Sickle cell trait is not associated with endemic Burkitt lymphoma: an ethnicity and malaria endemicity-matched case-control study suggests factors controlling EBV may serve as a predictive biomarker for this pediatric cancer
| dc.contributor.author | Mulama, David H. | |
| dc.contributor.author | Bailey, Jeffrey A. | |
| dc.contributor.author | Foley, Joslyn | |
| dc.contributor.author | Chelimo, Kiprotich | |
| dc.contributor.author | Ouma, Collins | |
| dc.contributor.author | Jura, Walter G.Z.O. | |
| dc.contributor.author | Otieno, Juliana A. | |
| dc.contributor.author | Vulule, John M. | |
| dc.contributor.author | Moormann, Ann M. | |
| dc.date | 2022-08-11T08:08:29.000 | |
| dc.date.accessioned | 2022-08-23T15:56:52Z | |
| dc.date.available | 2022-08-23T15:56:52Z | |
| dc.date.issued | 2014-02-01 | |
| dc.date.submitted | 2014-01-03 | |
| dc.identifier.citation | Mulama DH, Bailey JA, Foley J, Chelimo K, Ouma C, Jura WG, Otieno J, Vulule J, Moormann AM. Sickle cell trait is not associated with endemic Burkitt lymphoma: an ethnicity and malaria endemicity-matched case-control study suggests factors controlling EBV may serve as a predictive biomarker for this pediatric cancer. Int J Cancer. 2013 Feb 1;134(3):645-53. doi: 10.1002/ijc.28378. <a href="http://dx.doi.org/10.1002/ijc.28378" target="_blank">Link to article on publisher's site</a> | |
| dc.identifier.issn | 0020-7136 (Linking) | |
| dc.identifier.doi | 10.1002/ijc.28378 | |
| dc.identifier.pmid | 23832374 | |
| dc.identifier.uri | http://hdl.handle.net/20.500.14038/30064 | |
| dc.description.abstract | Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum coinfections. Malaria appears to dysregulate immunity that would otherwise control EBV, thereby contributing to eBL etiology. Juxtaposed to human genetic variants associated with protection from malaria, it has been hypothesized that such variants could decrease eBL susceptibility, historically referred to as "the protective hypothesis." Past studies attempting to link sickle cell trait (HbAS), which is known to be protective against malaria, with protection from eBL were contradictory and underpowered. Therefore, using a case-control study design, we examined HbAS frequency in 306 Kenyan children diagnosed with eBL compared to 537 geographically defined and ethnically matched controls. We found 23.8% HbAS for eBL patients, which was not significantly different compared to 27.0% HbAS for controls [odds ratio (OR) = 0.85; 95% confidence interval (CI) 0.61-1.17; p-value = 0.33]. Even though cellular EBV titers, indicative of the number of latently infected B cells, were significantly higher (p-value < 0.0003) in children residing in malaria holoendemic compared to hypoendemic areas, levels were not associated with HbAS genotype. Combined, this suggests that although HbAS protects against severe malaria and hyperparasitemia, it is not associated with viral control or eBL protection. However, based on receiver operating characteristic curves factors that enable the establishment of EBV persistence, in contrast to those involved in EBV lytic reactivation, may have utility as an eBL precursor biomarker. This has implications for future human genetic association studies to consider variants influencing control over EBV in addition to malaria as risk factors for eBL. | |
| dc.language.iso | en_US | |
| dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23832374&dopt=Abstract">Link to Article in PubMed</a></p> | |
| dc.rights | Copyright 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | |
