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219 results on '"Nichols, William C."'

1. Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension

Author

Tang, Haiyang, Gupta, Akash, Morrisroe, Seth A., Bao, Changlei, Schwantes-An, Tae-Hwi, Gupta, Geetanjali, Liang, Shuxin, Sun, Yanan, Chu, Aiai, Luo, Ang, Ramamoorthi Elangovan, Venkateswaran, Sangam, Shreya, Shi, Yinan, Naidu, Samisubbu R., Jheng, Jia-Rong, Ciftci-Yilmaz, Sultan, Warfel, Noel A., Hecker, Louise, Mitra, Sumegha, Coleman, Anna W., Lutz, Katie A., Pauciulo, Michael W., Lai, Yen-Chun, Javaheri, Ali, Dharmakumar, Rohan, Wu, Wen-Hui, Flaherty, Daniel P., Karnes, Jason H., Breuils-Bonnet, Sandra, Boucherat, Olivier, Bonnet, Sebastien, Yuan, Jason X.-J., Jacobson, Jeffrey R., Duarte, Julio D., Nichols, William C., Garcia, Joe G.N., and Desai, Ankit A.

Published
2024
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2. Metabolomic Profiles Differentiate Scleroderma-PAH From Idiopathic PAH and Correspond With Worsened Functional Capacity

Author

Alotaibi, Mona, Shao, Junzhe, Pauciulo, Michael W, Nichols, William C, Hemnes, Anna R, Malhotra, Atul, Kim, Nick H, Yuan, Jason X-J, Fernandes, Timothy, Kerr, Kim M, Alshawabkeh, Laith, Desai, Ankit A, Bujor, Andreea M, Lafyatis, Robert, Watrous, Jeramie D, Long, Tao, Cheng, Susan, Chan, Stephen Y, and Jain, Mohit

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Autoimmune Disease, Scleroderma, Lung, Rare Diseases, Clinical Research, Orphan Drug, Inflammatory and immune system, Humans, Familial Primary Pulmonary Hypertension, Hypertension, Pulmonary, Scleroderma, Systemic, Prognosis, Lipids, biomarkers, metabolomics, pulmonary hypertension, scleroderma, Clinical Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundThe prognosis and therapeutic responses are worse for pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) compared with idiopathic pulmonary arterial hypertension (IPAH). This discrepancy could be driven by divergence in underlying metabolic determinants of disease.Research questionAre circulating bioactive metabolites differentially altered in SSc-PAH vs IPAH, and can this alteration explain clinical disparity between these PAH subgroups?Study design and methodsPlasma biosamples from 400 patients with SSc-PAH and 1,082 patients with IPAH were included in the study. Another cohort of 100 patients with scleroderma with no PH and 44 patients with scleroderma with PH was included for external validation. More than 700 bioactive lipid metabolites, representing a range of vasoactive and immune-inflammatory pathways, were assayed in plasma samples from independent discovery and validation cohorts using liquid chromatography/high-resolution mass spectrometry-based approaches. Regression analyses were used to identify metabolites that exhibited differential levels between SSc-PAH and IPAH and associated with disease severity.ResultsFrom hundreds of circulating bioactive lipid molecules, five metabolites were found to distinguish between SSc-PAH and IPAH, as well as associate with markers of disease severity. Relative to IPAH, patients with SSc-PAH carried increased levels of fatty acid metabolites, including lignoceric acid and nervonic acid, as well as eicosanoids/oxylipins and sex hormone metabolites.InterpretationPatients with SSc-PAH are characterized by an unfavorable bioactive metabolic profile that may explain the poor and limited response to therapy. These data provide important metabolic insights into the molecular heterogeneity underlying differences between subgroups of PAH.

Published
2023

5. Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

Author

Callejo, Emily P., Day, Kristina M., Macaya, Daniela, Maldonado-Velez, Gabriel, Archer, Stephen L., Auckland, Kathryn, Austin, Eric D., Badagliacca, Roberto, Barberà, Joan-Albert, Belge, Catharina, Bogaard, Harm Jan, Bonnet, Sébastien, Boomars, Karin A., Boucherat, Olivier, Chakinala, Murali M., Condliffe, Robin, Damico, Rachel Lynn, Delcroix, Marion, Desai, Ankit A., Doboszynska, Anna, Elliott, C. Greg, Eyries, Melanie, Escribano Subías, Maria Pilar, Gall, Henning, Ghio, Stefano, Ghofrani, Ardeschir-Hossein, Grünig, Ekkehard, Hamid, Rizwan, Harbaum, Lars, Hassoun, Paul M., Hemnes, Anna R., Hinderhofer, Katrin, Howard, Luke S., Humbert, Marc, Kiely, David G., Langleben, David, Lawrie, Allan, Loyd, Jim E., Moledina, Shahin, Montani, David, Morrell, Nichols W., Nichols, William C., Olschewski, Andrea, Olschewski, Horst, Papa, Silvia, Pauciulo, Mike W., Provencher, Steve, Quarck, Rozenn, Rhodes, Christopher J., Scelsi, Laura, Seeger, Werner, Stewart, Duncan J., Sweatt, Andrew, Swietlik, Emilia M., Treacy, Carmen, Trembath, Richard C., Tura-Ceide, Olga, Vizza, Carmine Dario, Vonk Noordegraaf, Anton, Wilkins, Martin R., Zamanian, Roham T., Zateyshchikov, Dmitry, Welch, Carrie L., Aldred, Micheala A., Balachandar, Srimmitha, Dooijes, Dennis, Eichstaedt, Christina A., Gräf, Stefan, Houweling, Arjan C., Machado, Rajiv D., Pandya, Divya, Prapa, Matina, Shaukat, Memoona, Southgate, Laura, Tenorio-Castano, Jair, and Chung, Wendy K.

Published
2023
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6. Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension

Author

Karnes, Jason H, Wiener, Howard W, Schwantes-An, Tae-Hwi, Natarajan, Balaji, Sweatt, Andrew J, Chaturvedi, Abhishek, Arora, Amit, Batai, Ken, Nair, Vineet, Steiner, Heidi E, Giles, Jason B, Yu, Jeffrey, Hosseini, Maryam, Pauciulo, Michael W, Lutz, Katie A, Coleman, Anna W, Feldman, Jeremy, Vanderpool, Rebecca, Tang, Haiyang, Garcia, Joe GN, Yuan, Jason X-J, Kittles, Rick, de Jesus Perez, Vinicio, Zamanian, Roham T, Rischard, Franz, Tiwari, Hemant K, Nichols, William C, Benza, Raymond L, and Desai, Ankit A

Subjects
Lung, Good Health and Well Being, Adult, Black or African American, Aged, Female, Hispanic or Latino, Humans, Male, Middle Aged, Pulmonary Arterial Hypertension, Survival Rate, United States, White People, pulmonary arterial hypertension, Hispanic American, Native American, survival, health disparities, Medical and Health Sciences, Respiratory System
Abstract

Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

Published
2020

7. Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension

Author

Zhu, Na, Pauciulo, Michael W, Welch, Carrie L, Lutz, Katie A, Coleman, Anna W, Gonzaga-Jauregui, Claudia, Wang, Jiayao, Grimes, Joseph M, Martin, Lisa J, He, Hua, Shen, Yufeng, Chung, Wendy K, and Nichols, William C

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, Lung, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Adult, Age of Onset, Aged, Biomarkers, Exome, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Hemodynamics, Humans, Male, Middle Aged, Pulmonary Arterial Hypertension, Exome Sequencing, Pulmonary arterial hypertension, Exome sequencing, Case-control association testing, PAH Biobank Enrolling Centers’ Investigators, Clinical Sciences
Abstract

BackgroundGroup 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined.MethodsTo identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing.ResultsTissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH.ConclusionsWe report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.

