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Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings in vivo. Linear modeling of CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes revealed 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo. Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro; autosomal responses to Xi and/or Y dosage were largely cell-type specific (â¼2.6-fold more variation than sex-chromosomal responses). Targets of the sex-chromosomal transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable, yet they modulate autosomal and Xa genes in a cell-type-specific fashion.
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BACKGROUND: John Henryism (JH) is a behavioral predisposition for high-effort coping with adversity. JH has been associated with hypertension in Black Americans with low socioeconomic status (SES) and is also found to be associated with psychological well-being. Sickle cell disease (SCD), a rare genetic disease largely affecting Black Americans in the United States, presents as a chronic condition that may benefit from a deeper understanding of the impact of JH on overall health. PURPOSE: This study examined the association between high and low JH and diastolic blood pressure, systolic blood pressure, hypertension prevalence, and sleep function. We relied on the biopsychosocial transaction model to adjust for relevant clinical and sociodemographic variables. METHODS: This was a cross-sectional secondary analysis of 274 adults with SCD living in the United States and recruited between 2014 and 2020. Study visits consisted of physical examinations, medical history, demographic, and psychosocial questionnaires. Adjusted linear regressions estimated associations between high and low JH and diastolic and systolic blood pressure as well as self-reported sleep function. Multivariable logistic regression was used to examine associations with hypertension prevalence. RESULTS: High JH was significantly associated with lower diastolic blood pressure (ß = - 2.98; 95% confidence interval = - 5.92, - 0.04) but higher sleep dysfunction (ß = 2.76; 95% confidence interval = 1.45, 4.07). CONCLUSIONS: Overall, we found positive psychological coping resources associated with high JH, with the exception of sleep. CLINICALTRIALS: gov Identifier: NCT02156102.
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Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression in two cell types. We tested these findings in vivo in two additional cell types. Using linear modeling in CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes, we identified 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo . Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro across all four cell types examined. In contrast, autosomal responses to Xi and/or Y dosage were largely cell-type-specific, with up to 2.6-fold more variation than sex-chromosomal responses. Targets of the X- and Y-encoded transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro . We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable across the four cell types examined, yet they modulate autosomal and Xa genes - and cell function - in a cell-type-specific fashion. These emerging principles offer a foundation for exploring the wide-ranging regulatory roles of the sex chromosomes across the human body.
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Introduction: In the United States, sickle cell disease (SCD)-the homozygous inheritance of a point mutation within the beta-globin chain of hemoglobin-affects between 80,000 and 100,000 people. Adequate nutrition can influence the pathophysiology of SCD, and individuals with SCD who are undernourished are more likely to have impaired immune function and disease exacerbation. Undernourishment is often caused by food insecurity (FI), which is defined as "a household-level economic and social condition of limited or uncertain access to adequate food" by the USDA. FI disproportionately affects African Americans, a population disproportionately affected by SCD in the United States. Objectives: We performed a scoping review to better understand the relationship between FI and SCD severity. Methods: A comprehensive search for peer-reviewed research articles and meeting abstracts was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Selected studies were reviewed for descriptive analysis by three independent reviewers. Results: In total, 72 studies were identified, 62 were excluded for meeting inclusion criteria. The remaining 10 studies, 5 of which were meeting abstracts, were reviewed. Although limited evidence is available, the results of this scoping review suggest a bidirectional relationship between SCD and FI. Seven key themes were identified to help elucidate this relationship: 1) prevalence of FI among individuals with SCD, 2) child versus caregiver experiences of FI, 3) psychosocial factors, 4) food assistance benefits, 5) dietary intake, 6) external spending, 7) healthcare utilization. Conclusion: Findings from this scoping review suggest how SCD and FI work in tandem to exacerbate each other. Furthermore, the findings illustrate current gaps in the literature and opportunities for actions to address FI among individuals living with SCD.
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Leg ulcers in individuals living with Sickle Cell Disease are evidence of systemic dysfunction. Data from a U.S. study link leg ulcers to wider pulse pressure and markers of chronic hemolysis, inflammation, renal, and liver dysfunction.
