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3,080 results on '"Zhang, Yingze"'

1. Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Author

Jheng, Jia-Rong, DesJardin, Jacqueline, Chen, Yi-Yun, Huot, Joshua, Bai, Yang, Cook, Todd, Hibbard, Lainey, Rupp, Jennifer, Fisher, Amanda, Zhang, Yingze, Duarte, Julio, Desai, Ankit, Machado, Roberto, Simon, Marc, and Lai, Yen-Chun

Subjects
beta 2-microglobulin, heart failure, hypertension, pulmonary, proteomics, sirtuin 3, Adult, Aged, Animals, Humans, Male, Mice, Middle Aged, beta 2-Microglobulin, Biomarkers, Case-Control Studies, Cell Movement, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Heart Failure, Hypertension, Pulmonary, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Proteomics, Pulmonary Artery, Sirtuin 3, Stroke Volume, Vascular Remodeling, Ventricular Function, Left
Abstract

BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

Published
2024

7. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Author

Keener, Rebecca, Chhetri, Surya B, Connelly, Carla J, Taub, Margaret A, Conomos, Matthew P, Weinstock, Joshua, Ni, Bohan, Strober, Benjamin, Aslibekyan, Stella, Auer, Paul L, Barwick, Lucas, Becker, Lewis C, Blangero, John, Bleecker, Eugene R, Brody, Jennifer A, Cade, Brian E, Celedon, Juan C, Chang, Yi-Cheng, Cupples, L Adrienne, Custer, Brian, Freedman, Barry I, Gladwin, Mark T, Heckbert, Susan R, Hou, Lifang, Irvin, Marguerite R, Isasi, Carmen R, Johnsen, Jill M, Kenny, Eimear E, Kooperberg, Charles, Minster, Ryan L, Naseri, Take, Viali, Satupa’itea, Nekhai, Sergei, Pankratz, Nathan, Peyser, Patricia A, Taylor, Kent D, Telen, Marilyn J, Wu, Baojun, Yanek, Lisa R, Yang, Ivana V, Albert, Christine, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Bis, Joshua C, Blackwell, Thomas W, Boerwinkle, Eric, Burchard, Esteban G, Carson, April P, Chen, Zhanghua, Chen, Yii-Der Ida, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick T, Fornage, Myriam, Gelb, Bruce D, Gilliland, Frank D, He, Jiang, Islam, Talat, Kaab, Stefan, Kardia, Sharon LR, Kelly, Shannon, Konkle, Barbara A, Kumar, Rajesh, Loos, Ruth JF, Martinez, Fernando D, McGarvey, Stephen T, Meyers, Deborah A, Mitchell, Braxton D, Montgomery, Courtney G, North, Kari E, Palmer, Nicholette D, Peralta, Juan M, Raby, Benjamin A, Redline, Susan, Rich, Stephen S, Roden, Dan, Rotter, Jerome I, Ruczinski, Ingo, Schwartz, David, Sciurba, Frank, Shoemaker, M Benjamin, Silverman, Edwin K, Sinner, Moritz F, Smith, Nicholas L, Smith, Albert V, Tiwari, Hemant K, Vasan, Ramachandran S, Weiss, Scott T, Williams, L Keoki, Zhang, Yingze, Ziv, Elad, Raffield, Laura M, Reiner, Alexander P, Arvanitis, Marios, Greider, Carol W, Mathias, Rasika A, and Battle, Alexis

Subjects
Biological Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Humans, Genome-Wide Association Study, Telomere, K562 Cells, Telomere Homeostasis, Polymorphism, Single Nucleotide, Gene Expression Regulation, CRISPR-Cas Systems, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
Abstract

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Published
2024

26. Longitudinal multicompartment characterization of host-microbiota interactions in patients with acute respiratory failure

Author

Kitsios, Georgios D., Sayed, Khaled, Fitch, Adam, Yang, Haopu, Britton, Noel, Shah, Faraaz, Bain, William, Evankovich, John W., Qin, Shulin, Wang, Xiaohong, Li, Kelvin, Patel, Asha, Zhang, Yingze, Radder, Josiah, Dela Cruz, Charles, Okin, Daniel A., Huang, Ching‐Ying, Van Tyne, Daria, Benos, Panayiotis V., Methé, Barbara, Lai, Peggy, Morris, Alison, and McVerry, Bryan J.