Published
2019

10. Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

Author

Harvey, Lloyd D, primary, Alotaibi, Mona, additional, Kim, Hee-Jung Janice, additional, Tai, Yi-Yin, additional, Tang, Ying, additional, Sun, Wei, additional, El Khoury, Wadih, additional, Woodcock, Chen-Shan C, additional, Aaraj, Yassmin Al, additional, St. Croix, Claudette M, additional, Stolz, Donna B, additional, Lee, Jiyoung, additional, Cheng, Mary Hongying, additional, Schwantes-An, Tae-Hwi, additional, Desai, Ankit A, additional, Pauciulo, Michael W, additional, Nichols, William C, additional, Webb, Amy, additional, Lafyatis, Robert, additional, Nouraie, Mehdi, additional, Wu, Haodi, additional, McDonald, Jeffrey G, additional, Chauvet, Caroline, additional, Cheng, Susan, additional, Bahar, Ivet, additional, Bertero, Thomas, additional, Benza, Raymond L, additional, Jain, Mohit, additional, and Chan, Stephen Y, additional

Published
2024
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11. NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review

Author

Oldham, William M., Hemnes, Anna R., Aldred, Micheala A., Barnard, John, Brittain, Evan L., Chan, Stephen Y., Cheng, Feixiong, Cho, Michael H., Desai, Ankit A., Garcia, Joe G.N., Geraci, Mark W., Ghiassian, Susan D., Hall, Kathryn T., Horn, Evelyn M., Jain, Mohit, Kelly, Rachel S., Leopold, Jane A., Lindstrom, Sara, Modena, Brian D., Nichols, William C., Rhodes, Christopher J., Sun, Wei, Sweatt, Andrew J., Vanderpool, Rebecca R., Wilkins, Martin R., Wilmot, Beth, Zamanian, Roham T., Fessel, Joshua P., Aggarwal, Neil R., Loscalzo, Joseph, and Xiao, Lei

Published
2021
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14. Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension

Author

Tai, Yi-Yin, primary, Yu, Qiujun, additional, Tang, Ying, additional, Sun, Wei, additional, Kelly, Neil J., additional, Okawa, Satoshi, additional, Zhao, Jingsi, additional, Schwantes-An, Tae-Hwi, additional, Lacoux, Caroline, additional, Torrino, Stephanie, additional, Al Aaraj, Yassmin, additional, El Khoury, Wadih, additional, Negi, Vinny, additional, Liu, Mingjun, additional, Corey, Catherine G., additional, Belmonte, Frances, additional, Vargas, Sara O., additional, Schwartz, Brian, additional, Bhat, Bal, additional, Chau, B. Nelson, additional, Karnes, Jason H., additional, Satoh, Taijyu, additional, Barndt, Robert J., additional, Wu, Haodi, additional, Parikh, Victoria N., additional, Wang, Jianrong, additional, Zhang, Yingze, additional, McNamara, Dennis, additional, Li, Gang, additional, Speyer, Gil, additional, Wang, Bing, additional, Shiva, Sruti, additional, Kaufman, Brett, additional, Kim, Seungchan, additional, Gomez, Delphine, additional, Mari, Bernard, additional, Cho, Michael H., additional, Boueiz, Adel, additional, Pauciulo, Michael W., additional, Southgate, Laura, additional, Trembath, Richard C., additional, Sitbon, Olivier, additional, Humbert, Marc, additional, Graf, Stefan, additional, Morrell, Nicholas W., additional, Rhodes, Christopher J., additional, Wilkins, Martin R., additional, Nouraie, Mehdi, additional, Nichols, William C., additional, Desai, Ankit A., additional, Bertero, Thomas, additional, and Chan, Stephen Y., additional

Published
2024
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15. Pediatric pulmonary hypertension: insulin-like growth factor-binding protein 2 is a novel marker associated with disease severity and survival

Author

Griffiths, Megan, Yang, Jun, Nies, Melanie, Vaidya, Dhananjay, Brandal, Stephanie, Williams, Monica, Matsui, Elizabeth C., Grant, Torie, Damico, Rachel, Ivy, Dunbar, Austin, Eric D., Nichols, William C., Pauciulo, Michael W., Lutz, Katie, Rosenzweig, Erika B., Hirsch, Russel, Yung, Delphine, and Everett, Allen D.

Published
2020
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16. The relationship between obsessive‐compulsive symptoms and PARKIN genotype: The CORE‐PD study

Author

Sharp, Madeleine E, Caccappolo, Elise, Mejia‐Santana, Helen, Tang, Ming‐X, Rosado, Llency, Reilly, Martha Orbe, Ruiz, Diana, Louis, Elan D, Comella, Cynthia, Nance, Martha, Bressman, Susan, Scott, William K, Tanner, Caroline, Waters, Cheryl, Fahn, Stanley, Cote, Lucien, Ford, Blair, Rezak, Michael, Novak, Kevin, Friedman, Joseph H, Pfeiffer, Ronald, Payami, Haydeh, Molho, Eric, Factor, Stuart A, Nutt, John, Serrano, Carmen, Arroyo, Maritza, Pauciulo, Michael W, Nichols, William C, Clark, Lorraine N, Alcalay, Roy N, and Marder, Karen S

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Disorders, Parkinson's Disease, Neurodegenerative, Genetics, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Age of Onset, Aged, Female, Genetic Predisposition to Disease, Genetic Testing, Genotype, Heterozygote, Humans, Male, Middle Aged, Mutation, Obsessive-Compulsive Disorder, Parkinson Disease, Ubiquitin-Protein Ligases, Parkinson's, neuropsychological, obsessive-compulsive, parkin, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundFew studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS).MethodsThe Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers.ResultsAmong patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13).ConclusionsFirst, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.

Published
2015

17. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe G N, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, MacKenzie Ross, Robert V, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Walsworth, Anna K, Walter, Robert E, Wharton, John, White, R James, Wilt, Jeffrey, Wort, Stephen J, Yung, Delphine, Lawrie, Allan, Humbert, Marc, Soubrier, Florent, Trégouët, David-Alexandre, Prokopenko, Inga, Kittles, Richard, Gräf, Stefan, Nichols, William C, Trembath, Richard C, Desai, Ankit A, Morrell, Nicholas W, and Wilkins, Martin R

Published
2019
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20. Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

Author

Potus, François, Pauciulo, Michael W., Cook, Elina K., Zhu, Na, Hsieh, Alexander, Welch, Carrie L., Shen, Yufeng, Tian, Lian, Lima, Patricia, Mewburn, Jeffrey, D’Arsigny, Christine L., Lutz, Katie A., Coleman, Anna W., Damico, Rachel, Snetsinger, Brooke, Martin, Ashley Y., Hassoun, Paul M., Nichols, William C., Chung, Wendy K., Rauh, Michael J., and Archer, Stephen L.