| dc.subject | Biological Markers | |
| dc.subject | Burkitt Lymphoma | |
| dc.subject | Ethnic Groups | |
| dc.subject | Herpesvirus 4, Human | |
| dc.subject | Malaria | |
| dc.subject | Sickle Cell Trait | |
| dc.subject | UMCCTS funding | |
| dc.subject | Hemic and Lymphatic Diseases | |
| dc.subject | Immune System Diseases | |
| dc.subject | Immunology and Infectious Disease | |
| dc.subject | Neoplasms | |
| dc.subject | Parasitic Diseases | |
| dc.subject | Pediatrics | |
| dc.subject | Virus Diseases | |
| dc.title | Sickle cell trait is not associated with endemic Burkitt lymphoma: an ethnicity and malaria endemicity-matched case-control study suggests factors controlling EBV may serve as a predictive biomarker for this pediatric cancer | |
| dc.type | Journal Article | |
| dc.source.journaltitle | International journal of cancer. Journal international du cancer | |
| dc.source.volume | 134 | |
| dc.source.issue | 3 | |
| dc.identifier.legacyfulltext | https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1297&context=faculty_pubs&unstamped=1 | |
| dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/faculty_pubs/298 | |
| dc.identifier.contextkey | 4951749 | |
| refterms.dateFOA | 2022-08-23T15:56:52Z | |
| html.description.abstract | <p>Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum coinfections. Malaria appears to dysregulate immunity that would otherwise control EBV, thereby contributing to eBL etiology. Juxtaposed to human genetic variants associated with protection from malaria, it has been hypothesized that such variants could decrease eBL susceptibility, historically referred to as "the protective hypothesis." Past studies attempting to link sickle cell trait (HbAS), which is known to be protective against malaria, with protection from eBL were contradictory and underpowered. Therefore, using a case-control study design, we examined HbAS frequency in 306 Kenyan children diagnosed with eBL compared to 537 geographically defined and ethnically matched controls. We found 23.8% HbAS for eBL patients, which was not significantly different compared to 27.0% HbAS for controls [odds ratio (OR) = 0.85; 95% confidence interval (CI) 0.61-1.17; p-value = 0.33]. Even though cellular EBV titers, indicative of the number of latently infected B cells, were significantly higher (p-value < 0.0003) in children residing in malaria holoendemic compared to hypoendemic areas, levels were not associated with HbAS genotype. Combined, this suggests that although HbAS protects against severe malaria and hyperparasitemia, it is not associated with viral control or eBL protection. However, based on receiver operating characteristic curves factors that enable the establishment of EBV persistence, in contrast to those involved in EBV lytic reactivation, may have utility as an eBL precursor biomarker. This has implications for future human genetic association studies to consider variants influencing control over EBV in addition to malaria as risk factors for eBL.</p> | |
| dc.identifier.submissionpath | faculty_pubs/298 | |
| dc.contributor.department | Department of Quantitative Health Sciences | |
| dc.contributor.department | Department of Pediatrics | |
| dc.contributor.department | Program in Bioinformatics and Integrative Biology | |
| dc.contributor.department | Department of Medicine | |
| dc.source.pages | 645-53 |
Files in this item
This item appears in the following Collection(s)
Related items
Showing items related by title, author, creator and subject.