Published
2024
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40. PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Author

Oldham, Justin M, Allen, Richard J, Lorenzo-Salazar, Jose M, Molyneaux, Philip L, Ma, Shwu-Fan, Joseph, Chitra, Kim, John S, Guillen-Guio, Beatriz, Hernández-Beeftink, Tamara, Kropski, Jonathan A, Huang, Yong, Lee, Cathryn T, Adegunsoye, Ayodeji, Pugashetti, Janelle Vu, Linderholm, Angela L, Vo, Vivian, Strek, Mary E, Jou, Jonathan, Muñoz-Barrera, Adrian, Rubio-Rodriguez, Luis A, Hubbard, Richard, Hirani, Nik, Whyte, Moira KB, Hart, Simon, Nicholson, Andrew G, Lancaster, Lisa, Parfrey, Helen, Rassl, Doris, Wallace, William, Valenzi, Eleanor, Zhang, Yingze, Mychaleckyj, Josyf, Stockwell, Amy, Kaminski, Naftali, Wolters, Paul J, Molina-Molina, Maria, Banovich, Nicholas E, Fahy, William A, Martinez, Fernando J, Hall, Ian P, Tobin, Martin D, Maher, Toby M, Blackwell, Timothy S, Yaspan, Brian L, Jenkins, R Gisli, Flores, Carlos, Wain, Louise V, and Noth, Imre

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Lung, Genetics, Autoimmune Disease, Rare Diseases, Human Genome, Good Health and Well Being, Humans, Genome-Wide Association Study, Idiopathic Pulmonary Fibrosis, Proportional Hazards Models, Europe, Serine Endopeptidases, Proprotein Convertases, IPF, genome-wide association study, genomics, survival, PCSK6 protein, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P

Published
2023

41. Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Author

Peljto, Anna L, Blumhagen, Rachel Z, Walts, Avram D, Cardwell, Jonathan, Powers, Julia, Corte, Tamera J, Dickinson, Joanne L, Glaspole, Ian, Moodley, Yuben P, Vasakova, Martina Koziar, Bendstrup, Elisabeth, Davidsen, Jesper R, Borie, Raphael, Crestani, Bruno, Dieude, Philippe, Bonella, Francesco, Costabel, Ulrich, Gudmundsson, Gunnar, Donnelly, Seamas C, Egan, Jim, Henry, Michael T, Keane, Michael P, Kennedy, Marcus P, McCarthy, Cormac, McElroy, Aoife N, Olaniyi, Joshua A, O'Reilly, Katherine MA, Richeldi, Luca, Leone, Paolo M, Poletti, Venerino, Puppo, Francesco, Tomassetti, Sara, Luzzi, Valentina, Kokturk, Nurdan, Mogulkoc, Nesrin, Fiddler, Christine A, Hirani, Nikhil, Jenkins, R Gisli, Maher, Toby M, Molyneaux, Philip L, Parfrey, Helen, Braybrooke, Rebecca, Blackwell, Timothy S, Jackson, Peter D, Nathan, Steven D, Porteous, Mary K, Brown, Kevin K, Christie, Jason D, Collard, Harold R, Eickelberg, Oliver, Foster, Elena E, Gibson, Kevin F, Glassberg, Marilyn, Kass, Daniel J, Kropski, Jonathan A, Lederer, David, Linderholm, Angela L, Loyd, Jim, Mathai, Susan K, Montesi, Sydney B, Noth, Imre, Oldham, Justin M, Palmisciano, Amy J, Reichner, Cristina A, Rojas, Mauricio, Roman, Jesse, Schluger, Neil, Shea, Barry S, Swigris, Jeffrey J, Wolters, Paul J, Zhang, Yingze, Prele, Cecilia MA, Enghelmayer, Juan I, Otaola, Maria, Ryerson, Christopher J, Salinas, Mauricio, Sterclova, Martina, Gebremariam, Tewodros H, Myllärniemi, Marjukka, Carbone, Roberto G, Furusawa, Haruhiko, Hirose, Masaki, Inoue, Yoshikazu, Miyazaki, Yasunari, Ohta, Ken, Ohta, Shin, Okamoto, Tsukasa, Kim, Dong Soon, Pardo, Annie, Selman, Moises, Aranda, Alvaro U, Park, Moo Suk, Park, Jong Sun, Song, Jin Woo, Molina-Molina, Maria, Planas-Cerezales, Lurdes, Westergren-Thorsson, Gunilla, Smith, Albert V, Manichaikul, Ani W, and Kim, John S

