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1.
Am Heart J ; 243: 201-209, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34610283

RESUMO

BACKGROUND: Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations. METHODS: We used Ward's Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status. RESULTS: Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations. CONCLUSIONS: We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease.

3.
Brain Sci ; 11(7)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202057

RESUMO

BACKGROUND: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990-1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). METHODS: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene-gene and gene-environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. CONCLUSIONS: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

4.
Life Sci ; 282: 119808, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34242657

RESUMO

AIMS: Gulf War illness (GWI), a chronic symptom-based disorder, affects up to 30% of Veterans who served in the 1990-1991 Gulf War1. Because no diagnostic test or code for GWI exists, researchers typically determine case status using self-reported symptoms and conditions according to Kansas2 and CDC3 criteria. No validated algorithm has been published and case definitions have varied slightly by study. This paper aims to standardize the application of the original CDC and Kansas case definitions by defining a framework for writing reliable code for complex case definitions, implementing this framework on a sample of 1343 Gulf War Veterans (GWVs), and validating the framework by applying the code to a sample of 41,077 GWVs. MAIN METHODS: Methods were drawn from software engineering: write pseudocode, write test cases, and write code; then test code. Code was examined for accuracy, flexibility, replicability, and reusability. KEY FINDINGS: The pseudocode promoted understanding of the planned algorithm, encouraging discussion and leading to agreement on the case definition algorithms among all team members. The completed SAS code was written for and tested in the Gulf War Era Cohort and Biorepository (GWECB)4. This code was adapted and tested in the Million Veteran Program (MVP)5. The code was documented for reproducibility and reusability. SIGNIFICANCE: Ease of reuse suggests that this method could be used to standardize the application of other case definitions, reducing time and resources spent by each study team. Documentation, code, and test cases are available through the Department of Veterans Affairs (VA) Phenomics catalog6.


Assuntos
Algoritmos , Síndrome do Golfo Pérsico/classificação , Veteranos , Doença Crônica , Estudos de Coortes , Guerra do Golfo , Humanos , Masculino , Síndrome do Golfo Pérsico/diagnóstico
5.
Dig Dis Sci ; 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34089135

RESUMO

BACKGROUND: Colorectal cancer (CRC) screening guidelines recommend frequent colonoscopies and consideration of genetic testing in individuals with ≥10 cumulative adenomas. However, it is unclear how these guidelines apply to routine practice. AIMS: We estimated the proportion of participants found to have ≥10 cumulative adenomas in a screening population and described their outcomes of advanced neoplasia (AN), CRC, and extra-colonic malignancy. METHODS: We performed a secondary analysis of VA CSP#380, which includes 3121 veterans aged 50-75 who were followed up to 10 years after screening colonoscopy. We calculated the cumulative risk of ≥10 cumulative adenomas by Kaplan-Meier method. We compared baseline risk factors in those with and without ≥10 cumulative adenomas as well as the risk for AN (adenoma ≥1 cm, villous adenoma or high-grade dysplasia, or CRC) and extra-colonic malignancy by multivariate logistic regression. RESULTS: The cumulative risk of ≥10 cumulative adenomas over 10.5 years was 6.51% (95% CI 4.38%-9.62%). Age 60-69 or 70-75 at baseline colonoscopy was the only factors associated with the finding of ≥10 cumulative adenomas. Compared to those with 0-9 cumulative adenomas, participants with ≥10 cumulative adenomas were more likely to have had AN (OR 17.03; 95% CI 9.41-30.84), including CRC (OR 7.00; 95% CI 2.84-17.28), but not extra-colonic malignancies. CONCLUSIONS: Approximately 6.5% of participants in this screening population were found to have ≥10 cumulative adenomas over 10.5 years, which was uncommon before age 60. These participants were found to have AN and CRC significantly more often compared to those with lower cumulative adenomas.

