the akinetic rigid (AR) or tremor dominant (TD) Parkinson's disease clinical subtypes was used to further define taxa unique to these distinct clinical phenotypes. METHODS: Flow cytometry was used to separate IgA-coated and -uncoated bacteria from stool samples obtained from AR and TD patients followed by amplification and sequencing of the V4 region of the 16âS rDNA gene on the MiSeq platform (Illumina). RESULTS: IgA-Biome analyses identified significant alpha and beta diversity differences between the Parkinson's disease phenotypes and the Firmicutes/Bacteroides ratio was significantly higher in those with TD compared to those with AR. In addition, discriminant taxa analyses identified a more pro-inflammatory bacterial profile in the IgA+ fraction of those with the AR clinical subclass compared to IgA-Biome analyses of those with the TD subclass and with the taxa identified in the unsorted control samples. CONCLUSION: IgA-Biome analyses underscores the importance of the host immune response in shaping the gut microbiome potentially affecting disease progression and presentation. In the present study, IgA-Biome analyses identified a unique proinflammatory microbial signature in the IgA+ fraction of those with AR that would have otherwise been undetected using conventional microbiome analysis approaches.
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Microbioma Gastrointestinal , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Tremor/etiologia , Microbioma Gastrointestinal/fisiologia , Progressão da Doença , Imunoglobulina ARESUMO
PURPOSE: The purpose of the study was to examine the influences of sex and acculturation on dietary behaviors, macronutrient intake, and dietary quality in participants enrolled in a diabetes prevention initiative in Starr County, Texas. METHODS: Baseline data from the Starr County diabetes prevention study (N = 300) were analyzed-acculturation (country of origin, years in Starr County, language and food preferences), depressive symptoms (Patient Health Questionnaire-9), healthy eating self-efficacy (Weight Efficacy Lifestyle Questionnaire-Short Form), diet quality (USDA Healthy Eating Index), fat avoidance (Fat Avoidance Scale, Spanish version), and macronutrients. Descriptive statistics and univariate analysis of covariance were used to examine differences based on acculturation, controlling for sex. RESULTS: Participants were predominantly female (73%) and, on average, 51 years of age. Language and food preferences favored Spanish language and Hispanic foods, respectively. The majority (71%) was born in Mexico but had resided in Starr County for 33 years, on average. Depressive symptoms were moderate, and eating self-efficacy scores suggested low confidence in making healthy food choices, particularly for saturated fats. Spanish language preference was associated with worse dietary habits. The mean dietary quality score was lower than the national average (54 vs 59 nationally); females had slightly higher dietary quality than males and a higher mean fat avoidance score, although differences were not clinically significant. Intakes of carbohydrate, saturated fats, and cholesterol were higher than recommended daily allowances. CONCLUSIONS: The overall preference for speaking Spanish and the influence of language on dietary intake should inform future dietary interventions. Accommodating cultural norms and food preferences remain major challenges to improving dietary quality among the diverse Hispanic ethnic groups.
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Americanos Mexicanos , Estado Pré-Diabético , Masculino , Humanos , Feminino , Texas/epidemiologia , Aculturação , Ingestão de Alimentos , DietaRESUMO
Hispanics/Latinos have higher rates of type 2 diabetes (T2D), and the origins of these disparities are poorly understood. Environmental endocrine-disrupting chemicals (EDCs), including some metals and metalloids, are implicated as diabetes risk factors. Data indicate that Hispanics/Latinos may be disproportionately exposed to EDCs, yet they remain understudied with respect to environmental exposures and diabetes. The objective of this study is to determine how metal exposures contribute to T2D progression by evaluating the associations between 8 urinary metals and measures of glycemic status in 414 normoglycemic or prediabetic adults living in Starr County, Texas, a Hispanic/Latino community with high rates of diabetes and diabetes-associated mortality. We used multivariable linear regression to quantify the differences in homeostatic model assessments for pancreatic ß-cell function, insulin resistance, and insulin sensitivity (HOMA-ß, HOMA-IR, HOMA-S, respectively), plasma insulin, plasma glucose, and hemoglobin A1c (HbA1c) associated with increasing urinary metal concentrations. Quantile-based g-computation was utilized to assess mixture effects. After multivariable adjustment, urinary arsenic and molybdenum were associated with lower HOMA-ß, HOMA-IR, and plasma insulin levels and higher HOMA-S. Additionally, higher urinary copper levels were associated with a reduced HOMA-ß. Lastly, a higher concentration of the 8 metal mixtures was associated with lower HOMA-ß, HOMA-IR, and plasma insulin levels as well as higher HOMA-S. Our data indicate that arsenic, molybdenum, copper, and this metal mixture are associated with alterations in measures of glucose homeostasis among non-diabetics in Starr County. This study is one of the first to comprehensively evaluate associations of urinary metals with glycemic measures in a high-risk Mexican American population.