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Autoimmune Disease, Lung, Rare Diseases, Genetics, Human Genome, Prevention, Precision Medicine, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Idiopathic Pulmonary Fibrosis, Whole Genome Sequencing, Exome, whole-genome sequencing, interstitial lung disease, TOPMed, genetic association studies, telomerase, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Published
2023

42. Single Nucleotide Polymorphism rs9277336 Controls the Nuclear Alpha Actinin 4‐Human Leukocyte Antigen‐DPA1 Axis and Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension

Author

Hafeez, Neha, Kirillova, Anna, Yue, Yunshan, Rao, Rashmi J, Kelly, Neil J, Khoury, Wadih El, Aaraj, Yassmin Al, Tai, Yi‐Yin, Handen, Adam, Tang, Ying, Jiang, Danli, Wu, Ting, Zhang, Yingze, McNamara, Dennis, Kudryashova, Tatiana V, Goncharova, Elena A, Goncharov, Dmitry, Bertero, Thomas, Nouraie, Mehdi, Li, Gang, Sun, Wei, and Chan, Stephen Y

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Rare Diseases, Autoimmune Disease, Genetics, Lung, Clinical Research, Human Genome, Prevention, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Humans, Actinin, Endothelium, Genetic Predisposition to Disease, HLA-DP beta-Chains, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, endothelial dysfunction, genome-wide association study, linkage disequilibrium, pulmonary arterial hypertension, single nucleotide polymorphism, genome‐wide association study, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

Background Pulmonary arterial hypertension (PAH) is a complex, fatal disease where disease severity has been associated with the single nucleotide polymorphism (SNP) rs2856830, located near the human leukocyte antigen DPA1 (HLA-DPA1) gene. We aimed to define the genetic architecture of functional variants associated with PAH disease severity by identifying allele-specific binding transcription factors and downstream targets that control endothelial pathophenotypes and PAH. Methods and Results Electrophoretic mobility shift assays of oligonucleotides containing SNP rs2856830 and 8 SNPs in linkage disequilibrium revealed functional SNPs via allele-imbalanced binding to human pulmonary arterial endothelial cell nuclear proteins. DNA pulldown proteomics identified SNP-binding proteins. SNP genotyping and clinical correlation analysis were performed in 84 patients with PAH at University of Pittsburgh Medical Center and in 679 patients with PAH in the All of Us database. SNP rs9277336 was identified as a functional SNP in linkage disequilibrium (r2>0.8) defined by rs2856830, and the minor allele was associated with decreased hospitalizations and improved cardiac output in patients with PAH, an index of disease severity. SNP pulldown proteomics showed allele-specific binding of nuclear ACTN4 (alpha actinin 4) protein to rs9277336 minor allele. Both ACTN4 and HLA-DPA1 were downregulated in pulmonary endothelium in human patients and rodent models of PAH. Via transcriptomic and phenotypic analyses, knockdown of HLA-DPA1 phenocopied knockdown of ACTN4, both similarly controlling cell structure pathways, immune pathways, and endothelial dysfunction. Conclusions We defined the pathogenic activity of functional SNP rs9277336, entailing the allele-specific binding of ACTN4 and controlling expression of the neighboring HLA-DPA1 gene. Through inflammatory or genetic means, downregulation of this ACTN4-HLA-DPA1 regulatory axis promotes endothelial pathophenotypes, providing a mechanistic explanation for the association between this SNP and PAH outcomes.

