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1.
medRxiv ; 2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35262092

RESUMO

Background: People hospitalized with COVID-19 often exhibit hematological alterations, such as lower lymphocyte and platelet counts, which have been reported to associate with disease prognosis. It is unclear whether inter-individual variability in baseline hematological parameters prior to acute infection influences risk of SARS-CoV-2 infection and progression to severe COVID-19. Methods: We assessed the association of blood cell counts and indices with incident SARS-CoV-2 infection and severe COVID-19 in UK Biobank and the Vanderbilt University Medical Center Synthetic Derivative (VUMC SD). Since genetically determined blood cell measures better represent cell abundance across the lifecourse, we used summary statistics from genome-wide association studies to assess the shared genetic architecture of baseline blood cell counts and indices on COVID-19 outcomes. Results: We observed inconsistent associations between measured blood cell indices and both SARS-CoV-2 infection and COVID-19 hospitalization in UK Biobank and VUMC SD. In Mendelian randomization analyses using genetic summary statistics, no putative causal relationships were identified between COVID-19 related outcomes and hematological indices after adjusting for multiple testing. We observed overlapping genetic association signals between hematological parameters and COVID-19 traits. For example, we observed overlap between infection susceptibility-associated variants at PPP1R15A and red blood cell parameters, and between disease severity-associated variants at TYK2 and lymphocyte and platelet phenotypes. Conclusions: We did not find convincing evidence of a relationship between baseline hematological parameters and susceptibility to SARS-CoV-2 infection or COVID-19 severity, though this relationship should be re-examined as larger and better-powered genetic analyses of SARS-CoV-2 infection and severe COVID-19 become available.

2.
Hum Mol Genet ; 2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35138379

RESUMO

Previous genome-wide association studies (GWAS) of hematological traits have identified over 10 000 distinct trait-specific risk loci. However, at these loci, the underlying causal mechanisms remain incompletely characterized. To elucidate novel biology and better understand causal mechanisms at known loci, we performed a transcriptome-wide association study (TWAS) of 29 hematological traits in 399 835 UK Biobank (UKB) participants of European ancestry using gene expression prediction models trained from whole blood RNA-seq data in 922 individuals. We discovered 557 gene-trait associations for hematological traits distinct from previously reported GWAS variants in European populations. Among the 557 associations, 301 were available for replication in a cohort of 141 286 participants of European ancestry from the Million Veteran Program (MVP). Of these 301 associations, 108 replicated at a strict Bonferroni adjusted threshold ($\alpha$ = 0.05/301). Using our TWAS results, we systematically assigned 4261 out of 16 900 previously identified hematological trait GWAS variants to putative target genes. Compared to coloc, our TWAS results show reduced specificity and increased sensitivity in external datasets to assign variants to target genes.

3.
J Clin Invest ; 132(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34990411

RESUMO

BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a premalignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDINGNew York Stem Cell Foundation and the NIH.


Assuntos
Anemia Falciforme/genética , Hematopoiese Clonal/genética , Anemia Falciforme/terapia , Feminino , Humanos , Masculino , Sequenciamento Completo do Genoma
4.
PLoS Genet ; 18(1): e1009984, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35100265

RESUMO

Existing studies of chromatin conformation have primarily focused on potential enhancers interacting with gene promoters. By contrast, the interactivity of promoters per se, while equally critical to understanding transcriptional control, has been largely unexplored, particularly in a cell type-specific manner for blood lineage cell types. In this study, we leverage promoter capture Hi-C data across a compendium of blood lineage cell types to identify and characterize cell type-specific super-interactive promoters (SIPs). Notably, promoter-interacting regions (PIRs) of SIPs are more likely to overlap with cell type-specific ATAC-seq peaks and GWAS variants for relevant blood cell traits than PIRs of non-SIPs. Moreover, PIRs of cell-type-specific SIPs show enriched heritability of relevant blood cell trait (s), and are more enriched with GWAS variants associated with blood cell traits compared to PIRs of non-SIPs. Further, SIP genes tend to express at a higher level in the corresponding cell type. Importantly, SIP subnetworks incorporating cell-type-specific SIPs and ATAC-seq peaks help interpret GWAS variants. Examples include GWAS variants associated with platelet count near the megakaryocyte SIP gene EPHB3 and variants associated lymphocyte count near the native CD4 T-Cell SIP gene ETS1. Interestingly, around 25.7% ~ 39.6% blood cell traits GWAS variants residing in SIP PIR regions disrupt transcription factor binding motifs. Importantly, our analysis shows the potential of using promoter-centric analyses of chromatin spatial organization data to identify biologically important genes and their regulatory regions.