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Anemia de Células Falciformes , Úlcera de la Pierna , Humanos , Anemia de Células Falciformes/complicaciones , Hemólisis , Inflamación , Úlcera de la Pierna/etiología , Presión SanguíneaRESUMEN
Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.
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Factores de Transcripción , Cromosoma Y , Humanos , Masculino , Femenino , Factores de Transcripción/genética , Cromosomas Humanos X/genética , Aberraciones Cromosómicas Sexuales , Expresión Génica/genéticaRESUMEN
PURPOSE: Although the body of research investigating research participants' opinions on the return of actionable secondary genomic findings grows, there has been limited study of individuals with genetic conditions, such as sickle cell disease (SCD). It is imperative that the views of diverse research participants on return of results (RoR) be investigated and rooted in the context of advancing health equity in genomics research. METHODS: We conducted qualitative, semi-structured interviews with 30 adults living with SCD with differing insurance coverages and utilized a directed content analysis to derive themes. RESULTS: Study findings show that living with SCD is a key influence on views of RoR. Participants were in favor of RoR while expressing concern regarding the burden RoR would place on their SCD management. Respondents also expressed an expectation for researchers to devote resources toward seeking ancillary care downstream and discussed how barriers faced when navigating SCD would inform their access to ancillary care. CONCLUSION: Research participants living with chronic genetic conditions such as SCD are generally in favor of RoR but anticipate experiencing barriers to care similar to those faced navigating their SCD. Understanding the views of diverse cohorts on RoR will help researchers better understand downstream barriers participants may face.
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Anemia de Células Falciformes , Genómica , Adulto , Humanos , Enfermedad Crónica , Anemia de Células Falciformes/genética , InvestigadoresRESUMEN
Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex-chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors - ZFX and ZFY - encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.
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The "inactive" X chromosome (Xi) has been assumed to have little impact, in trans, on the "active" X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes.
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PURPOSE: To craft evidence-based educational approaches related to polygenic risk score (PRS) implementation, it is crucial to forecast issues and biases that may arise when PRS are introduced in clinical care. METHODS: Medical students (N = 84) were randomized to a simulated primary care encounter with a Black or White virtual reality-based patient and received either a direct-to-consumer-style PRS report for 5 common complex conditions or control information. The virtual patient inquired about 2 health concerns and her genetic report in the encounter. Data sources included participants' verbalizations in the simulation, care plan recommendations, and self-report outcomes. RESULTS: When medical students received PRSs, they rated the patient as less healthy and requiring more strict advice. Patterns suggest that PRSs influenced specific medical recommendations related to the patient's concerns, despite student reports that participants did not use it for that purpose. We observed complex patterns regarding the effect of patient race on recommendations and behaviors. CONCLUSION: Educational approaches should consider potential unintentional influences of PRSs on decision-making and evaluate ways that they may be applied inconsistently across patients from different racial groups.
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Estudiantes de Medicina , Femenino , Humanos , Herencia Multifactorial/genética , Grupos Raciales , Derivación y Consulta , Factores de RiesgoRESUMEN
BACKGROUND: The COVID-19 pandemic has impacted the physical and mental health of people worldwide including those living with genetic conditions. Sickle cell disease (SCD) is a hematologic chronic disease that causes multisystem damage and morbidity. Individuals living with SCD have had to continue managing their care for their chronic disease while following public health measures to protect against infection with COVID-19. Promoting resilience has been posited as being psychologically protective for those living with SCD. This study examines changes in resilience over time in a SCD population in the context of the COVID-19 pandemic. METHODS: Ninety-seven adults living with SCD completed two parent studies: (1) The INSIGHTS Study, a cross-sectional natural history study conducted from 2014-2019 and (2) The Living with SCD in COVID-19 Pandemic Study, an online survey conducted in 2020. Changes over time in resilience, perceived stress, emotional distress, and physical and mental health were analyzed in multivariable repeated measures model. RESULTS: Results showed that the psychological resilience of our study cohort had significantly decreased (0.19, p=0.01) over time. Resilience during the pandemic was associated with better mental health and physical health and lower perceived stress and emotional distress. In addition, results showed that marital status, education level, and employment were significantly associated with the psychological resilience of study participants. CONCLUSION: Resilience declined during the COVID-19 pandemic but was still associated with better physical and mental health outcomes. Future studies should investigate the relationship between resilience and sociodemographic factors.