6.
Front Genet ; 12: 661497, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140969

RESUMO

Objective: Coronary artery disease (CAD) is an age-associated condition that greatly increases the risk of mortality. The purpose of this study was to identify gene variants associated with all-cause mortality among individuals with clinically phenotyped CAD using a genome-wide screening approach. Approach and Results: We performed discovery (n = 1,099), replication (n = 404), and meta-analyses (N = 1,503) for association of genomic variants with survival outcome using secondary data from White participants with CAD from two GWAS sub-studies of the Duke Catheterization Genetics Biorepository. We modeled time from catheterization to death or last follow-up (median 7.1 years, max 12 years) using Cox multivariable regression analysis. Target statistical screening thresholds were p × 10-8 for the discovery phase and Bonferroni-calculated p-values for the replication (p < 5.3 × 10-4) and meta-analysis (p < 1.6 × 10-3) phases. Genome-wide analysis of 785,945 autosomal SNPs revealed two SNPs (rs13007553 and rs587936) that had the same direction of effect across all three phases of the analysis, with suggestive p-value association in discovery and replication and significant meta-analysis association in models adjusted for clinical covariates. The rs13007553 SNP variant, LINC01250, which resides between MYTIL and EIPR1, conferred increased risk for all-cause mortality even after controlling for clinical covariates [HR 1.47, 95% CI 1.17-1.86, p(adj) = 1.07 × 10-3 (discovery), p(adj) = 0.03 (replication), p(adj) = 9.53 × 10-5 (meta-analysis)]. MYT1L is involved in neuronal differentiation. TSSC1 is involved in endosomal recycling and is implicated in breast cancer. The rs587936 variant annotated to DAB2IP was associated with increased survival time [HR 0.65, 95% CI 0.51-0.83, p(adj) = 4.79 × 10-4 (discovery), p(adj) = 0.02 (replication), p(adj) = 2.25 × 10-5 (meta-analysis)]. DAB2IP is a ras/GAP tumor suppressor gene which is highly expressed in vascular tissue. DAB2IP has multiple lines of evidence for protection against atherosclerosis. Conclusion: Replicated findings identified two candidate genes for further study regarding association with survival in high-risk CAD patients: novel loci LINC01250 (rs13007553) and biologically relevant candidate DAB2IP (rs587936). These candidates did not overlap with validated longevity candidate genes. Future research could further define the role of common variants in survival outcomes for people with CAD and, ultimately, improve longitudinal outcomes for these patients.

7.
Genome Med ; 13(1): 83, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001247

RESUMO

BACKGROUND: While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. RESULTS: Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. CONCLUSIONS: Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .


Assuntos
COVID-19/genética , Bases de Dados de Ácidos Nucleicos , Predisposição Genética para Doença , Desequilíbrio de Ligação , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , SARS-CoV-2/genética , Estudo de Associação Genômica Ampla , Humanos
8.
Genome Med ; 13(1): 74, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931109

RESUMO

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

9.
Front Immunol ; 12: 661290, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995384

RESUMO

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.


Assuntos
Colo/imunologia , Células Dendríticas/imunologia , Macrófagos/imunologia , Fagócitos/imunologia , Células Th17/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígeno CD24/imunologia , Antígeno CD24/metabolismo , Colo/citologia , Colo/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Expressão Gênica/imunologia , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Intestino Delgado/imunologia , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Camundongos da Linhagem 129 , Camundongos Knockout , Camundongos Transgênicos , Fagócitos/metabolismo , Receptor da Anafilatoxina C5a/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Células Th17/metabolismo
10.
Life Sci ; 278: 119454, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33811897

RESUMO

AIMS: This study characterizes Gulf War Illness (GWI) among U.S. veterans who participated in the Gulf War Era Cohort and Biorepository (GWECB). MAIN METHODS: Mailed questionnaires were collected between 2014 and 2016. Self-reported GWI symptoms, symptom domain criteria, exclusionary diagnoses, and case status were examined based on the originally published Kansas and Centers for Disease Control (CDC) definitions in the GWECB cohort (n = 849 deployed to Gulf and n = 267 non-deployed). Associations among GWI and deployment status, demographic, and military service characteristics were examined using logistic regression. KEY FINDINGS: Among deployed veterans in our sample, 39.9% met the Kansas criteria and 84.2% met the CDC criteria for GWI. Relative to non-deployed veterans, deployed veterans had a higher odds of meeting four GWI case status-related measures including the Kansas symptom criteria (aOR = 2.05, 95% CI = 1.50, 2.80), Kansas GWI case status (aOR = 1.42, 95% CI = 1.05, 1.93), the CDC GWI case status (aOR = 1.57, 95% CI = 1.07, 2.29) and the CDC severe criteria (aOR = 2.67, 95% CI = 1.79, 3.99). Forty percent met the Kansas exclusionary criteria, with no difference by deployment status. Some symptoms were nearly universally endorsed. SIGNIFICANCE: This analysis provides evidence of a sustained, multisymptom illness in veterans who deployed to the Persian Gulf War compared to non-deployed Gulf War era veterans nearly 25 years later. Differences in symptoms attributed to GWI by deployment status have diminished since initial reports, suggesting the need to update GWI definitions to account for aging-related conditions and symptoms. This study provides a foundation for future efforts to establish a single GWI case definition and analyses that employ the biorepository.


