Browsing by Author "Telen, Marilyn J"

Now showing 1 - 6 of 6
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    Depression, quality of life, and medical resource utilization in sickle cell disease.
    (Blood advances, 2017-10-12) Adam, Soheir S; Flahiff, Charlene M; Kamble, Shital; Telen, Marilyn J; Reed, Shelby D; De Castro, Laura M
    Sickle cell disease (SCD) is a chronic, debilitating disorder. Chronically ill patients are at risk for depression, which can affect health-related quality of life (HRQoL), health care utilization, and cost. We performed an analytic epidemiologic prospective study to determine the prevalence of depression in adult patients with SCD and its association with HRQoL and medical resource utilization. Depression was measured by the Beck Depression Inventory and clinical history in adult SCD outpatients at a comprehensive SCD center. HRQoL was assessed using the SF36 form, and data were collected on medical resource utilization and corresponding cost. Neurocognitive functions were assessed using the CNS Vital Signs tool. Pain diaries were used to record daily pain. Out of 142 enrolled patients, 42 (35.2%) had depression. Depression was associated with worse physical and mental HRQoL scores (P < .0001 and P < .0001, respectively). Mean total inpatient costs ($25 000 vs $7487, P = .02) and total health care costs ($30 665 vs $13 016, P = .01) were significantly higher in patients with depression during the 12 months preceding diagnosis. Similarly, during the 6 months following diagnosis, mean total health care costs were significantly higher in depressed patients than in nondepressed patients ($13 766 vs $8670, P = .04). Depression is prevalent in adult patients with SCD and is associated with worse HRQoL and higher total health care costs. Efforts should focus on prevention, early diagnosis, and therapy for depression in SCD.
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    Genetic diversity fuels gene discovery for tobacco and alcohol use.
    (Nature, 2022-12) Saunders, Gretchen RB; Wang, Xingyan; Chen, Fang; Jang, Seon-Kyeong; Liu, Mengzhen; Wang, Chen; Gao, Shuang; Jiang, Yu; Khunsriraksakul, Chachrit; Otto, Jacqueline M; Addison, Clifton; Akiyama, Masato; Albert, Christine M; Aliev, Fazil; Alonso, Alvaro; Arnett, Donna K; Ashley-Koch, Allison E; Ashrani, Aneel A; Barnes, Kathleen C; Barr, R Graham; Bartz, Traci M; Becker, Diane M; Bielak, Lawrence F; Benjamin, Emelia J; Bis, Joshua C; Bjornsdottir, Gyda; Blangero, John; Bleecker, Eugene R; Boardman, Jason D; Boerwinkle, Eric; Boomsma, Dorret I; Boorgula, Meher Preethi; Bowden, Donald W; Brody, Jennifer A; Cade, Brian E; Chasman, Daniel I; Chavan, Sameer; Chen, Yii-Der Ida; Chen, Zhengming; Cheng, Iona; Cho, Michael H; Choquet, Hélène; Cole, John W; Cornelis, Marilyn C; Cucca, Francesco; Curran, Joanne E; de Andrade, Mariza; Dick, Danielle M; Docherty, Anna R; Duggirala, Ravindranath; Eaton, Charles B; Ehringer, Marissa A; Esko, Tõnu; Faul, Jessica D; Fernandes Silva, Lilian; Fiorillo, Edoardo; Fornage, Myriam; Freedman, Barry I; Gabrielsen, Maiken E; Garrett, Melanie E; Gharib, Sina A; Gieger, Christian; Gillespie, Nathan; Glahn, David C; Gordon, Scott