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Anemia de Células Falciformes , COVID-19 , Resiliencia Psicológica , Adulto , COVID-19/epidemiología , Estudios Transversales , Humanos , PandemiasRESUMEN
INTRODUCTION: Sickle cell disease (SCD) is a chronic illness that presents with a wide range of phenotypic variation. Stress may be a contributing factor to differences that are found in this population. OBJECTIVES: Our objective is to determine the relationship between hair cortisol content (HCC), a biomarker of stress, and other clinical measures in individuals with SCD. METHODS: We collected hair samples and other clinical measures from 73 subjects with SCD (mean age: 39 ± 12 years, 63% female). RESULTS: HCC was lower among individuals who had greater than 30% hemoglobin S, compared with those who had less than 30% hemoglobin S (W=272.5, P=0.01). Lower HCC was also associated with report of not being on a chronic transfusion program (ß=48.34, SE=14.09, P=0.001) and higher ferritin levels (ß=-0.006, SE=0.002, P=0.02). Furthermore, HCC was significantly correlated with serum cortisol (rs=0.26, P=0.03) and corticosterone (rs=0.29, P=0.01). We also observed a consistent pattern of low steroid values among our population. CONCLUSION: Our findings suggest that individuals with higher hemoglobin S and ferritin, both markers of severe SCD, may have decreased cortisol levels. This is consistent with the relationship we observed between higher HCC among individuals who are on a chronic blood transfusion program, which typically increases quality of life. Our results suggest that hair cortisol may be an indicator in patients with SCD who could be at risk for developing adrenal insufficiency. We recommend that clinicians treating patients with SCD follow the Endocrine Society guidelines for testing for adrenal insufficiency and treat accordingly.
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Leg ulcers are estimated to occur in 1%-10% of North American patients with sickle cell disease (SCD). Their pathophysiology remains poorly defined, but as with other chronic wounds, it is hypothesised that the microbial milieu, or microbiome, contributes to their healing and clinical outcomes. This study utilises 16S ribosomal RNA (rRNA) gene sequencing to describe, for the first time, the microbiome of the SCD leg ulcer and its association with clinical factors. In a cross-sectional analysis of 42 ulcers, we recovered microbial profiles similar to other chronic wounds in the predominance of anaerobic bacteria and opportunistic pathogens including Staphylococcus, Corynebacterium, and Finegoldia. Ulcers separated into two clusters: one defined by predominance of Staphylococcus and smaller surface area, and the other displaying a greater diversity of taxa and larger surface area. We also find that the relative abundance of Porphyromonas is negatively associated with haemoglobin levels, a key clinical severity indicator for SCD, and that Finegoldia relative abundance is negatively associated with CD19+ B cell count. Finally, ratios of Corynebacterium:Lactobacillus and Staphylococcus:Lactobacillus are elevated in the intact skin of individuals with a history of SCD leg ulcers, while the ratio of Lactobacillus:Bacillus is elevated in that of individuals without a history of ulcers. Investigations of the skin microbiome in relation to SCD ulcer pathophysiology can inform clinical guidelines for this poorly understood chronic wound, as well as enhance broader understanding about the role of the skin microbiome in delayed wound healing.