Assuntos
Síndrome do Golfo Pérsico/classificação , Síndrome do Golfo Pérsico/diagnóstico , Veteranos/estatística & dados numéricos , Adulto , Idoso , Centers for Disease Control and Prevention, U.S. , Estudos de Coortes , Feminino , Guerra do Golfo , Humanos , Kansas , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Militares , Síndrome do Golfo Pérsico/epidemiologia , Avaliação de Sintomas , Estados Unidos
11.
Cardiovasc Res ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33914863

RESUMO

AIMS: The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation and pro-inflammatory signaling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis. METHODS AND RESULTS: SM22-Cre+/Dbnflox/flox/Ldlr-/- (SMC-Dbn-/-/Ldlr-/-) and control mice (SM22-Cre+/Ldlr-/-, Dbnflox/flox/Ldlr-/-, and Ldlr-/-) were fed a Western diet for 14-20 weeks. Brachiocephalic arteries of SMC-Dbn-/-/Ldlr-/- mice exhibited 1.5- or 1.8-fold greater cross-sectional lesion area than control mice at 14 or 20 wk, respectively. Aortic atherosclerotic lesion surface area was 1.2-fold greater in SMC-Dbn-/-/Ldlr-/- mice. SMC-Dbn-/-/Ldlr-/- lesions comprised necrotic cores that were two-fold greater in size than those of control mice. Consistent with their bigger necrotic core size, lesions in SMC-Dbn-/- arteries also showed more transdifferentiation of SMCs to macrophage-like cells: 1.5- to 2.5-fold greater, assessed with BODIPY or with CD68, respectively. In vitro data were concordant: Dbn-/- SMCs had 1.7-fold higher levels of KLF4 and transdifferentiated to macrophage-like cells more readily than Dbnflox/flox SMCs upon cholesterol loading, as evidenced by greater up-regulation of CD68 and galectin-3. Adenovirally mediated Drebrin rescue produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. During early atherogenesis, SMC-Dbn-/-/Ldlr-/- aortas demonstrated 1.6-fold higher levels of reactive oxygen species than control mouse aortas. The 1.8-fold higher levels of Nox1 in Dbn-/- SMCs was reduced to WT levels with KLF4 silencing. Inhibition of Nox1 chemically or with siRNA produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. CONCLUSIONS: We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells. TRANSLATIONAL PERSPECTIVE: Drebrin is abundantly expressed in vascular smooth muscle cells (SMCs) and is up-regulated in human atherosclerosis. A hallmark of atherosclerosis is the accumulation of foam cells that secrete pro-inflammatory cytokines and contribute to plaque instability. A large proportion of these foam cells in humans derive from SMCs. We found that SMC Drebrin limits atherosclerosis by reducing SMC transdifferentiation to macrophage-like foam cells in a manner dependent on Nox1 and KLF4. For this reason, strategies aimed at augmenting SMC Drebrin expression in atherosclerotic plaques may limit atherosclerosis progression and enhance plaque stability by bridling SMC-to-foam-cell transdifferentiation.

12.
Sci Rep ; 11(1): 8104, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854078

RESUMO

Understanding patient accumulation of comorbidities can facilitate healthcare strategy and personalized preventative care. We applied a directed network graph to electronic health record (EHR) data and characterized comorbidities in a cohort of healthy veterans undergoing screening colonoscopy. The Veterans Affairs Cooperative Studies Program #380 was a prospective longitudinal study of screening and surveillance colonoscopy. We identified initial instances of three-digit ICD-9 diagnoses for participants with at least 5 years of linked EHR history (October 1999 to December 2015). For diagnoses affecting at least 10% of patients, we calculated pairwise chronological relative risk (RR). iGraph was used to produce directed graphs of comorbidities with RR > 1, as well as summary statistics, key diseases, and communities. A directed graph based on 2210 patients visualized longitudinal development of comorbidities. Top hub (preceding) diseases included ischemic heart disease, inflammatory and toxic neuropathy, and diabetes. Top authority (subsequent) diagnoses were acute kidney failure and hypertensive chronic kidney failure. Four communities of correlated comorbidities were identified. Close analysis of top hub and authority diagnoses demonstrated known relationships, correlated sequelae, and novel hypotheses. Directed network graphs portray chronologic comorbidity relationships. We identified relationships between comorbid diagnoses in this aging veteran cohort. This may direct healthcare prioritization and personalized care.