D; Gu, Charles C; Gu, Dongfeng; Gudbjartsson, Daniel F; Guo, Xiuqing; Haessler, Jeffrey; Hall, Michael E; Haller, Toomas; Harris, Kathleen Mullan; He, Jiang; Herd, Pamela; Hewitt, John K; Hickie, Ian; Hidalgo, Bertha; Hokanson, John E; Hopfer, Christian; Hottenga, JoukeJan; Hou, Lifang; Huang, Hongyan; Hung, Yi-Jen; Hunter, David J; Hveem, Kristian; Hwang, Shih-Jen; Hwu, Chii-Min; Iacono, William; Irvin, Marguerite R; Jee, Yon Ho; Johnson, Eric O; Joo, Yoonjung Y; Jorgenson, Eric; Justice, Anne E; Kamatani, Yoichiro; Kaplan, Robert C; Kaprio, Jaakko; Kardia, Sharon LR; Keller, Matthew C; Kelly, Tanika N; Kooperberg, Charles; Korhonen, Tellervo; Kraft, Peter; Krauter, Kenneth; Kuusisto, Johanna; Laakso, Markku; Lasky-Su, Jessica; Lee, Wen-Jane; Lee, James J; Levy, Daniel; Li, Liming; Li, Kevin; Li, Yuqing; Lin, Kuang; Lind, Penelope A; Liu, Chunyu; Lloyd-Jones, Donald M; Lutz, Sharon M; Ma, Jiantao; Mägi, Reedik; Manichaikul, Ani; Martin, Nicholas G; Mathur, Ravi; Matoba, Nana; McArdle, Patrick F; McGue, Matt; McQueen, Matthew B; Medland, Sarah E; Metspalu, Andres; Meyers, Deborah A; Millwood, Iona Y; Mitchell, Braxton D; Mohlke, Karen L; Moll, Matthew; Montasser, May E; Morrison, Alanna C; Mulas, Antonella; Nielsen, Jonas B; North, Kari E; Oelsner, Elizabeth C; Okada, Yukinori; Orrù, Valeria; Palmer, Nicholette D; Palviainen, Teemu; Pandit, Anita; Park, S Lani; Peters, Ulrike; Peters, Annette; Peyser, Patricia A; Polderman, Tinca JC; Rafaels, Nicholas; Redline, Susan; Reed, Robert M; Reiner, Alex P; Rice, John P; Rich, Stephen S; Richmond, Nicole E; Roan, Carol; Rotter, Jerome I; Rueschman, Michael N; Runarsdottir, Valgerdur; Saccone, Nancy L; Schwartz, David A; Shadyab, Aladdin H; Shi, Jingchunzi; Shringarpure, Suyash S; Sicinski, Kamil; Skogholt, Anne Heidi; Smith, Jennifer A; Smith, Nicholas L; Sotoodehnia, Nona; Stallings, Michael C; Stefansson, Hreinn; Stefansson, Kari; Stitzel, Jerry A; Sun, Xiao; Syed, Moin; Tal-Singer, Ruth; Taylor, Amy E; Taylor, Kent D; Telen, Marilyn J; Thai, Khanh K; Tiwari, Hemant; Turman, Constance; Tyrfingsson, Thorarinn; Wall, Tamara L; Walters, Robin G; Weir, David R; Weiss, Scott T; White, Wendy B; Whitfield, John B; Wiggins, Kerri L; Willemsen, Gonneke; Willer, Cristen J; Winsvold, Bendik S; Xu, Huichun; Yanek, Lisa R; Yin, Jie; Young, Kristin L; Young, Kendra A; Yu, Bing; Zhao, Wei; Zhou, Wei; Zöllner, Sebastian; Zuccolo, Luisa; 23andMe Research Team; Biobank Japan Project; Batini, Chiara; Bergen, Andrew W; Bierut, Laura J; David, Sean P; Gagliano Taliun, Sarah A; Hancock, Dana B; Jiang, Bibo; Munafò, Marcus R; Thorgeirsson, Thorgeir E; Liu, Dajiang J; Vrieze, Scott
    Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
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    In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
    (PLoS Genet, 2015-07) Anderson, Blair R; Howell, David N; Soldano, Karen; Garrett, Melanie E; Katsanis, Nicholas; Telen, Marilyn J; Davis, Erica E; Ashley-Koch, Allison E
    African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.
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    Nitric oxide loading reduces sickle red cell adhesion and vaso-occlusion in vivo.