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Arsênio , Cobre , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Molibdênio , Adulto , Humanos , Arsênio/urina , Glicemia , Cobre/urina , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/urina , Insulinas/sangue , Americanos Mexicanos , Molibdênio/urina , TexasRESUMO
OBJECTIVES: Examine acculturation and psychological, lifestyle, and physiological factors based on gender and country of origin (U.S. vs. Mexico). METHODS: Baseline data from the Starr County diabetes prevention study (N = 300) were analyzed - acculturation (language), psychological factors (depression), lifestyle factors (sedentary behaviors), and diabetes-related physiological outcomes (insulin resistance). MANOVA and linear regression were used to examine variable relationships based on gender and country of origin and identify predictors of depression and insulin resistance. RESULTS: Participants were: predominantly female (73%); 51 years of age, on average; born in Mexico (71%); and Spanish-speaking. Individuals spent 11 of their waking hours (range = 0-18â h) in sedentary activities. Compared to females, more males spoke English and reported fewer hours in sedentary activities. Compared to participants born in Mexico, those born in the U.S. were more likely to: speak English; report depressive symptoms; and exhibit elevated BMI and insulin resistance rates. Two distinct models significantly predicted depression (R2 = 14.5%) and insulin resistance (R2 = 26.8%), with acculturation-language entering into both models. DISCUSSION: Significant gender and country-of-origin differences were found. Future research on diabetes prevention should examine other Hispanic subgroups and strategies for addressing individual differences, while employing cost-effective group interventions that incorporate these differences and reach more at-risk individuals.
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Diabetes Mellitus , Resistência à Insulina , Masculino , Humanos , Feminino , Americanos Mexicanos , Aculturação , Estilo de VidaRESUMO
Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of diverse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For example, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 (PRIM1) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV1/FVC), and an eQTL of matrix metallopeptidase 15 (MMP15) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 (HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble diverse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases.
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Estudo de Associação Genômica Ampla , Apneia Obstrutiva do Sono , Humanos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Estudos de Associação Genética , Sono , Pleiotropia Genética , Polimorfismo de Nucleotídeo Único , DNA PrimaseRESUMO
Numerous host and environmental factors contribute to persistent and intermittent nasal Staphylococcus aureus carriage in humans. The effects of worsening glycemia on the odds of S. aureus intermittent and persistent nasal carriage was established in two cohorts from an adult Mexican American population living in Starr County, Texas. The anterior nares were sampled at two time points and the presence of S. aureus determined by laboratory culture and spa-typing. Persistent carriers were defined by the presence of S. aureus of the same spa-type at both time points, intermittent carriers were S. aureus-positive for 1 of 2 swabs, and noncarriers were negative for S. aureus at both time points. Diabetes status was obtained through personal interview and physical examination that included a blood draw for the determination of percent glycated hemoglobin A1c (%HbA1c), fasting plasma glucose, and other blood chemistry values. Using logistic regression and general estimating equations, the odds of persistent and intermittent nasal carriage compared to noncarriers across the glycemic spectrum was determined controlling for covariates. Increasing fasting plasma glucose and %HbA1c in the primary and replication cohort, respectively, were significantly associated with increasing odds of S. aureus intermittent, but not persistent nasal carriage. These data suggest that increasing dysglycemia is a risk factor for intermittent S. aureus nasal carriage potentially placing those with poorly controlled diabetes at an increased risk of acquiring an S. aureus infection. IMPORTANCE Factors affecting nasal S. aureus colonization have been studied primarily in the context of persistent carriage. In contrast, few studies have examined factors affecting intermittent nasal carriage with this pathogen. This study demonstrates that the odds of intermittent but not persistent nasal carriage of S. aureus significantly increases with worsening measures of dysglycemia. This is important in the context of poorly controlled diabetes since the risk of becoming colonized with one of the primary organisms associated with diabetic foot infections can lead to increased morbidity and mortality.