Published
2020
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21. SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics

Author

Sangam, Shreya, primary, Sun, Xutong, additional, Schwantes-An, Tae-Hwi, additional, Yegambaram, Manivannan, additional, Lu, Qing, additional, Shi, Yinan, additional, Cook, Todd, additional, Fisher, Amanda, additional, Frump, Andrea L., additional, Coleman, Anna, additional, Sun, Yanan, additional, Liang, Shuxin, additional, Crawford, Howard, additional, Lutz, Katie A., additional, Maun, Avinash D., additional, Pauciulo, Michael W., additional, Karnes, Jason H., additional, Chaudhary, Ketul R., additional, Stewart, Duncan J., additional, Langlais, Paul R., additional, Jain, Mohit, additional, Alotaibi, Mona, additional, Lahm, Tim, additional, Jin, Yan, additional, Gu, Haiwei, additional, Tang, Haiyang, additional, Nichols, William C., additional, Black, Stephen M., additional, and Desai, Ankit A., additional

Published
2023
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22. RASA3 is a Candidate Gene in Sickle Cell Disease‐Associated Pulmonary Hypertension and Pulmonary Arterial Hypertension

Author

Prohaska, Clare C., primary, Zhang, Xu, additional, Schwantes‐An, Tae‐Hwi L., additional, Stearman, Robert S., additional, Hooker, Stanley, additional, Kittles, Rick A., additional, Aldred, Micheala A., additional, Lutz, Katie A., additional, Pauciulo, Michael W., additional, Nichols, William C., additional, Desai, Ankit A., additional, Gordeuk, Victor R., additional, and Machado, Roberto F., additional

Published
2023
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23. Insulin‐like growth factor binding Protein‐4: A novel indicator of pulmonary arterial hypertension severity and survival

Author

Torres, Guillermo, primary, Yang, Jun, additional, Griffiths, Megan, additional, Brandal, Stephanie, additional, Damico, Rachel, additional, Vaidya, Dhananjay, additional, Simpson, Catherine E., additional, Pauciulo, Michael W., additional, Nichols, William C., additional, Ivy, David D., additional, Austin, Eric D., additional, Hassoun, Paul M., additional, and Everett, Allen D., additional

Published
2023
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25. Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension

Author

Hong, Jason, primary, Wong, Brenda, additional, Rhodes, Christopher J., additional, Kurt, Zeyneb, additional, Schwantes-An, Tae-Hwi, additional, Mickler, Elizabeth A., additional, Gräf, Stefan, additional, Eyries, Mélanie, additional, Lutz, Katie A., additional, Pauciulo, Michael W., additional, Trembath, Richard C., additional, Montani, David, additional, Morrell, Nicholas W., additional, Wilkins, Martin R., additional, Nichols, William C., additional, Trégouët, David-Alexandre, additional, Aldred, Micheala A., additional, Desai, Ankit A., additional, Tuder, Rubin M., additional, Geraci, Mark W., additional, Eghbali, Mansoureh, additional, Stearman, Robert S., additional, and Yang, Xia, additional

Published
2023
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26. Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension

Author

Hong, Jason, Wong, Brenda, Rhodes, Christopher J., Kurt, Zeyneb, Schwantes-An, Tae-Hwi, Mickler, Elizabeth A., Gräf, Stefan, Eyries, Mélanie, Lutz, Katie A., Pauciulo, Michael W., Trembath, Richard C., Montani, David, Morrell, Nicholas W., Wilkins, Martin R., Nichols, William C., Trégouët, David-Alexandre, Aldred, Micheala A., Desai, Ankit A., Tuder, Rubin M., Geraci, Mark W., Eghbali, Mansoureh, Stearman, Robert S., and Yang, Xia

Subjects
Article
Abstract

Pulmonary arterial hypertension (PAH) remains an incurable and often fatal disease despite currently available therapies. Multiomics systems biology analysis can shed new light on PAH pathobiology and inform translational research efforts. Using RNA sequencing on the largest PAH lung biobank to date (96 disease and 52 control), we aim to identify gene co-expression network modules associated with PAH and potential therapeutic targets. Co-expression network analysis was performed to identify modules of co-expressed genes which were then assessed for and prioritized by importance in PAH, regulatory role, and therapeutic potential via integration with clinicopathologic data, human genome-wide association studies (GWAS) of PAH, lung Bayesian regulatory networks, single-cell RNA-sequencing data, and pharmacotranscriptomic profiles. We identified a co-expression module of 266 genes, called the pink module, which may be a response to the underlying disease process to counteract disease progression in PAH. This module was associated not only with PAH severity such as increased PVR and intimal thickness, but also with compensated PAH such as lower number of hospitalizations, WHO functional class and NT-proBNP. GWAS integration demonstrated the pink module is enriched for PAH-associated genetic variation in multiple cohorts. Regulatory network analysis revealed that BMPR2 regulates the main target of FDA-approved riociguat, GUCY1A2, in the pink module. Analysis of pathway enrichment and pink hub genes (i.e. ANTXR1 and SFRP4) suggests the pink module inhibits Wnt signaling and epithelial-mesenchymal transition. Cell type deconvolution showed the pink module correlates with higher vascular cell fractions (i.e. myofibroblasts). A pharmacotranscriptomic screen discovered ubiquitin-specific peptidases (USPs) as potential therapeutic targets to mimic the pink module signature. Our multiomics integrative study uncovered a novel gene subnetwork associated with clinicopathologic severity, genetic risk, specific vascular cell types, and new therapeutic targets in PAH. Future studies are warranted to investigate the role and therapeutic potential of the pink module and targeting USPs in PAH.

Published
2023

27. Low‐affinity insulin‐like growth factor binding protein 7 and its association with pulmonary arterial hypertension severity and survival.

Author

Torres, Guillermo, Lancaster, Andrew C., Yang, Jun, Griffiths, Megan, Brandal, Stephanie, Damico, Rachel, Vaidya, Dhananjay, Simpson, Catherine E., Martin, Lisa J., Pauciulo, Michael W., Nichols, William C., Ivy, David D., Austin, Eric D., Hassoun, Paul M., and Everett, Allen D.

Abstract

Insulin‐like growth factor (IGF) binding proteins (IGFBPs) are a family of growth factor modifiers, some of which are known to be independently associated with pulmonary arterial hypertension (PAH) survival. IGF factor binding protein 7 (IGFBP7) is a unique low‐affinity IGFBP that, independent of IGF, stimulates prostacyclin production. This study proposed to establish associations between IGFBP7 and PAH severity and survival, using enrollment and longitudinal samples. Serum IGFBP7 levels were significantly elevated in patients with PAH compared to controls. After adjusting for age and sex, logarithmic increases in IGFBP7 were associated with a 20 m shorter six‐minute walk distance (6MWD; p < 0.001), a 2−3 mmHg higher mean right atrial pressure (p < 0.001 and 0.02), and a higher likelihood of a greater REVEAL 2.0 risk category placement (p < 0.001). Kaplan−Meier analysis demonstrated significantly decreased survival with IGFBP7 above the median and Cox multivariable analysis adjusted for age and sex, demonstrated higher serum IGFBP7 was an independent predictor of survival. Though the exact mechanism is still unknown, given IGFBP7's role as a prostacyclin stimulant, it has potential use as a therapeutic target for disease modulation. [ABSTRACT FROM AUTHOR]

Published
2023
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28. Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

Author

Zhu, Na, Welch, Carrie L., Wang, Jiayao, Allen, Philip M., Gonzaga-Jauregui, Claudia, Ma, Lijiang, King, Alejandra K., Krishnan, Usha, Rosenzweig, Erika B., Ivy, D. Dunbar, Austin, Eric D., Hamid, Rizwan, Pauciulo, Michael W., Lutz, Katie A., Nichols, William C., Reid, Jeffrey G., Overton, John D., Baras, Aris, Dewey, Frederick E., Shen, Yufeng, and Chung, Wendy K.