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Anemia de Células Falciformes , Úlcera de la Pierna , Microbiota , Estudios Transversales , Humanos , Cicatrización de HeridasRESUMEN
The diversity of the U.S. population is currently not reflected in the genomic workforce and across the greater scientific enterprise. Although diversity and inclusion efforts have focused on increasing the number of individuals from underrepresented groups across scientific fields, structural racism remains. Thus, the cultivation and adoption of diversity as an ethos requires shifting our focus to being intentional about an institution's character, culture, and climate. One way for this ethos to be sustained is by facilitating an intentional anti-racism approach within the field. Adopting a new perspective on diversity utilizing an anti-racism approach will support genomics researchers as we build supportive, collaborative research environments. We seek to expand critical thought in the framing of diversity in the research enterprise and propose an anti-racism approach that informs deliberate actions required to address structural racism.
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STUDY OBJECTIVE: Individuals living with sickle cell disease (SCD) often require urgent care; however, some patients hesitate to present to the emergency department (ED), which may increase the risk of serious clinical complications. Our study aims to examine psychosocial, clinical, and demographic factors associated with delaying ED care. METHODS: This was a cross-sectional study of 267 adults with SCD from the national INSIGHTS Study. The binary outcome variable asked whether, in the past 12 months, participants had delayed going to an ED when they thought they needed care. Logistic regression was performed with clinical, demographic, and psychosocial measures. RESULTS: Approximately 67% of the participants reported delaying ED care. Individuals who delayed care were more likely to have reported higher stigma experiences (odds ratio [OR]=1.09; 95% confidence interval [CI] 1.03 to 1.16), more frequent pain episodes (OR=1.15; 95% CI 1.01 to 1.32), lower health care satisfaction (OR= 0.74; 95% CI 0.59 to 0.94), and more frequent ED visits (OR=6.07; 95% CI 1.18 to 31.19). Disease severity and demographics, including sex, age, and health insurance status, were not significantly associated with delay in care. CONCLUSION: Psychosocial factors, including disease stigma and previous negative health care experiences, are associated with delay of ED care in this SCD cohort. There is a need to further investigate the influence of psychosocial factors on the health care-seeking behaviors of SCD patients, as well as the downstream consequences of these behaviors on morbidity and mortality. The resulting knowledge can contribute to efforts to improve health care experiences and patient-provider relationships in the SCD community.
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Anemia de Células Falciformes/terapia , Servicio de Urgencia en Hospital/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Adulto , Anciano , Anemia de Células Falciformes/psicología , Estudios Transversales , Diagnóstico Tardío/psicología , Diagnóstico Tardío/estadística & datos numéricos , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud/psicología , Satisfacción del Paciente/estadística & datos numéricos , Psicología , Estigma Social , Adulto JovenRESUMEN
Differences between female and male immunity may contribute to variations in response to infections and predisposition to autoimmunity. We previously reported that neutrophils from reproductive-age males are more immature and less activated than their female counterparts. To further characterize the mechanisms that drive differential neutrophil phenotypes, we performed RNA sequencing on circulating neutrophils from healthy adult females and males. Female neutrophils displayed significant up-regulation of type I IFN (IFN)-stimulated genes (ISGs). Single-cell RNA-sequencing analysis indicated that these differences are neutrophil specific, driven by a distinct neutrophil subset and related to maturation status. Neutrophil hyperresponsiveness to type I IFNs promoted enhanced responses to Toll-like receptor agonists. Neutrophils from young adult males had significantly increased mitochondrial metabolism compared to those from females and this was modulated by estradiol. Assessment of ISGs and neutrophil maturation genes in Klinefelter syndrome (47, XXY) males and in prepubescent children supported that differences in neutrophil phenotype between adult male and female neutrophils are hormonally driven and not explained by X chromosome gene dosage. Our results indicate that there are distinct sex differences in neutrophil biology related to responses to type I IFNs, immunometabolism, and maturation status that may have prominent functional and pathogenic implications.