-
Role of WFS1 in Regulating Endoplasmic Reticulum Stress Signaling: A DissertationThe endoplasmic reticulum (ER) is a multi-functional cellular compartment that functions in protein folding, lipid biosynthesis, and calcium homeostasis. Perturbations to ER function lead to the dysregulation of ER homeostasis, causing the accumulation of unfolded and misfolded proteins in the cell. This is a state of ER stress. ER stress elicits a cytoprotective, adaptive signaling cascade to mitigate stress, the Unfolded Protein Response (UPR). As long as the UPR can moderate stress, cells can produce the proper amount of proteins and maintain a state of homeostasis. If the UPR, however, is dysfunctional and fails to achieve this, cells will undergo apoptosis. Diabetes mellitus is a group of metabolic disorders characterized by persistent high blood glucose levels. The pathogenesis of this disease involves pancreatic β-cell dysfunction: an abnormality in the primary function of the β-cell, insulin production and secretion. Activation of the UPR is critical to pancreatic β-cell survival, where a disruption in ER stress signaling can lead to cell death and consequently diabetes. There are several models of ER stress leading to diabetes. Wolcott-Rallison syndrome, for example, occurs when there is a mutation in the gene encoding one of the master regulators of the UPR, PKR-like ER kinase (PERK). In this dissertation, we show that Wolfram Syndrome 1 (WFS1), an ER transmembrane protein, is a component of the UPR and is a downstream target of two of the master regulators of the UPR, Inositol Requiring 1 (IRE1) and PERK. WFS1 mutations lead to Wolfram syndrome, a non-autoimmune form of type 1 diabetes accompanied by optical atrophy and other neurological disorders. It has been shown that patients develop diabetes due to the selective loss of their pancreatic β-cells. Here we define the underlying molecular mechanism of β-cell loss in Wolfram syndrome, and link this cell loss to ER stress and a dysfunction in a component of the UPR, WFS1. We show that WFS1 expression is localized to the β-cell of the pancreas, it is upregulated during insulin secretion and ER stress, and its inactivation leads to chronic ER stress and apoptosis. This dissertation also reveals the previously unknown function of WFS1 in the UPR. Positive regulation of the UPR has been extensively studied, however, the precise mechanisms of negative regulation of this signaling pathway have not. Here we report that WFS1 regulates a key transcription factor of the UPR, activating transcription factor 6 (ATF6), through the ubiquitin-proteasome pathway. WFS1 expression decreases expression levels of ATF6 target genes and represses ATF6-mediated activation of the ER stress response (ERSE) promoter. WFS1 recruits and stabilizes an E3 ubiquitin ligase, HMG-CoA reductase degradation protein 1 (HRD1), on the ER membrane. The WFS1-HRD1 complex recruits ATF6 to the proteasome and enhances its ubiquitination and proteasome-mediated degradation, leading to suppression of the UPR under non-stress conditions. In response to ER stress, ATF6 is released from WFS1 and activates the UPR to mitigate ER stress. This body of work reveals a novel role for WFS1 in the UPR, and a novel mechanism for regulating ER stress signaling. These findings also indicate that hyperactivation of the UPR can lead to cellular dysfunction and death. This supports the notion that tight regulation of ER stress signaling is crucial to cell survival. This unanticipated role of WFS1 for a feedback loop of the UPR is relevant to diseases caused by chronic hyperactivation of ER stress signaling network such as pancreatic β-cell death in diabetes and neurodegeneration.
-
COVID-19: Pathophysiology and implications for cystic fibrosis, diabetes and cystic fibrosis-related diabetesThe novel SARS-CoV-2 coronavirus (COVID-19) has become a global health crisis since its initial outbreak in Wuhan, China in December 2019. On January 30, 2020, the WHO recognized the COVID-19 outbreak as a Public Health Emergency, and on March 11, 2020, it was declared a pandemic. Although all age groups have been affected, patients with cystic fibrosis (CF) and patients with type 1 or type 2 diabetes have been categorized as highly vulnerable to SARS-CoV-2 infection. Thus far, studies have found that the incidence of SARS-CoV-2 in the CF population is lower than the general population. We review the underlying protective mechanisms which may reduce inflammation and lung damage in CF patients, thus decreasing their risk of severe COVID-19. While the effect of SARS-CoV-2 in those with diabetes related to CF is unknown, other forms of diabetes have been associated with more severe disease. To further understand the potential impact of SARS-CoV-2 in cystic fibrosis-related diabetes, we provide a comprehensive overview of the potential factors contributing to COVID-19 severity in other forms of diabetes, including direct viral effect on the pancreas and indirect effects related to hyperglycemia and immune dysregulation.
-
Gaucher disease in the COVID-19 pandemic environment: The good, the bad and the unknownEarly in the course of the novel coronavirus disease 2019 (COVID-19) pandemic, the rare disease community anticipated that patients with lysosomal and other metabolic disorders would be at increased risk for poor disease outcomes and mortality from the SARS-CoV-2 virus.