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Infecções Estafilocócicas , Staphylococcus aureus , Adulto , Glicemia , Portador Sadio/epidemiologia , Hemoglobinas Glicadas , Humanos , Americanos Mexicanos , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/genéticaRESUMO
Background: The U.S.-Mexico Border is an area of opportunity for improved health care access; however, gaps remain as to how and where U.S. border residents, particularly those who are underinsured, obtain care. Antibiotics are one of the most common reported drivers of cross-border healthcare access and a medication of particular concern since indiscriminate or inappropriate use is associated with antimicrobial resistance. In addition, many studies assessing preferences for Mexican pharmaceuticals and healthcare in U.S. border residents were done prior to 2010 when many prescription medications, including antibiotics, were available over the counter in Mexico. Methods: Data used in this study were collected during the baseline examination of an ongoing longitudinal cohort study in Starr Country, Texas, one of 14 counties on the Texas-Mexico border. Participants self-reported the name, date of use, and the source country of each antibiotic used in the past 12 months. Logistic regression was used to determine social, cultural, and clinical features associated with cross-border procurement of antibiotics. Results: Over 10% of the study cohort reported using antibiotics in the past 30 days with over 60% of all rounds used in the past 12 months sourced from Mexico. A lack of health insurance and generation score, a measure of acculturation, were the strongest predictors of cross-border procurement of antibiotics. Conclusions: Factors previously associated with cross-border acquisition of antibiotics are still present despite changes in 2010 to prescription drug regulations in Mexico. These results may be used to inform future public health initiatives to provide culturally sensitive education about responsible antibiotic stewardship and to address barriers to U.S. healthcare and pharmaceutical access in medically underserved, impoverished U.S.-Mexico border communities.
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Antibacterianos , Americanos Mexicanos , Antibacterianos/provisão & distribuição , Antibacterianos/uso terapêutico , Acessibilidade aos Serviços de Saúde , Humanos , Estudos Longitudinais , México , TexasRESUMO
Secretory IgA (SIgA) is released into mucosal surfaces where its function extends beyond that of host defense to include the shaping of resident microbial communities by mediating exclusion/inclusion of respective microbes and regulating bacterial gene expression. In this capacity, SIgA acts as the fulcrum on which host immunity and the health of the microbiota are balanced. We recently completed an analysis of the gut and salivary IgA-Biomes (16S rDNA sequencing of SIgA-coated/uncoated bacteria) in Mexican-American adults that identified IgA-Biome differences across the glycemic spectrum. As Th17:Treg ratio imbalances are associated with gut microbiome dysbiosis and chronic inflammatory conditions such as type 2 diabetes, the present study extends our prior work by examining the impact of Th17:Treg ratios (pro-inflammatory:anti-inflammatory T-cell ratios) and the SIgA response (Th17:Treg-SIgA axis) in shaping microbial communities. Examining the impact of Th17:Treg ratios (determined by epigenetic qPCR lymphocyte subset quantification) on the IgA-Biome across diabetes phenotypes identified a proportional relationship between Th17:Treg ratios and alpha diversity in the stool IgA-Biome of those with dysglycemia, significant changes in community composition of the stool and salivary microbiomes across glycemic profiles, and genera preferentially abundant by T-cell inflammatory phenotype. This is the first study to associate epigenetically quantified Th17:Treg ratios with both the larger and SIgA-fractionated microbiome, assess these associations in the context of a chronic inflammatory disease, and offers a novel frame through which to evaluate mucosal microbiomes in the context of host responses and inflammation.