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Interferón Tipo I/inmunología , Neutrófilos/inmunología , Adulto , Femenino , Humanos , Inmunidad Innata , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/inmunología , Síndrome de Klinefelter/metabolismo , Masculino , Factores Sexuales , Adulto JovenRESUMEN
Advances in CRISPR technology and the announcement of the first gene-edited babies have sparked a global dialogue about the future of heritable genome editing (HGE). There has been an international call for public input to inform a substantive debate about benefits and risks of HGE. This study investigates the views of the sickle cell disease (SCD) community. We utilized a mixed-methods approach to examine SCD stakeholders' views in the United States. We found SCD stakeholders hold a nuanced view of HGE. Assuming the technology is shown to be safe and effective, they are just as supportive of HGE as genetics professionals, but more supportive than the general public. However, they are also concerned about the potential implications of HGE, despite this support. As discourse surrounding HGE advances, it is crucial to engage disease communities and other key stakeholders whose lives could be altered by these interventions.
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Anemia de Células Falciformes/genética , Anemia de Células Falciformes/terapia , Edición Génica/ética , Adulto , Sistemas CRISPR-Cas/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Femenino , Grupos Focales , Edición Génica/métodos , Terapia Genética/ética , Terapia Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Participación de los Interesados/psicologíaRESUMEN
PURPOSE: Turner syndrome (TS) is the most common sex chromosome disorder in women and is associated with a higher than expected death rate secondary to cerebrovascular disease, including stroke. This study evaluates the cerebral vascular anatomy of individuals with TS. METHODS: Twenty-one women with TS had brain magnetic resonance angiography (MRA). These MRAs were evaluated in a blinded manner with a control group of 25 men and 25 women who had MRA imaging for multiple indications including migraine headaches, psychiatric disorders, and seizures. RESULTS: Twenty-nine percent of women with TS were missing an A1 segment of the anterior cerebral artery (ACA) compared to 0% in the control group (p < .001). There were no other significant differences in the circle of Willis (COW) in women with TS compared with the control group. A complete COW was found in 3 of 21 (14%) of women with TS and 12 of 47 (26%) controls (p = .36). CONCLUSION: Women with TS have a significantly different intracranial vascular anatomy, specifically the absence of the A1 segment of the ACA when compared to male and female controls. More research in brain imaging in women with TS and stroke and other cerebrovascular diseases is needed to determine the clinical significance of this anomaly.
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Arteria Cerebral Anterior/anatomía & histología , Círculo Arterial Cerebral/anatomía & histología , Síndrome de Turner/fisiopatología , Adulto , Arteria Cerebral Anterior/patología , Encéfalo/irrigación sanguínea , Círculo Arterial Cerebral/patología , Femenino , Humanos , Angiografía por Resonancia Magnética/métodos , MasculinoRESUMEN
BACKGROUND: Sickle cell disease (SCD) impacts millions of individuals worldwide and more than 100,000 people in the United States. Leg ulcers are the most common cutaneous manifestation of SCD. The health status of individuals living with chronic leg ulcers is not only influenced by clinical manifestations such as pain duration and intensity, but also by psychosocial factors. Garnering insights into the psychosocial impact can provide a more holistic view of their influence on quality of life. METHODS: Semi-structured interviews were conducted with participants living with active SCD-associated leg ulcers or with a history of ulcers. Subjects were recruited from an ongoing study (INSIGHTS, Clin Trial.Gov NCT02156102) and consented to this qualitative phase of the study. Five areas were explored: leg ulcer pain, physical function, social-isolation, social relationships and religious support. Data was collected from 20 individuals during these interviews and a thematic analysis was performed and reported. RESULTS: Twenty participants with a mean age of 42.4 (SD ± 11.1years) were included in the study. Major themes identified included:1) pain (acute and chronic); 2) compromised physical function as demonstrated by decreased ability to walk, run, and play sports; 3) social isolation from activities either by others or self-induced as a means of avoiding certain emotions, such as embarrassment; 4) social relationships (family support and social network); 5) support and comfort through their religion or spirituality. CONCLUSIONS: SCD patients with leg ulcers expressed that they experience social isolation, intense and frequent ulcer pain, and difficulty in physical function. SCD-associated leg ulcers have been studied from a clinical approach, but the psychosocial factors investigated in this study informs how quality of life is impacted by the leg ulcers.