Assuntos
Comorbidade , Redes Neurais de Computação , Veteranos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/diagnóstico , Bases de Dados Factuais , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Insuficiência Renal Crônica/diagnóstico , Risco
13.
Environ Pollut ; 275: 116663, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581627

RESUMO

Exposure to fine particulate matter (PM2.5) has been associated with a higher risk for coronary events. Elevated circulating cardiac troponins (cTn) are suggestive of myocardial injury in both ischemic and non-ischemic conditions. However, little is known about the association between PM2.5 and cTn. In this study, we investigated short-term PM2.5 effects on cardiac troponin T (cTnT), as well as N-terminal-pro brain natriuretic peptide (NT-pro BNP) and inflammatory biomarkers among cardiac catheterized participants. We analyzed 7444 plasma cTnT measurements in 2732 participants who presented to Duke University Hospital with myocardial infarction symptoms between 2001 and 2012, partly along with measurements of NT-pro BNP and inflammatory biomarkers. Daily PM2.5 concentrations were predicted by a neural network-based hybrid model and were assigned to participants' residential addresses. We applied generalized estimating equations to assess associations of PM2.5 with biomarker levels and the risk of a positive cTnT test (cTnT > 0.1 ng/mL). The median plasma cTnT concentration at presentation was 0.05 ng/mL and the prevalence of a positive cTnT test was 35.4%. For an interquartile range (7.6 µg/m3) increase in PM2.5 on the previous day, cTnT concentrations increased by 7.7% (95% CI: 3.4-12.3) and the odds ratio of a positive cTnT test was 1.08 (1.01-1.16). Participants under 60 years (effect estimate: 15.2%; 95% CI: 7.4-23.5) or living in rural areas (12.3%; 95% CI: 4.8-20.3) were more susceptible. There was evidence for increases in fibrinogen and NT-pro BNP associated with elevated PM2.5 on the concurrent and previous two days. Our study suggests that acute PM2.5 exposure may elevate indicators of myocardial tissue damage. This finding substantiates the association of air pollution exposure with adverse cardiovascular events.


Assuntos
Infarto do Miocárdio , Material Particulado , Biomarcadores , Estudos de Coortes , Humanos , Miocárdio , Troponina T
14.
Eur Heart J ; 42(9): 919-933, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33532862

RESUMO

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.


Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio , Doença da Artéria Coronariana/genética , Células Endoteliais , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Japão , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
15.
Aging (Albany NY) ; 12(23): 24141-24155, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33289704

RESUMO

BACKGROUND: Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures. METHODS: Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status. RESULTS: We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5. CONCLUSION: Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.


Assuntos
Envelhecimento/genética , Pressão Sanguínea/genética , Metilação de DNA , Exposição Ambiental/efeitos adversos , Epigênese Genética , Doença Arterial Periférica/genética , Poluição Relacionada com o Tráfego/efeitos adversos , Emissões de Veículos , Fatores Etários , Idoso , Monitoramento Ambiental , Feminino , Marcadores Genéticos , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Características de Residência , Medição de Risco , Saúde da População Urbana
16.
Transl Psychiatry ; 10(1): 351, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33077726

RESUMO

In prior work, we identified a novel gene-by-stress association of EBF1's common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to "racism/discrimination" (P = 0.036) and "not meeting basic needs" (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e-03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.


Assuntos
Diabetes Mellitus Tipo 2 , Estresse Psicológico/genética , Transativadores , Afro-Americanos , Fatores Etários , Alelos , Feminino , Humanos , Masculino , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores Sexuais , Estresse Psicológico/etnologia , Transativadores/genética
17.
Environ Int ; 145: 106091, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32892005

RESUMO

BACKGROUND: Per- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown. OBJECTIVE: The aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults. METHODS: A total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated. RESULTS: Higher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p < 0.001). PFAS exposure was also associated with altered lipid pathways, which contributed to the metabolic network connecting PFOA and higher glucose levels following the OGTT. Targeted metabolomics analysis indicated that higher PFOA exposure was associated with higher levels of glycerol (p = 0.006), which itself was associated with higher 30-minute glucose (p = 0.006). CONCLUSIONS: Increased lipolysis and fatty acid oxidation could contribute to the biological mechanisms linking PFAS exposure and impaired glucose metabolism among young adults. Findings of this study warrants future experimental studies and epidemiological studies with larger sample size to replicate.