Published
2018
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29. Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension

Author

Harbaum, Lars, primary, Rhodes, Christopher J., additional, Wharton, John, additional, Lawrie, Allan, additional, Karnes, Jason H., additional, Desai, Ankit A., additional, Nichols, William C., additional, Humbert, Marc, additional, Montani, David, additional, Girerd, Barbara, additional, Sitbon, Olivier, additional, Boehm, Mario, additional, Novoyatleva, Tatyana, additional, Schermuly, Ralph T., additional, Ghofrani, H. Ardeschir, additional, Toshner, Mark, additional, Kiely, David G., additional, Howard, Luke S., additional, Swietlik, Emilia M., additional, Gräf, Stefan, additional, Pietzner, Maik, additional, Morrell, Nicholas W., additional, Wilkins, Martin R., additional, Southgate, L, additional, Machado, RD, additional, Martin, J, additional, Ouwehand, WH, additional, Pauciulo, MW, additional, Arora, A, additional, Lutz, K, additional, Ahmad, F, additional, Archer, SL, additional, Argula, R, additional, Austin, ED, additional, Badesch, D, additional, Bakshi, S, additional, Barnett, C, additional, Benza, R, additional, Bhatt, N, additional, Burger, CD, additional, Chakinala, M, additional, Elwing, J, additional, Fortin, T, additional, Frantz, RP, additional, Frost, A, additional, Garcia, JGN, additional, Harley, J, additional, He, H, additional, Hill, NS, additional, Hirsch, R, additional, Ivy, D, additional, Klinger, J, additional, Lahm, T, additional, Marsolo, K, additional, Martin, LJ, additional, Nathan, SD, additional, Oudiz, RJ, additional, Rehman, Z, additional, Robbins, I, additional, Roden, DM, additional, Rosenzweig, EB, additional, Saydain, G, additional, Schilz, R, additional, Simms, RW, additional, Simon, M, additional, Tang, H, additional, Tchourbanov, AY, additional, Thenappan, T, additional, Torres, F, additional, Walsworth, AK, additional, Walter, RE, additional, White, RJ, additional, Wilt, J, additional, Yung, D, additional, Kittles, R, additional, Aman, J, additional, Knight, J, additional, Hanscombe, KB, additional, Gall, H, additional, Ulrich, A, additional, Bogaard, HJ, additional, Church, C, additional, Coghlan, JG, additional, Condliffe, R, additional, Corris, PA, additional, Danesino, C, additional, Elliott, CG, additional, Franke, A, additional, Ghio, S, additional, Gibbs, JSR, additional, Houweling, AC, additional, Kovacs, G, additional, Laudes, M, additional, MacKenzie Ross, RV, additional, Moledina, S, additional, Newnham, M, additional, Olschewski, A, additional, Olschewski, H, additional, Peacock, AJ, additional, Pepke-Zaba, J, additional, Scelsi, L, additional, Seeger, W, additional, Shaffer, CM, additional, Sitbon, O, additional, Suntharalingam, J, additional, Treacy, C, additional, Vonk Noordegraaf, A, additional, Waisfisz, Q, additional, Wort, SJ, additional, Trembath, RC, additional, Germain, M, additional, Cebola, I, additional, Ferrer, J, additional, Amouyel, P, additional, Debette, S, additional, Eyries, M, additional, Soubrier, F, additional, and Trégouët, DA, additional

Published
2022
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30. Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH

Author

Toshner, Mark, Church, Colin, Harbaum, Lars, Rhodes, Christopher, Villar Moreschi, Sofia S, Liley, James, Jones, Rowena, Arora, Amit, Batai, Ken, Desai, Ankit A, Coghlan, John G, Gibbs, J Simon R, Gor, Dee, Gräf, Stefan, Harlow, Louise, Hernandez-Sanchez, Jules, Howard, Luke S, Humbert, Marc, Karnes, Jason, Kiely, David G, Kittles, Rick, Knightbridge, Emily, Lam, Brian, Lutz, Katie A, Nichols, William C, Pauciulo, Michael W, Pepke-Zaba, Joanna, Suntharalingam, Jay, Soubrier, Florent, Trembath, Richard C, Schwantes-An, Tae-Hwi L, Wort, S John, Wilkins, Martin, Gaine, Sean, Morrell, Nicholas W, Corris, Paul A, Toshner, Mark [0000-0002-3969-6143], Villar, Sofia [0000-0001-7755-2637], Jones, Rowena [0000-0002-4551-2320], Graf, Stefan [0000-0002-1315-8873], Lam, Brian [0000-0002-3638-9025], Morrell, Nicholas [0000-0001-5700-9792], Apollo - University of Cambridge Repository, and British Heart Foundation

Subjects
Adult, Male, Pulmonary Arterial Hypertension, Biomedical Research, Interleukin-6, Respiratory System, Uniphy Clinical Trials Network, Middle Aged, Treatment Outcome, Humans, Familial Primary Pulmonary Hypertension, Female, 11 Medical and Health Sciences, Aged
Abstract

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg-1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Published
2022
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31. COL18A1 genotypic associations with endostatin levels and clinical features in pulmonary arterial hypertension: a quantitative trait association study

Author

Simpson, Catherine E., primary, Griffiths, Megan, additional, Yang, Jun, additional, Nies, Melanie K., additional, Vaidya, Dhananjay, additional, Brandal, Stephanie, additional, Martin, Lisa J., additional, Pauciulo, Michael W., additional, Lutz, Katie A., additional, Coleman, Anna W., additional, Austin, Eric D., additional, Ivy, D. Dunbar, additional, Nichols, William C., additional, Everett, Allen D., additional, Hassoun, Paul M., additional, and Damico, Rachel L., additional

Published
2022
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32. Biomarkers of Pulmonary Hypertension Are Altered in Children with Down Syndrome and Pulmonary Hypertension

Author

Griffiths, Megan, primary, Yang, Jun, additional, Vaidya, Dhananjay, additional, Nies, Melanie, additional, Brandal, Stephanie, additional, Ivy, D. Dunbar, additional, Hickey, Francis, additional, Wolter-Warmerdam, Kristine, additional, Austin, Eric D., additional, Mullen, Mary, additional, Pauciulo, Michael W., additional, Lutz, Katie A., additional, Rosenzweig, Erika B., additional, Hirsch, Russel, additional, Yung, Delphine, additional, Nichols, William C., additional, and Everett, Allen D., additional

Published
2022
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33. Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects inGBAMutation Carriers

Author

Pal, Gian, primary, Mangone, Graziella, additional, Hill, Emily J., additional, Ouyang, Bichun, additional, Liu, Yuanqing, additional, Lythe, Vanessa, additional, Ehrlich, Debra, additional, Saunders‐Pullman, Rachel, additional, Shanker, Vicki, additional, Bressman, Susan, additional, Alcalay, Roy N., additional, Garcia, Priscilla, additional, Marder, Karen S., additional, Aasly, Jan, additional, Mouradian, M. Maral, additional, Link, Samantha, additional, Rosenbaum, Marc, additional, Anderson, Sharlet, additional, Bernard, Bryan, additional, Wilson, Robert, additional, Stebbins, Glenn, additional, Nichols, William C., additional, Welter, Marie‐Laure, additional, Sani, Sepehr, additional, Afshari, Mitra, additional, Verhagen, Leo, additional, Bie, Rob M.A., additional, Foltynie, Tom, additional, Hall, Deborah, additional, Corvol, Jean‐Christophe, additional, and Goetz, Christopher G., additional

Published
2022
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34. Hepatoma‐derived growth factor is associated with pulmonary vascular remodeling and PAH disease severity and survival

Author

Yang, Jun, primary, Ambade, Anjira S., additional, Nies, Melanie, additional, Griffiths, Megan, additional, Damico, Rachel, additional, Vaidya, Dhananjay, additional, Brandal, Stephanie, additional, Pauciulo, Michael W., additional, Lutz, Katie A., additional, Coleman, Anna W., additional, Nichols, William C., additional, Austin, Eric D., additional, Ivy, Dunbar, additional, Hassoun, Paul M., additional, and Everett, Allen D., additional

Published
2022
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35. Abstract 12319: 16alpha-Hydroxyestrone Downregulates SOX17 During the Development of Pulmonary Arterial Hypertension

Author

Sangam, Shreya, primary, Schwantes-An, Tae-Hwi, additional, Zagorski, John, additional, Shi, Yinan, additional, Morrisroe, Seth, additional, Cook, Todd, additional, Fisher, Amanda, additional, Frump, Andrea, additional, Coleman, Anna, additional, Tang, Haiyang, additional, Crawford, Howard, additional, Lutz, Katie, additional, Pauciulo, Michael W, additional, Chaudhary, Ketul R, additional, Stewart, Duncan J, additional, Lahm, Tim, additional, Nichols, William C, additional, and Desai, Ankit A, additional

Published
2021
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36. Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Author