Assuntos
Células Sanguíneas/metabolismo , Linhagem da Célula/genética , Redes Reguladoras de Genes , Regiões Promotoras Genéticas , Estudo de Associação Genômica Ampla , Humanos , Proteína Proto-Oncogênica c-ets-1/genética , Receptor EphB3/genética
5.
Sci Rep ; 12(1): 1472, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-35087136

RESUMO

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10-3). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity.


Assuntos
Heme/biossíntese , Redes e Vias Metabólicas/genética , Apneia Obstrutiva do Sono/epidemiologia , Idoso , Conjuntos de Dados como Assunto , Feminino , Predisposição Genética para Doença , Humanos , Ferro/metabolismo , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polissonografia , Locos de Características Quantitativas , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/sangue , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/genética , Regulação para Cima
6.
HGG Adv ; 3(1): 100063, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35047852

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of thousands of genetic variants associated with complex diseases and traits. However, most variants are noncoding and not clearly linked to genes, making it challenging to interpret these GWAS signals. We present a systematic variant-to-function study, prioritizing the most likely functional elements of the genome for experimental follow-up, for >148,000 variants identified for hematological traits. Specifically, we developed VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny. This tool efficiently integrates and displays information from multiple complementary sources, including epigenomic signatures from blood-cell-relevant tissues or cells, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Leveraging data generated from independently performed functional validation experiments, we demonstrate that our prioritized variants, genes, or variant-gene links are significantly more likely to be experimentally validated. This study not only has important implications for systematic and efficient revelation of functional mechanisms underlying GWAS variants for hematological traits but also provides a prototype that can be adapted to many other complex traits, paving the path for efficient variant-to-function (V2F) analyses.

7.
Stroke ; 53(3): 788-797, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34743536

RESUMO

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.


Assuntos
Hematopoiese Clonal/fisiologia , AVC Hemorrágico/epidemiologia , AVC Isquêmico/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Hematopoiese Clonal/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Feminino , AVC Hemorrágico/genética , AVC Hemorrágico/fisiopatologia , Humanos , Incidência , AVC Isquêmico/genética , AVC Isquêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Repressoras/genética , Risco
8.
Genet Epidemiol ; 46(1): 3-16, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34779012

RESUMO

Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping.


Assuntos
Estudo de Associação Genômica Ampla , Transcriptoma , Células Sanguíneas , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
9.
Circ Genom Precis Med ; 14(6): e003421, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34706549

RESUMO

BACKGROUND: suPAR (Soluble urokinase plasminogen activator receptor) has emerged as an important biomarker of coagulation, inflammation, and cardiovascular disease (CVD) risk. The contribution of suPAR to CVD risk and its genetic influence in Black populations have not been evaluated. METHODS: We measured suPAR in 3492 Black adults from the prospective, community-based JHS (Jackson Heart Study). Cross-sectional associations of suPAR with lifestyle and CVD risk factors were assessed, whole-genome sequence data were used to evaluate genetic associations of suPAR, and relationships of suPAR with incident CVD outcomes and overall mortality were estimated over follow-up. RESULTS: In Cox models adjusted for traditional CVD risk factors, estimated glomerular filtration rate, and CRP (C-reactive protein), each 1-SD higher suPAR was associated with a 21% to 31% increased risk of incident coronary heart disease, heart failure, stroke, and mortality. In the genome-wide association study, 2 missense (rs399145 encoding p.Thr86Ala, rs4760 encoding p.Phe272Leu) and 2 noncoding regulatory variants (rs73935023 within an enhancer element and rs4251805 within the promoter) of PLAUR on chromosome 19 were each independently associated with suPAR and together explained 14% of suPAR phenotypic variation. The allele frequencies of each of the four suPAR-associated genetic variants differ considerably across African and European populations. We further show that PLAUR rs73935023 can alter transcriptional activity in vitro. We did not find any association between genetically determined suPAR and CVD in JHS or a larger electronic medical record-based analyses of Blacks or Whites. CONCLUSIONS: Our results demonstrate the importance of ancestry-differentiated genetic variation on suPAR levels and indicate suPAR is a CVD biomarker in Black adults.