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Bactérias/classificação , Diabetes Mellitus Tipo 2/imunologia , Imunoglobulina A Secretora/metabolismo , RNA Ribossômico 16S/genética , Análise de Sequência de DNA/métodos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Bactérias/genética , Bactérias/isolamento & purificação , DNA Bacteriano/genética , DNA Ribossômico/genética , Diabetes Mellitus Tipo 2/microbiologia , Epigênese Genética , Feminino , Microbioma Gastrointestinal , Humanos , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , FilogeniaRESUMO
BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10-8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.
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Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/etiologia , Sequenciamento Completo do Genoma , Alelos , Sequenciamento de Cromatina por Imunoprecipitação , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Medicina de Precisão/métodos , Pesquisa , Transdução de Sinais , Síndromes da Apneia do Sono/metabolismo , Estados UnidosRESUMO
Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
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Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Predisposição Genética para Doença/genética , Adulto , Variação Biológica da População , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Exoma/genética , Genótipo , Humanos , Herança Multifatorial , Penetrância , Medição de RiscoRESUMO
Mucosal surfaces like those present in the lung, gut, and mouth interface with distinct external environments. These mucosal gateways are not only portals of entry for potential pathogens but also homes to microbial communities that impact host health. Secretory immunoglobulin A (SIgA) is the single most abundant acquired immune component secreted onto mucosal surfaces and, via the process of immune exclusion, shapes the architecture of these microbiomes. Not all microorganisms at mucosal surfaces are targeted by SIgA; therefore, a better understanding of the SIgA-coated fraction may identify the microbial constituents that stimulate host immune responses in the context of health and disease. Chronic diseases like type 2 diabetes are associated with altered microbial communities (dysbiosis) that in turn affect immune-mediated homeostasis. 16S rRNA gene sequencing of SIgA-coated/uncoated bacteria (IgA-Biome) was conducted on stool and saliva samples of normoglycemic participants and individuals with prediabetes or diabetes (n = 8/group). These analyses demonstrated shifts in relative abundance in the IgA-Biome profiles between normoglycemic, prediabetic, or diabetic samples distinct from that of the overall microbiome. Differences in IgA-Biome alpha diversity were apparent for both stool and saliva, while overarching bacterial community differences (beta diversity) were also observed in saliva. These data suggest that IgA-Biome analyses can be used to identify novel microbial signatures associated with diabetes and support the need for further studies exploring these communities. Ultimately, an understanding of the IgA-Biome may promote the development of novel strategies to restructure the microbiome as a means of preventing or treating diseases associated with dysbiosis at mucosal surfaces.
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Bactérias/genética , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal/genética , Imunoglobulina A Secretora/análise , Adulto , Bactérias/classificação , Classificação , Diabetes Mellitus Tipo 2/imunologia , Análise Discriminante , Disbiose , Fezes/microbiologia , Feminino , Humanos , Imunoglobulina A Secretora/imunologia , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Saliva/microbiologiaRESUMO
AIMS/HYPOTHESIS: To understand the complex metabolic changes that occur long before the diagnosis of type 2 diabetes, we investigated differences in metabolomic profiles in plasma between prediabetic and normoglycaemic individuals for subtypes of prediabetes defined by fasting glucose, 2 h glucose and HbA1c measures. METHODS: Untargeted metabolomics data were obtained from 155 plasma samples from 127 Mexican American individuals from Starr County, TX, USA. None had type 2 diabetes at the time of sample collection and 69 had prediabetes by at least one criterion. We tested statistical associations of amino acids and other metabolites with each subtype of prediabetes. RESULTS: We identified distinctive differences in amino acid profiles between prediabetic and normoglycaemic individuals, with further differences in amino acid levels among subtypes of prediabetes. When testing all named metabolites, several fatty acids were also significantly associated with 2 h glucose levels. Multivariate discriminative analyses show that untargeted metabolomic data have considerable potential for identifying metabolic differences among subtypes of prediabetes. CONCLUSIONS/INTERPRETATION: People with each subtype of prediabetes have a distinctive metabolomic signature, beyond the well-known differences in branched-chain amino acids. DATA AVAILABILITY: Metabolomics data are available through the NCBI database of Genotypes and Phenotypes (dbGaP, accession number phs001166; www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001166.v1.p1).