Published
2023

43. Genome-wide association study of early ischaemic stroke risk in Brazilian individuals with sickle cell disease implicates ADAMTS2 and CDK18 and uncovers novel loci.

Author

Earley, Eric, Kelly, Shannon, Fang, Fang, Alencar, Cecília, Rodrigues, Daniela, Soares Cruz, Dahra, Flanagan, Jonathan, Ware, Russell, Zhang, Xu, Gordeuk, Victor, Gladwin, Mark, Zhang, Yingze, Nouraie, Mehdi, Nekhai, Sergei, Sabino, Ester, Custer, Brian, Dinardo, Carla, and Page, Grier

Subjects
Brazil, GWAS, ischaemic stroke, sickle cell disease, stroke, Adolescent, Adult, Child, Humans, Middle Aged, Young Adult, ADAMTS Proteins, Adaptor Proteins, Signal Transducing, Anemia, Sickle Cell, Brain Ischemia, Brazil, Genome-Wide Association Study, Ischemic Stroke, Stroke
Abstract

Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional-hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome-wide significance (p

Published
2023

46. Rare genetic variants explain missing heritability in smoking.

Author

Jang, Seon-Kyeong, Evans, Luke, Fialkowski, Allison, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Becker, Diane M, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Boorgula, Meher Preethi, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Jenkins, Brenda W Campbell, Carson, April P, Chavan, Sameer, Cupples, L Adrienne, Custer, Brian, Damrauer, Scott M, David, Sean P, de Andrade, Mariza, Dinardo, Carla L, Fingerlin, Tasha E, Fornage, Myriam, Freedman, Barry I, Garrett, Melanie E, Gharib, Sina A, Glahn, David C, Haessler, Jeffrey, Heckbert, Susan R, Hokanson, John E, Hou, Lifang, Hwang, Shih-Jen, Hyman, Matthew C, Judy, Renae, Justice, Anne E, Kaplan, Robert C, Kardia, Sharon LR, Kelly, Shannon, Kim, Wonji, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald M, Loos, Ruth JF, Manichaikul, Ani W, Gladwin, Mark T, Martin, Lisa Warsinger, Nouraie, Mehdi, Melander, Olle, Meyers, Deborah A, Montgomery, Courtney G, North, Kari E, Oelsner, Elizabeth C, Palmer, Nicholette D, Payton, Marinelle, Peljto, Anna L, Peyser, Patricia A, Preuss, Michael, Psaty, Bruce M, Qiao, Dandi, Rader, Daniel J, Rafaels, Nicholas, Redline, Susan, Reed, Robert M, Reiner, Alexander P, Rich, Stephen S, Rotter, Jerome I, Schwartz, David A, Shadyab, Aladdin H, Silverman, Edwin K, Smith, Nicholas L, Smith, J Gustav, Smith, Albert V, Smith, Jennifer A, Tang, Weihong, Taylor, Kent D, Telen, Marilyn J, Vasan, Ramachandran S, Gordeuk, Victor R, Wang, Zhe, Wiggins, Kerri L, Yanek, Lisa R, Yang, Ivana V, Young, Kendra A, Young, Kristin L, Zhang, Yingze, Liu, Dajiang J, Keller, Matthew C, and Vrieze, Scott

Subjects
Smoking, Gene Frequency, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Tobacco, Genetics, Tobacco Smoke and Health, Human Genome, Cancer
Abstract

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Published
2022

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