Zhu, Na, Swietlik, Emilia M., Welch, Carrie L., Pauciulo, Michael W., Hagen, Jacob J., Zhou, Xueya, Guo, Yicheng, Karten, Johannes, Pandya, Divya, Tilly, Tobias, Lutz, Katie A., Martin, Jennifer M., Treacy, Carmen M., Rosenzweig, Erika B., Krishnan, Usha, Coleman, Anna W., Gonzaga-Jauregui, Claudia, Lawrie, Allan, Trembath, Richard C., Wilkins, Martin R., Morrell, Nicholas W., Shen, Yufeng, Gräf, Stefan, Nichols, William C., Chung, Wendy K., Hirsch, Russel, White, R. James, Simon, Marc, Badesch, David, Rosenzweig, Erika, Burger, Charles, Chakinala, Murali, Thenappan, Thenappan, Elliott, Greg, Simms, Robert, Farber, Harrison, Frantz, Robert, Elwing, Jean, Hill, Nicholas, Ivy, Dunbar, Klinger, James, Nathan, Steven, Oudiz, Ronald, Robbins, Ivan, Schilz, Robert, Fortin, Terry, Wilt, Jeffrey, Yung, Delphine, Austin, Eric, Ahmad, Ferhaan, Bhatt, Nitin, Lahm, Tim, Frost, Adaani, Safdar, Zeenat, Rehman, Zia, Walter, Robert, Torres, Fernando, Bakshi, Sahil, Archer, Stephen, Argula, Rahul, Barnett, Christopher, Benza, Raymond, Desai, Ankit, Maddipati, Veeranna, Bogaard, Harm J., Church, Colin, Coghlin, Gerry, Condliffe, Robin, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Girerd, Barbara, Holden, Simon, Howard, Luke, Humbert, Marc, Kiely, David G., Kovacs, Gabor, Lordan, Jim, Machado, Rajiv D., MacKenzie Ross, Robert V., McCabe, Colm, Moledina, Shahin, Montani, David, Olschewski, Horst, Penkett, Christopher J., Pepke-Zaba, Joanna, Price, Laura, Rhodes, Christopher J., Seeger, Werner, Soubrier, Florent, Southgate, Laura, Suntharalingam, Jay, Swift, Andrew J., Toshner, Mark R., Noordegraaf, Anton Vonk, Wharton, John, Wild, Jim, Wort, Stephen John, and Apollo - University of Cambridge Repository

Subjects
Exome sequencing, Case-control association testing, Research, FOS: Biological sciences, Genetics, De novo variant analysis, Pulmonary arterial hypertension, Genome sequencing
Abstract

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

Published
2021
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37. Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease–Associated Pulmonary Hypertension

Author

Daly, Caroline M., primary, Griffiths, Megan, additional, Simpson, Catherine E., additional, Yang, Jun, additional, Damico, Rachel L., additional, Vaidya, R. Dhananjay, additional, Williams, Monica, additional, Brandal, Stephanie, additional, Jone, Pei‐Ni, additional, Polsen, Cassandra, additional, Ivy, D. Dunbar, additional, Austin, Eric D., additional, Nichols, William C., additional, Pauciulo, Michael W., additional, Lutz, Katie, additional, Nies, Melanie K., additional, Rosenzweig, Erika B., additional, Hirsch, Russel, additional, Yung, Delphine, additional, and Everett, Allen D., additional

Published
2021
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38. Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study

Author

David, Fabian J., primary, Munoz, Miranda J., additional, Shils, Jay L., additional, Pauciulo, Michael W., additional, Hale, Philip T., additional, Nichols, William C., additional, Afshari, Mitra, additional, Sani, Sepehr, additional, Verhagen Metman, Leo, additional, Corcos, Daniel M., additional, and Pal, Gian D., additional

Published
2021
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39. Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

Author

Toshner, Mark, primary, Church, Colin, additional, Harbaum, Lars, additional, Rhodes, Christopher, additional, Villar Moreschi, Sofia S., additional, Liley, James, additional, Jones, Rowena, additional, Arora, Amit, additional, Batai, Ken, additional, Desai, Ankit A., additional, Coghlan, John G., additional, Gibbs, J. Simon R., additional, Gor, Dee, additional, Gräf, Stefan, additional, Harlow, Louise, additional, Hernandez-Sanchez, Jules, additional, Howard, Luke S., additional, Humbert, Marc, additional, Karnes, Jason, additional, Kiely, David G., additional, Kittles, Rick, additional, Knightbridge, Emily, additional, Lam, Brian, additional, Lutz, Katie A., additional, Nichols, William C., additional, Pauciulo, Michael W., additional, Pepke-Zaba, Joanna, additional, Suntharalingam, Jay, additional, Soubrier, Florent, additional, Trembath, Richard C., additional, Schwantes-An, Tae-Hwi L., additional, Wort, S. John, additional, Wilkins, Martin R., additional, Gaine, Sean, additional, Morrell, Nicholas W., additional, and Corris, Paul A., additional

Published
2021
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40. The angiostatic peptide endostatin enhances mortality risk prediction in pulmonary arterial hypertension

Author

Simpson, Catherine E., primary, Griffiths, Megan, additional, Yang, Jun, additional, Nies, Melanie K., additional, Vaidya, R. Dhananjay, additional, Brandal, Stephanie, additional, Martin, Lisa J., additional, Pauciulo, Michael W., additional, Lutz, Katie A., additional, Coleman, Anna W., additional, Austin, Eric D., additional, Ivy, D. Dunbar, additional, Nichols, William C., additional, Everett, Allen D., additional, Hassoun, Paul M., additional, and Damico, Rachel L., additional

Published
2021
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42. Metabolomic Profiles of Scleroderma-PAH are different than idiopathic PAH and associated with worse clinical outcomes

Author

Alotaibi, Mona, primary, Shao, Junzhe, additional, Pauciulo, Michael W., additional, Nichols, William C., additional, Hemnes, Anna R., additional, Malhotra, Atul, additional, Kim, Nick H., additional, Yuan, Jason X.-J., additional, Fernandes, Timothy, additional, Kerr, Kim M., additional, Alshawabkeh, Laith, additional, Desai, Ankit A., additional, Watrous, Jeramie D., additional, Cheng, Susan, additional, Long, Tao, additional, Chan, Stephen Y., additional, and Jain, Mohit, additional

Published
2021
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43. ST2 Is a Biomarker of Pediatric Pulmonary Arterial Hypertension Severity and Clinical Worsening

Author

Griffiths, Megan, primary, Yang, Jun, additional, Simpson, Catherine E., additional, Vaidya, Dhananjay, additional, Nies, Melanie, additional, Brandal, Stephanie, additional, Damico, Rachel, additional, Ivy, D. Dunbar, additional, Austin, Eric D., additional, Pauciulo, Michael W., additional, Lutz, Katie A., additional, Rosenzweig, Erika B., additional, Hirsch, Russel, additional, Yung, Delphine, additional, Nichols, William C., additional, and Everett, Allen D., additional

Published
2021
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44. Additional file 1 of Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Author

Zhu, Na, Swietlik, Emilia M., Welch, Carrie L., Pauciulo, Michael W., Hagen, Jacob J., Xueya Zhou, Yicheng Guo, Karten, Johannes, Pandya, Divya, Tilly, Tobias, Lutz, Katie A., Martin, Jennifer M., Treacy, Carmen M., Rosenzweig, Erika B., Krishnan, Usha, Coleman, Anna W., Gonzaga-Juaregui, Claudia, Lawrie, Allan, Trembath, Richard C., Wilkins, Martin R., Morrell, Nicholas W., Yufeng Shen, Gräf, Stefan, Nichols, William C., and Chung, Wendy K.