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Metabolômica/métodos , Adulto , Idoso , Aminoácidos de Cadeia Ramificada/sangue , Aminoácidos de Cadeia Ramificada/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Jejum/sangue , Hemoglobinas Glicadas/metabolismo , Humanos , Americanos Mexicanos , Pessoa de Meia-Idade , Análise Multivariada , Estado Pré-Diabético/sangue , Estado Pré-Diabético/metabolismo , Texas , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored. METHODS: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis. RESULTS: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos. CONCLUSIONS: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.
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Eletrocardiografia , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Humanos , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
OBJECTIVE: We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS: We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. RESULTS: Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had â¼10 times larger effect sizes on HbA1c levels (ß = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS: This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.
Assuntos
Diabetes Mellitus/genética , Variação Genética/genética , Hemoglobinas Glicadas/genética , Doenças Hematológicas/genética , Hispânico ou Latino/genética , Adulto , Alelos , Glicemia/metabolismo , Diabetes Mellitus/etnologia , Jejum/sangue , Feminino , Estudo de Associação Genômica Ampla , Teste de Tolerância a Glucose , Doenças Hematológicas/etnologia , Humanos , Hiperglicemia/epidemiologia , Hiperglicemia/etnologia , Hiperglicemia/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Estado Pré-Diabético/etnologia , Estado Pré-Diabético/genética , Prevalência , Estados Unidos/epidemiologiaRESUMO
Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
Assuntos
Hexoquinase/genética , Subunidade alfa de Receptor de Interleucina-18/genética , Oxiemoglobinas/metabolismo , Sono/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Moléculas de Adesão Celular Neuronais/genética , Biologia Computacional , Proteínas da Matriz Extracelular/genética , Feminino , Redes Reguladoras de Genes , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Hipóxia/sangue , Hipóxia/genética , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas do Tecido Nervoso/genética , Oxigênio/sangue , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteína Reelina , Serina Endopeptidases/genética , Síndromes da Apneia do Sono/sangue , Síndromes da Apneia do Sono/genética , Adulto JovemRESUMO
PURPOSE: Sleep apnea is associated with increased risk of cardiovascular disease. Elevated plasma galectin-3 levels, a biomarker associated with myocardial fibrosis, are also associated with adverse cardiovascular events, including heart failure. Our objective was to determine the relationship between severity of sleep apnea and plasma levels of galectin-3 and to determine whether this relationship was modified by sex. METHODS: We performed a cross-sectional study of 471 Mexican Americans from Starr County, TX who underwent an overnight, in-home sleep evaluation, and plasma measurement of galectin-3. Severity of sleep apnea was based on apnea hypopnea index (AHI). Multivariable linear regression modeling was used to determine the association between categories of sleep apnea and galectin-3. We also tested for interactions by sex. RESULTS: The mean age was 53 years, and 74% of the cohort was female. The prevalence of moderate to severe sleep apnea (AHI > 15 apnea-hypopnea events per hour) was 36.7%. Moderate to severe sleep apnea was associated with increased levels of galectin-3 in the entire population, but we identified a statistically significant interaction between galectin-3 levels and category of sleep apnea by sex (p for interaction = 0.02). Plasma galectin levels were significantly higher in women with moderate or severe sleep apnea than women with no/mild sleep apnea (multivariable adjusted p < 0.001), but not in men (p = 0.5). CONCLUSIONS: Sleep apnea is associated elevated galectin-3 levels in women but not men. Our findings highlight a possible sex-specific relationship between sleep apnea and galectin-3, a biomarker of potential myocardial fibrosis that has been associated with increased cardiovascular risk.