Assuntos
Ácidos Alcanossulfônicos , Poluentes Ambientais , Fluorcarbonetos , Teorema de Bayes , Poluentes Ambientais/toxicidade , Ácidos Graxos , Fluorcarbonetos/toxicidade , Glucose , Humanos , Metabolismo dos Lipídeos , Lipídeos , Adulto Jovem
18.
Cancer Epidemiol Biomarkers Prev ; 29(11): 2269-2276, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32928932

RESUMO

BACKGROUND: The genetic basis for most individuals with high cumulative lifetime colonic adenomas is unknown. We investigated associations between known colorectal cancer-risk single-nucleotide polymorphisms (SNP) and increasing cumulative adenoma counts. METHODS: The Cooperative Studies Program #380 screening colonoscopy cohort includes 612 selected participants age 50 to 75 with genotyped blood samples and 10 years of clinical follow-up. We evaluated 41 published "colorectal cancer-risk SNPs" for associations with individual cumulative adenoma counts or having ≥10 cumulative adenomas. SNPs were analyzed singly or combined in a polygenic risk score (PRS). The PRS was constructed from eight published SNPs associated with multiple adenomas, termed "adenoma-risk SNPs." RESULTS: Four colorectal cancer-risk SNPs were associated with increasing cumulative adenoma counts (P < 0.05): rs12241008 (gene: VTI1A), rs2423279 (BMP2/HAO1), rs3184504 (SH2B3), and rs961253 (FERMT1/BMP2), with risk allele risk ratios of 1.31, 1.29, 1.24, and 1.23, respectively. Three colorectal cancer-risk SNPs were associated with ≥10 cumulative adenomas (P < 0.05), with risk allele odds ratios of 2.09 (rs3184504), 2.30 (rs961253), and 1.94 (rs3217901). A weighted PRS comprised of adenoma-risk SNPs was associated with higher cumulative adenomas (weighted rate ratio = 1.57; P = 0.03). CONCLUSIONS: In this mostly male veteran colorectal cancer screening cohort, several known colorectal cancer-risk SNPs were associated with increasing cumulative adenoma counts and the finding of ≥10 cumulative adenomas. In addition, an increasing burden of adenoma-risk SNPs, measured by a weighted PRS, was associated with higher cumulative adenomas. IMPACT: Future work will seek to validate these findings in different populations and then augment current colorectal cancer risk prediction tools with precancerous, adenoma genetic data.

19.
Am J Gastroenterol ; 115(8): 1275-1282, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32483010

RESUMO

INTRODUCTION: Limited data inform the current postpolypectomy surveillance guidelines, which suggest a shortened interval to third colonoscopy after a negative second examination if high-risk adenomas (HRA) were present on the initial screening colonoscopy. Therefore, we examined the risk of HRA at third colonoscopy stratified by findings on 2 previous examinations in a prospective screening colonoscopy cohort of US veterans. METHODS: We identified participants who had 3 or more colonoscopies from CSP#380. We examined the risk of HRA on the third examination based on findings from the previous 2 examinations. Multivariate logistic regression was used to adjust for multiple covariates. RESULTS: HRA were found at the third examination in 114 (12.8%) of 891 participants. Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56, 25.0%). Compared with those with no adenomas on both previous examinations, participants with HRA on the first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.28-9.08), 5 years (OR 3.14, 95% CI 1.49-6.61), and 7 years (OR 2.89, 95% CI 1.08-7.74). DISCUSSION: In a screening population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination. This finding supports current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.


Assuntos
Adenoma/epidemiologia , Neoplasias Colorretais/epidemiologia , Adenoma/diagnóstico , Adenoma/diagnóstico por imagem , Adenoma/patologia , Idoso , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia , United States Department of Veterans Affairs , Veteranos
20.
Am J Hum Genet ; 106(4): 535-548, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32243820

RESUMO

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.


Assuntos
Grupos Étnicos/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Medicina de Precisão/métodos , Controle de Qualidade , Veteranos , Sequenciamento Completo do Genoma/métodos
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