Abstract

Additional file 1: Supplementary Figure 1. Selection of single-cell RNAseq data. Supplementary Figure 2. Gene-level burden test for rare synonymous variants. Supplementary Figure 3. Gene-based association analysis for all PAH subclasses. Supplementary Figure 4. Power analysis. Supplementary Figure 5. Depth of coding sequence coverage for FBLN2 and PDGFD. Supplementary Figure 6. Gene-based association analysis for APAH alone.

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2021
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45. Additional file 2 of Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Author

Zhu, Na, Swietlik, Emilia M., Welch, Carrie L., Pauciulo, Michael W., Hagen, Jacob J., Xueya Zhou, Yicheng Guo, Karten, Johannes, Pandya, Divya, Tilly, Tobias, Lutz, Katie A., Martin, Jennifer M., Treacy, Carmen M., Rosenzweig, Erika B., Krishnan, Usha, Coleman, Anna W., Gonzaga-Juaregui, Claudia, Lawrie, Allan, Trembath, Richard C., Wilkins, Martin R., Morrell, Nicholas W., Yufeng Shen, Gräf, Stefan, Nichols, William C., and Chung, Wendy K.

Abstract

Additional file 2: Supplementary Table 1. Clinical characteristics and hemodynamic parameters of child- vs adult-onset PAH cases. Supplementary Table 2. Similar frequency of rare synonymous variants among cases and controls. Supplementary Table 3. Rare predicted deleterious KDR missense variants. Supplementary Table 4. Haplotype analysis of PAH cases with recurrent variants in new candidate genes. Supplementary Table 5. Burden of de novo variants in pediatric-onset IPAH. Supplementary Table 6. Rare de novo risk variants identified in pediatric-onset PAH. Supplementary Table 7. Clinical characteristics of pediatric PAH cases with rare de novo variants.

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2021
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46. Cognitive Functioning of Glucocerebrosidase (GBA) Non-manifesting Carriers

Author

Moran, Eileen E., primary, Bressman, Susan B., additional, Ortega, Roberto A., additional, Raymond, Deborah, additional, Nichols, William C., additional, Palmese, Christina A., additional, Elango, Sonya, additional, Swan, Matthew, additional, Shanker, Vicki, additional, Perera, Imali, additional, Wang, Cuiling, additional, Zimmerman, Molly E., additional, and Saunders-Pullman, Rachel, additional