Assuntos
Doenças Cardiovasculares , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Adulto , Doenças Cardiovasculares/genética , Estudos Transversais , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Estudos Prospectivos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética
11.
Genes (Basel) ; 12(7)2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34356065

RESUMO

BACKGROUND: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. METHODS: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. RESULTS: Our results revealed 24 suggestive signals (p < 1 × 10-4) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. CONCLUSIONS: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.


Assuntos
Afro-Americanos/genética , Células Sanguíneas/patologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Transcriptoma , Células Sanguíneas/metabolismo , Estudos de Coortes , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , /genética
12.
BMC Genomics ; 22(1): 432, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107879

RESUMO

BACKGROUND: Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. RESULTS: We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. CONCLUSIONS: Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Genômica , Humanos , Leucócitos , Fenótipo
13.
Genetics ; 218(1)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33720349

RESUMO

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.


Assuntos
Frequência do Gene/genética , Genética Populacional/métodos , Desequilíbrio de Ligação/genética , Alelos , Genótipo , Humanos , Modelos Genéticos , Modelos Estatísticos , Fenótipo , Software
14.
J Am Heart Assoc ; 10(5): e018789, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619969

RESUMO

Background Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship between a healthy lifestyle and CHIP is unknown. Methods and Results This analysis included 8709 postmenopausal women (mean age, 66.5 years) enrolled in the WHI (Women's Health Initiative), free of cancer or cardiovascular disease, with deep-coverage whole genome sequencing data available. Information on lifestyle factors (body mass index, smoking, physical activity, and diet quality) was obtained, and a healthy lifestyle score was created on the basis of healthy criteria met (0 point [least healthy] to 4 points [most healthy]). CHIP was derived on the basis of a prespecified list of leukemogenic driver mutations. The prevalence of CHIP was 8.6%. A higher healthy lifestyle score was not associated with CHIP (multivariable-adjusted odds ratio [OR] [95% CI], 0.99 [0.80-1.23] and 1.13 [0.93-1.37]) for the upper (3 or 4 points) and middle category (2 points), respectively, versus referent (0 or 1 point). Across score components, a normal and overweight body mass index compared with obese was significantly associated with a lower odds for CHIP (OR, 0.71 [95% CI, 0.57-0.88] and 0.83 [95% CI, 0.68-1.01], respectively; P-trend 0.0015). Having never smoked compared with being a current smoker tended to be associated with lower odds for CHIP. Conclusions A healthy lifestyle, based on a composite score, was not related to CHIP among postmenopausal women. However, across individual lifestyle factors, having a normal body mass index was strongly associated with a lower prevalence of CHIP. These findings support the idea that certain healthy lifestyle factors are associated with a lower frequency of CHIP.


Assuntos
Doenças Cardiovasculares/etiologia , Hematopoiese Clonal/fisiologia , DNA/genética , Estilo de Vida , Pós-Menopausa , Saúde da Mulher , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Feminino , Frequência do Gene , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Estados Unidos/epidemiologia
15.
JAMA Netw Open ; 4(1): e2030435, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33399855

RESUMO

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. Design, Setting, and Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Main Outcomes and Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). Conclusions and Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.