    (Blood advances, 2019-09) McMahon, Timothy J; Shan, Siqing; Riccio, Daniel A; Batchvarova, Milena; Zhu, Hongmei; Telen, Marilyn J; Zennadi, Rahima
    Sickle red blood cells (SSRBCs) are adherent to the endothelium, activate leukocyte adhesion, and are deficient in bioactive nitric oxide (NO) adducts such as S-nitrosothiols (SNOs), with reduced ability to induce vasodilation in response to hypoxia. All these pathophysiologic characteristics promote vascular occlusion, the hallmark of sickle cell disease (SCD). Loading hypoxic SSRBCs in vitro with NO followed by reoxygenation significantly decreased epinephrine-activated SSRBC adhesion to the endothelium, the ability of activated SSRBCs to mediate leukocyte adhesion in vitro, and vessel obstruction in vivo. Because transfusion is frequently used in SCD, we also determined the effects of banked (SNO-depleted) red blood cells (RBCs) on vaso-occlusion in vivo. Fresh or 14-day-old normal RBCs (AARBCs) reduced epinephrine-activated SSRBC adhesion to the vascular endothelium and prevented vaso-occlusion. In contrast, AARBCs stored for 30 days failed to decrease activated SSRBC adhesivity or vaso-occlusion, unless these RBCs were loaded with NO. Furthermore, NO loading of SSRBCs increased S-nitrosohemoglobin and modulated epinephrine's effect by upregulating phosphorylation of membrane proteins, including pyruvate kinase, E3 ubiquitin ligase, and the cytoskeletal protein 4.1. Thus, abnormal SSRBC NO/SNO content both contributes to the vaso-occlusive pathophysiology of SCD, potentially by affecting at least protein phosphorylation, and is potentially amenable to correction by (S)NO repletion or by RBC transfusion.
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    Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.
    (PLoS One, 2013) Terman, David S; Viglianti, Benjamin L; Zennadi, Rahima; Fels, Diane; Boruta, Richard J; Yuan, Hong; Dreher, Mathew R; Grant, Gerald; Rabbani, Zahid N; Moon, Ejung; Lan, Lan; Eble, Joseph; Cao, Yiting; Sorg, Brian; Ashcraft, Kathleen; Palmer, Greg; Telen, Marilyn J; Dewhirst, Mark W
    Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.
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    The genomic analysis of erythrocyte microRNA expression in sickle cell diseases.
    (PLoS One, 2008-06-04) Chen, Shao-Yin; Wang, Yulei; Telen, Marilyn J; Chi, Jen-Tsan
    BACKGROUND: Since mature erythrocytes are terminally differentiated cells without nuclei and organelles, it is commonly thought that they do not contain nucleic acids. In this study, we have re-examined this issue by analyzing the transcriptome of a purified population of human mature erythrocytes from individuals with normal hemoglobin (HbAA) and homozygous sickle cell disease (HbSS). METHODS AND FINDINGS: Using a combination of microarray analysis, real-time RT-PCR and Northern blots, we found that mature erythrocytes, while lacking ribosomal and large-sized RNAs, contain abundant and diverse microRNAs. MicroRNA expression of erythrocytes was different from that of reticulocytes and leukocytes, and contributed the majority of the microRNA expression in whole blood. When we used microRNA microarrays to analyze erythrocytes from HbAA and HbSS individuals, we noted a dramatic difference in their microRNA expression pattern. We found that miR-320 played an important role for the down-regulation of its target gene, CD71 during reticulocyte terminal differentiation. Further investigation revealed that poor expression of miR-320 in HbSS cells was associated with their defective downregulation CD71 during terminal differentiation. CONCLUSIONS: In summary, we have discovered significant microRNA expression in human mature erythrocytes, which is dramatically altered in HbSS erythrocytes and their defect in terminal differentiation. Thus, the global analysis of microRNA expression in circulating erythrocytes can provide mechanistic insights into the disease phenotypes of erythrocyte diseases.