Published
2021
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47. Bayesian Inference Associates Rare KDR Variants With Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Swietlik, Emilia M., primary, Greene, Daniel, additional, Zhu, Na, additional, Megy, Karyn, additional, Cogliano, Marcella, additional, Rajaram, Smitha, additional, Pandya, Divya, additional, Tilly, Tobias, additional, Lutz, Katie A., additional, Welch, Carrie C.L., additional, Pauciulo, Michael W., additional, Southgate, Laura, additional, Martin, Jennifer M., additional, Treacy, Carmen M., additional, Penkett, Christopher J., additional, Stephens, Jonathan C., additional, Bogaard, Harm J., additional, Church, Colin, additional, Coghlan, Gerry, additional, Coleman, Anna W., additional, Condliffe, Robin, additional, Eichstaedt, Christina A., additional, Eyries, Mélanie, additional, Gall, Henning, additional, Ghio, Stefano, additional, Girerd, Barbara, additional, Grünig, Ekkehard, additional, Holden, Simon, additional, Howard, Luke, additional, Humbert, Marc, additional, Kiely, David G., additional, Kovacs, Gabor, additional, Lordan, Jim, additional, Machado, Rajiv D., additional, MacKenzie Ross, Robert V., additional, McCabe, Colm, additional, Moledina, Shahin, additional, Montani, David, additional, Olschewski, Horst, additional, Pepke-Zaba, Joanna, additional, Price, Laura, additional, Rhodes, Christopher J., additional, Seeger, Werner, additional, Soubrier, Florent, additional, Suntharalingam, Jay, additional, Toshner, Mark R., additional, Vonk Noordegraaf, Anton, additional, Wharton, John, additional, Wild, James M., additional, Wort, Stephen John, additional, Lawrie, Allan, additional, Wilkins, Martin R., additional, Trembath, Richard C., additional, Shen, Yufeng, additional, Chung, Wendy K., additional, Swift, Andrew J., additional, Nichols, William C., additional, Morrell, Nicholas W., additional, Gräf, Stefan, additional, Abbs, Stephen, additional, Abulhoul, Lara, additional, Adlard, Julian, additional, Ahmed, Munaza, additional, Aitman, Timothy J., additional, Alachkar, Hana, additional, Allsup, David J., additional, Ancliff, Philip, additional, Antrobus, Richard, additional, Armstrong, Ruth, additional, Arno, Gavin, additional, Ashford, Sofie, additional, Astle, William J., additional, Attwood, Anthony, additional, Aurora, Paul, additional, Babbs, Christian, additional, Bacchelli, Chiara, additional, Bakchoul, Tamam, additional, Banka, Siddharth, additional, Bariana, Tadbir, additional, Barwell, Julian, additional, Batista, Joana, additional, Baxendale, Helen E., additional, Beales, Phil L., additional, Bennett, David L., additional, Bierzynska, Agnieszka, additional, Biss, Tina, additional, Bitner-Glindzicz, Maria A.K., additional, Black, Graeme C., additional, Bleda, Marta, additional, Blesneac, Iulia, additional, Bockenhauer, Detlef, additional, Boyce, Sara, additional, Bradley, John R., additional, Breen, Gerome, additional, Brennan, Paul, additional, Brewer, Carole, additional, Brown, Matthew, additional, Browning, Andrew C., additional, Browning, Michael J., additional, Buchan, Rachel J., additional, Buckland, Matthew S., additional, Bueser, Teofila, additional, Diz, Carmen Bugarin, additional, Burn, John, additional, Burns, Siobhan O., additional, Burren, Oliver S., additional, Burrows, Nigel, additional, Campbell, Carolyn, additional, Carr-White, Gerald, additional, Carss, Keren, additional, Casey, Ruth, additional, Caulfield, Mark J., additional, Chambers, Jenny, additional, Chambers, John, additional, Chan, Melanie M.Y., additional, Cheng, Floria, additional, Chinnery, Patrick F., additional, Chitre, Manali, additional, Christian, Martin T., additional, Clayton-Smith, Jill, additional, Cleary, Maureen, additional, Brod, Naomi Clements, additional, Colby, Elizabeth, additional, Cole, Trevor R.P., additional, Collins, Janine, additional, Collins, Peter W., additional, Compton, Cecilia J., additional, Cook, H. Terence, additional, Cook, Stuart, additional, Cooper, Nichola, additional, Corris, Paul A., additional, Curry, Nicola S., additional, Daniels, Matthew J., additional, Dattani, Mehul, additional, Daugherty, Louise C., additional, Davis, John, additional, De Soyza, Anthony, additional, Deevi, Sri V.V., additional, Dent, Timothy, additional, Deshpande, Charu, additional, Dewhurst, Eleanor F., additional, Dixon, Peter H., additional, Douzgou, Sofia, additional, Downes, Kate, additional, Drazyk, Anna M., additional, Drewe, Elizabeth, additional, Duarte, Daniel, additional, Dutt, Tina, additional, Edgar, J. David M., additional, Edwards, Karen, additional, Egner, William, additional, Ekani, Melanie N., additional, Elliott, Perry, additional, Erber, Wendy N., additional, Erwood, Marie, additional, Estiu, Maria C., additional, Evans, Dafydd Gareth, additional, Evans, Gillian, additional, Everington, Tamara, additional, Fassihi, Hiva, additional, Favier, Remi, additional, Fletcher, Debra, additional, Flinter, Frances A., additional, Floto, R. Andres, additional, Fowler, Tom, additional, Fox, James, additional, Frary, Amy J., additional, French, Courtney E., additional, Freson, Kathleen, additional, Frontini, Mattia, additional, Furnell, Abigail, additional, Gale, Daniel P., additional, Ganesan, Vijeya, additional, Gattens, Michael, additional, Ghofrani, Hossein-Ardeschir, additional, Gibbs, J. Simon R., additional, Gibson, Kate, additional, Gilmour, Kimberly C., additional, Gleadall, Nicholas S., additional, Goddard, Sarah, additional, Gomez, Keith, additional, Gordins, Pavels, additional, Gosal, David, additional, Graham, Jodie, additional, Grassi, Luigi, additional, Greenhalgh, Lynn, additional, Greinacher, Andreas, additional, Gresele, Paolo, additional, Griffiths, Philip, additional, Grigoriadou, Sofia, additional, Grozeva, Detelina, additional, Gurnell, Mark, additional, Hackett, Scott, additional, Hadinnapola, Charaka, additional, Hague, Rosie, additional, Hague, William M., additional, Haimel, Matthias, additional, Hall, Matthew, additional, Hanson, Helen L., additional, Haque, Eshika, additional, Harkness, Kirsty, additional, Harper, Andrew R., additional, Harris, Claire L., additional, Hart, Daniel, additional, Hassan, Ahamad, additional, Hayman, Grant, additional, Henderson, Alex, additional, Herwadkar, Archana, additional, Hoffman, Jonathan, additional, Horvath, Rita, additional, Houlden, Henry, additional, Houweling, Arjan C., additional, Hu, Fengyuan, additional, Hudson, Gavin, additional, Huissoon, Aarnoud P., additional, Hurles, Matthew, additional, Irving, Melita, additional, Izatt, Louise, additional, James, Roger, additional, Johnson, Sally A., additional, Jolles, Stephen, additional, Jolley, Jennifer, additional, Josifova, Dragana, additional, Jurkute, Neringa, additional, Kasanicki, Mary A., additional, Kazkaz, Hanadi, additional, Kazmi, Rashid, additional, Kelleher, Peter, additional, Kelly, Anne M, additional, Kelsall, Wilf, additional, Kempster, Carly, additional, Kingston, Nathalie, additional, Koelling, Nils, additional, Kostadima, Myrto, additional, Koziell, Ania, additional, Kreuzhuber, Roman, additional, Kuijpers, Taco W., additional, Kumar, Ajith, additional, Kumararatne, Dinakantha, additional, Kurian, Manju A., additional, Laffan, Michael A., additional, Lalloo, Fiona, additional, Lambert, Michele, additional, Allen, Hana Lango, additional, Layton, D. Mark, additional, Lentaigne, Claire, additional, Lester, Tracy, additional, Levine, Adam P., additional, Linger, Rachel, additional, Longhurst, Hilary, additional, Lorenzo, Lorena E., additional, Louka, Eleni, additional, Lyons, Paul A., additional, Madan, Bella, additional, Maher, Eamonn R., additional, Maimaris, Jesmeen, additional, Malka, Samantha, additional, Mangles, Sarah, additional, Mapeta, Rutendo, additional, Marchbank, Kevin J., additional, Marks, Stephen, additional, Markus, Hugh S., additional, Marschall, Hanns-Ulrich, additional, Marshall, Andrew, additional, Mathias, Mary, additional, Matthews, Emma, additional, Maxwell, Heather, additional, McAlinden, Paul, additional, McCarthy, Mark I., additional, McKinney, Harriet, additional, Meacham, Stuart, additional, Mead, Adam J., additional, Mehta, Sarju G., additional, Michaelides, Michel, additional, Millar, Carolyn, additional, Mohammed, Shehla N., additional, Moore, Anthony T., additional, Mozere, Monika, additional, Muir, Keith W., additional, Mumford, Andrew D., additional, Nemeth, Andrea H., additional, Newman, William G., additional, Newnham, Michael, additional, Noorani, Sadia, additional, Nurden, Paquita, additional, O’Sullivan, Jennifer, additional, Obaji, Samya, additional, Odhams, Chris, additional, Okoli, Steven, additional, Olschewski, Andrea, additional, Ong, Kai Ren, additional, Oram, S. Helen, additional, Ormondroyd, Elizabeth, additional, Ouwehand, Willem H., additional, Palles, Claire, additional, Papadia, Sofia, additional, Park, Soo-Mi, additional, Parry, David, additional, Patel, Smita, additional, Paterson, Joan, additional, Peacock, Andrew, additional, Pearce, Simon H., additional, Peerlinck, Kathelijne, additional, Petersen, Romina, additional, Pilkington, Clarissa, additional, Poole, Kenneth E.S., additional, Psaila, Bethan, additional, Pyle, Angela, additional, Quinton, Richard, additional, Rahman, Shamima, additional, Rao, Anupama, additional, Raymond, F. Lucy, additional, Rayner-Matthews, Paula J., additional, Rendon, Augusto, additional, Renton, Tara, additional, Rice, Andrew S.C., additional, Richter, Alex, additional, Robert, Leema, additional, Roberts, Irene, additional, Rose, Sarah J., additional, Ross-Russell, Robert, additional, Roughley, Catherine, additional, Roy, Noemi B.A., additional, Ruddy, Deborah M., additional, Sadeghi-Alavijeh, Omid, additional, Saleem, Moin A., additional, Samani, Nilesh, additional, Samarghitean, Crina, additional, Sanchis-Juan, Alba, additional, Sargur, Ravishankar B., additional, Sarkany, Robert N., additional, Satchell, Simon, additional, Savic, Sinisa, additional, Sayer, Genevieve, additional, Sayer, John A., additional, Scelsi, Laura, additional, Schaefer, Andrew M., additional, Schulman, Sol, additional, Scott, Richard, additional, Scully, Marie, additional, Searle, Claire, additional, Sen, Arjune, additional, Sewell, W.A. Carrock, additional, Seyres, Denis, additional, Shah, Neil, additional, Shamardina, Olga, additional, Shapiro, Susan E., additional, Shaw, Adam C., additional, Sibson, Keith, additional, Side, Lucy, additional, Simeoni, Ilenia, additional, Simpson, Michael A., additional, Sims, Matthew C., additional, Sivapalaratnam, Suthesh, additional, Smedley, Damian, additional, Smith, Katherine R., additional, Smith, Kenneth G.C., additional, Snape, Katie, additional, Soranzo, Nicole, additional, Spasic-Boskovic, Olivera, additional, Staines, Simon, additional, Staples, Emily, additional, Stark, Hannah, additional, Stirrups, Kathleen E., additional, Stuckey, Alex, additional, Syrris, Petros, additional, Tait, R. Campbell, additional, Talks, Kate, additional, Tan, Rhea Y.Y., additional, Taylor, Jenny C., additional, Taylor, John M., additional, Thaventhiran, James E., additional, Themistocleous, Andreas C., additional, Thomas, David, additional, Thomas, Ellen, additional, Thomas, Moira J., additional, Thomas, Patrick, additional, Thomson, Kate, additional, Thrasher, Adrian J., additional, Thys, Chantal, additional, Tischkowitz, Marc, additional, Titterton, Catherine, additional, Toh, Cheng-Hock, additional, Tomlinson, Ian P., additional, Traylor, Matthew, additional, Treadaway, Paul, additional, Tuna, Salih, additional, Turro, Ernest, additional, Twiss, Philip, additional, Vale, Tom, additional, Van Geet, Chris, additional, van Zuydam, Natalie, additional, Vandersteen, Anthony M, additional, Vazquez-Lopez, Marta, additional, von Ziegenweidt, Julie, additional, Wagner, Annette, additional, Waisfisz, Quinten, additional, Walker, Neil, additional, Walker, Suellen M., additional, Ware, James S., additional, Watkins, Hugh, additional, Watt, Christopher, additional, Webster, Andrew R., additional, Wedderburn, Lucy, additional, Wei, Wei, additional, Welch, Steven B., additional, Wessels, Julie, additional, Westbury, Sarah K., additional, Westwood, John-Paul, additional, Whitehorn, Deborah, additional, Whitworth, James, additional, Wilkie, Andrew O.M., additional, Williamson, Catherine, additional, Wilson, Brian T., additional, Wong, Edwin K.S., additional, Wood, Nicholas, additional, Wood, Yvette, additional, Woods, Christopher Geoffrey, additional, Woodward, Emma R., additional, Worth, Austen, additional, Wright, Michael, additional, Yates, Katherine, additional, Yong, Patrick F.K., additional, Young, Timothy, additional, Yu, Ping, additional, Yu-Wai-Man, Patrick, additional, Zlamalova, Eliska, additional, Hirsch, Russel, additional, White, R. James, additional, Simon, Marc, additional, Badesch, David, additional, Rosenzweig, Erika, additional, Burger, Charles, additional, Chakinala, Murali, additional, Thenappan, Thenappan, additional, Elliott, Greg, additional, Simms, Robert, additional, Farber, Harrison, additional, Frantz, Robert, additional, Elwing, Jean, additional, Hill, Nicholas, additional, Ivy, Dunbar, additional, Klinger, James, additional, Nathan, Steven, additional, Oudiz, Ronald, additional, Robbins, Ivan, additional, Schilz, Robert, additional, Fortin, Terry, additional, Wilt, Jeffrey, additional, Yung, Delphine, additional, Austin, Eric, additional, Ahmad, Ferhaan, additional, Bhatt, Nitin, additional, Lahm, Tim, additional, Frost, Adaani, additional, Safdar, Zeenat, additional, Rehman, Zia, additional, Walter, Robert, additional, Torres, Fernando, additional, Bakshi, Sahil, additional, Archer, Stephen, additional, Argula, Rahul, additional, Barnett, Christopher, additional, Benza, Raymond, additional, Desai, Ankit, additional, and Maddipati, Veeranna, additional