Assuntos
Afro-Americanos/estatística & dados numéricos , Doença das Coronárias , Traço Falciforme , Idoso , Estudos de Coortes , Doença das Coronárias/complicações , Doença das Coronárias/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Traço Falciforme/complicações , Traço Falciforme/epidemiologia
16.
Alzheimers Dement ; 17(2): 215-225, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32966694

RESUMO

INTRODUCTION: Recent studies suggest that both sex-specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis. METHODS: We performed both single-variant and gene-based genome-wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia-related tissues and samples was gathered for each locus. RESULTS: Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's disease. DISCUSSION: Our association of MYH11, FZD3, SORCS3, and GOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia.


Assuntos
Doença de Alzheimer/genética , Receptores Frizzled/genética , Estudo de Associação Genômica Ampla , Cadeias Pesadas de Miosina/genética , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genética , Doença de Alzheimer/etnologia , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco
17.
Circulation ; 143(5): 410-423, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33161765

RESUMO

BACKGROUND: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. METHODS: We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease. RESULTS: The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; P=0.005). CONCLUSIONS: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.


Assuntos
Hematopoiese Clonal/fisiologia , Doença da Artéria Coronariana/etiologia , Menopausa Precoce/fisiologia , Pós-Menopausa/fisiologia , Adulto , Idoso , Doença da Artéria Coronariana/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Saúde da Mulher
19.
J Am Coll Cardiol ; 75(17): 2156-2165, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32194198

RESUMO

BACKGROUND: E-selectin and intercellular adhesion molecule (ICAM)-1 are biomarkers of endothelial activation, which has been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF). However, the temporal associations between E-selectin and ICAM-1 with subclinical cardiac dysfunction are unclear. OBJECTIVES: This study sought to assess the longitudinal associations of E-selectin and ICAM-1 with subclinical alterations in cardiac function. METHODS: In the Coronary Artery Disease Risk Development in Young Adults study, a cohort of black and white young adults, we evaluated the associations of E-selectin and ICAM-1, obtained at year (Y) 7 (Y7) and Y15 examinations, with cardiac function assessed at Y30 after adjustment for key covariates. RESULTS: Higher E-selectin (n = 1,810) and ICAM-1 (n = 1,548) at Y7 were associated with black race, smoking, hypertension, and higher body mass index. After multivariable adjustment, higher E-selectin at Y7 (ß coefficient per 1 SD higher: 0.22; SE: 0.06; p < 0.001) and Y15 (ß coefficient per 1 SD higher: 0.19; SE: 0.06; p = 0.002) was associated with worse left ventricular (LV) global longitudinal strain (GLS). Additionally, higher Y15 ICAM-1 (ß coefficient per 1 SD higher: 0.18; SE: 0.06; p = 0.004) and its increase from Y7 to Y15 (ß coefficient per 1 SD higher: 0.16; SE: 0.07; p = 0.03) were also independently associated with worse LV GLS. E-selectin and ICAM-1 partially mediated the associations between higher body mass index and black race with worse GLS. Neither E-selectin nor ICAM-1 was associated with measures of LV diastolic function after multivariable adjustment. CONCLUSION: Circulating levels of E-selectin and ICAM-1 and increases in ICAM-1 over the course of young adulthood are associated with worse indices of LV systolic function in midlife. These findings suggest associations of endothelial activation with subclinical HF with preserved ejection fraction.


Assuntos
Doença da Artéria Coronariana/sangue , Selectina E/sangue , Molécula 1 de Adesão Intercelular/sangue , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Adulto , Biomarcadores/sangue , Adesão Celular/fisiologia , Moléculas de Adesão Celular/sangue , Estudos de Coortes , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores Sexuais , Adulto Jovem
20.
JAMA Netw Open ; 3(2): e200023, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32101305

RESUMO

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span. Objective: To examine whether LTL is associated with the life span of contemporary humans. Design, Setting, and Participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019. Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees. Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77). Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.


Assuntos
Leucócitos/fisiologia , Expectativa de Vida , Telômero/genética , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/mortalidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade
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