Published
2021
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48. Whole Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome

Author

Rhodes, Christopher J, Otero-Núñez, Pablo, Wharton, John, Swietlik, Emilia M, Kariotis, Sokratis, Harbaum, Lars, Dunning, Mark J, Elinoff, Jason M, Errington, Niamh, Thomson, AA Roger, Iremonger, James, Coghlan, J Gerry, Corris, Paul A, Howard, Luke S, Kiely, David G, Church, Colin, Pepke-Zaba, Joanna, Toshner, Mark, Wort, Stephen J, Desai, Ankit A, Humbert, Marc, Nichols, William C, Southgate, Laura, Trégouët, David-Alexandre, Trembath, Richard C, Prokopenko, Inga, Gräf, Stefan, Morrell, Nicholas W, Wang, Dennis, Lawrie, Allan, Wilkins, Martin R, NIHR BioResource – Rare Diseases PAH Consortium And The UK National PAH Cohort Study Consortium, Swietlik, Emilia [0000-0002-4095-8489], Toshner, Mark [0000-0002-3969-6143], Graf, Stefan [0000-0002-1315-8873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
pulmonary arterial hypertension, RNAseq, whole blood RNA
Abstract

RATIONALE: Idiopathic and hereditary pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA-sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signalling pathways and stratify patients more robustly according to clinical risk. OBJECTIVES: Using a three-stage design of RNA discovery, RNA validation/model construction and model validation to define a set of PAH-associated RNAs and a single summarising RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomisation (MR) analysis. METHODS: RNA-sequencing was performed on whole blood samples from 359 patients with idiopathic, heritable and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known eQTL and summary statistics from a PAH GWAS. MEASUREMENTS AND MAIN RESULTS: We identified 507 genes with differential RNA expression in PAH patients compared to controls. A model of 25 RNAs was able to distinguish PAH with 87% accuracy (AUC 95% CI: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (p=4.66x10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (OR:0.317, 95%CI:0.129-0.776, p=0.012). CONCLUSIONS: A whole blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.

Published
2020
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49. Reduced transfer coefficient of carbon monoxide in pulmonary arterial hypertension implicates rare protein-truncating variants in KDR

Author

Swietlik, Emilia M., Greene, Daniel, Zhu, Na, Megy, Karyn, Cogliano, Marcella, Rajaram, Smitha, Pandya, Divya, Tilly, Tobias, Lutz, Katie A., Welch, Carrie C. L., Pauciulo, Michael W., Southgate, Laura, Martin, Jennifer M., Treacy, Carmen M., Bogaard, Harm J., Church, Colin, Coghlan, Gerry, Coleman, Anna W., Condliffe, Robin, Eyries, Mélanie, Gall, Henning, Ghio, Stefano, Girerd, Barbara, Holden, Simon, Howard, Luke, Humbert, Marc, Kiely, David G., Kovacs, Gabor, Lordan, Jim, Machado, Rajiv D., MacKenzie Ross, Robert V., Moledina, Shahin, Montani, David, Olschewski, Horst, Pepke-Zaba, Joanna, Rhodes, Christopher J., Seeger, Werner, Soubrier, Florent, Suntharalingam, Jay, Toshner, Mark R., Noordegraaf, Anton Vonk, Wharton, John, Wild, Jim, Wort, Stephen John, Lawrie, Allan, Wilkins, Martin R., Trembath, Richard C., Shen, Yufeng, Chung, Wendy K., Swift, Andrew J., Nichols, William C., Morrell, Nicholas W., and Gräf, Stefan

Abstract

Background To date, approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbour rare mutations in disease-causing genes. Given the small number of patients affected by mutations in most PAH genes, the identification of the missing heritability in PAH is challenging. We hypothesised that integrating deep phenotyping data with whole-genome sequencing data will reveal additional disease variants that are extremely rare and/or have a unique phenotypic signature. Methods We analysed whole-genome sequencing data from 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NIHRBR-RD) study, of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. We defined the groups for comparison by assigning labels (‘tags’) inferred from the current diagnostic classification of PAH, stratification by age at diagnosis and transfer coefficient of carbon monoxide (KCO). Results Protein truncating variants (PTV) in KDR were strongly associated with the lower KCO tertile (posterior probability (PP)=0.989) and the higher age tertile (PP=0.912) groups. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the patients harbouring PTV in KDR . KCO stratification also highlighted an association between Isocitrate Dehydrogenase (NAD(+)) 3 Non-Catalytic Subunit Gamma ( IDH3G ) and moderately reduced KCO in patients with pulmonary hypertension (PP=0.920). The US PAH Biobank was used to independently validate these findings and identified four additional PAH cases with PTV in KDR and two in IDH3G . We confirmed associations between previously established genes and PAH. Conclusions PTVs in KDR , the gene encoding vascular endothelial growth factor receptor 2 (VEGFR2), are significantly associated with two specific phenotypes of PAH, reduced KCO and later age of onset, highlighting a role for VEGF signalling in the pathogenesis of human PAH. We also report IDH3G as a new PAH risk gene. Moreover, we demonstrate that the use of deep clinical phenotyping data advances the identification of novel causative rare variants.

Published
2019
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50. United States Pulmonary Hypertension Scientific Registry

Author

Badlam, Jessica B., primary, Badesch, David B., additional, Austin, Eric D., additional, Benza, Raymond L., additional, Chung, Wendy K., additional, Farber, Harrison W., additional, Feldkircher, Kathy, additional, Frost, Adaani E., additional, Poms, Abby D., additional, Lutz, Katie A., additional, Pauciulo, Michael W., additional, Yu, Chang, additional, Nichols, William C., additional, Elliott, C. Gregory, additional, Simms, Robert, additional, Fortin, Terry, additional, Safdar, Zeenat, additional, Burger, Charles D., additional, Frantz, Robert P., additional, Hill, Nicholas S., additional, Airhart, Sophia, additional, Elwing, Jean, additional, Simon, Marc, additional, White, R. James, additional, Robbins, Ivan M., additional, and Chakinala, Murali M., additional

Published
2021
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