70 results on '"Michael W. Pauciulo"'
Search Results
2. RASA3 is a candidate gene in sickle cell disease‐associated pulmonary hypertension and pulmonary arterial hypertension
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Clare C. Prohaska, Xu Zhang, Tae‐Hwi L. Schwantes‐An, Robert S. Stearman, Stanley Hooker, Rick A. Kittles, Micheala A. Aldred, Katie A. Lutz, Michael W. Pauciulo, William C. Nichols, Ankit A. Desai, Victor R. Gordeuk, and Roberto F. Machado
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Pulmonary and Respiratory Medicine - Published
- 2023
3. COL18A1 genotypic associations with endostatin levels and clinical features in pulmonary arterial hypertension: a quantitative trait association study
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Catherine E. Simpson, Megan Griffiths, Jun Yang, Melanie K. Nies, Dhananjay Vaidya, Stephanie Brandal, Lisa J. Martin, Michael W. Pauciulo, Katie A. Lutz, Anna W. Coleman, Eric D. Austin, D. Dunbar Ivy, William C. Nichols, Allen D. Everett, Paul M. Hassoun, and Rachel L. Damico
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Pulmonary and Respiratory Medicine - Published
- 2022
4. Validation of low‐coverage whole‐genome sequencing for mitochondrial DNA variants suggests mitochondrial DNA as a genetic cause of preterm birth
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Kenneth M. Kaufman, Jesse Slone, Yongbo Huang, Louis J. Muglia, Michael W. Pauciulo, Taosheng Huang, Xinjian Wang, Iouri Chepelev, Jack Zhan, Bahram Namjou, John B. Harley, and Zeyu Yang
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Genetics ,Whole genome sequencing ,Mitochondrial DNA ,Whole Genome Sequencing ,Mitochondrial disease ,Infant, Newborn ,Infant ,Gestational age ,Biology ,medicine.disease ,DNA, Mitochondrial ,Haplogroup ,Human genetics ,Heteroplasmy ,Mitochondria ,Genome, Mitochondrial ,Cohort ,medicine ,Humans ,Premature Birth ,Genetics (clinical) - Abstract
Preterm birth (PTB), or birth that occurs earlier than 37 weeks of gestational age, is a major contributor to infant mortality and neonatal hospitalization. Mutations in the mitochondrial genome (mtDNA) have been linked to various rare mitochondrial disorders, and may be a contributing factor in PTB given that maternal genetic factors have been strongly linked to PTB. However, to date, no study has found a conclusive connection between a particular mtDNA variant and PTB. Given the high mtDNA copy number per cell, an automated pipeline was developed for detecting mtDNA variants using low-pass whole genome sequencing (lcWGS) data. The pipeline was first validated against samples of known heteroplasmy, and then applied to 929 samples from a PTB cohort from diverse ethnic backgrounds with an average gestational age of 27.18 weeks (range: 21-30). Our new pipeline successfully identified haplogroups and a large number of mtDNA variants in this large PTB cohort, including 8 samples carrying known pathogenic variants and 47 samples carrying rare mtDNA variants. These results confirm that lcWGS can be utilized to reliably identify mtDNA variants. These mtDNA variants may make a contribution toward preterm birth in a small proportion of live births. This article is protected by copyright. All rights reserved.
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- 2021
5. Oxylipins and the Surgical Classification of Chronic Thromboembolic Pulmonary Hypertension
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Mona Alotaibi, Timothy Fernandes, Amber Tang, Kim Kerr, Timothy Morris, Atul Malhotra, Jason X-Y. Yuan, Victor Pretorius, Michael Madani, Jeramie D. Watrous, Tao Long, Michael W. Pauciulo, William C. Nicholls, Mohit Jain, Susan Cheng, and Nick Kim
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Surgically accessible lesions of chronic thromboembolic pulmonary hypertension (CTEPH) are classified as proximal or distal based on the distribution of thrombus burden in the pulmonary vasculature post operatively. Surgically accessible distal CTEPH lesions typically has a higher risk profile and worse clinical outcomes in less experienced centers, but the underlying molecular differences between proximal and distal CTEPH lesions remain unknown. Oxylipins, a diverse group of bioactive lipid mediators, have previously been implicated in a range of disorders including pulmonary hypertension. Therefore, we sought to characterize oxylipin profiles among patients with proximal and distal operable CTEPH lesions, as well as those with idiopathic pulmonary arterial hypertension (IPAH). We studied 271 patients with proximal operable CTEPH (n=123), distal operable CTEPH (n=74), or IPAH (n=74). Liquid chromatography-mass spectrometry was used to analyze oxylipin profiles in each patient. We found that patients with distal operable CTEPH had elevated levels of proinflammatory oxylipins while those with proximal CTEPH had an increase in procoagulant oxylipins. Notably, the proinflammatory oxylipins elevated in distal operable CTEPH were similarly elevated in IPAH. These findings suggest that distal operable and proximal CTEPH represent heterogenous disease processes. Furthermore, oxylipin profiles may be useful for potential risk stratification and therapeutic targeting in CTEPH.
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- 2022
6. Metabolomic Profiles Differentiate Scleroderma-PAH From Idiopathic PAH and Correspond With Worsened Functional Capacity
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Mona Alotaibi, Junzhe Shao, Michael W. Pauciulo, William C. Nichols, Anna R. Hemnes, Atul Malhotra, Nick H. Kim, Jason X.-J. Yuan, Timothy Fernandes, Kim M. Kerr, Laith Alshawabkeh, Ankit A. Desai, Andreea M. Bujor, Robert Lafyatis, Jeramie D. Watrous, Tao Long, Susan Cheng, Stephen Y. Chan, and Mohit Jain
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Pulmonary and Respiratory Medicine ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine - Abstract
The 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.Are circulating bioactive metabolites differentially altered in SSc-PAH vs IPAH, and can this alteration explain clinical disparity between these PAH subgroups?Plasma 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.From 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.Patients 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.
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- 2022
7. United States Pulmonary Hypertension Scientific Registry
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Eric D. Austin, Nicholas S. Hill, Zeenat Safdar, Robert W. Simms, Abby Poms, William C. Nichols, Harrison W. Farber, Katie A. Lutz, K. Feldkircher, Robert P. Frantz, Terry Fortin, J. Badlam, R. James White, Charles D. Burger, Jean M. Elwing, Murali M. Chakinala, Raymond L. Benza, C. Gregory Elliott, Wendy K. Chung, Ivan M. Robbins, Michael W. Pauciulo, Chang Yu, Marc A. Simon, Sophia Airhart, David B. Badesch, and Adaani E. Frost
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pregnancy ,medicine.diagnostic_test ,business.industry ,Pulmonary capillary hemangiomatosis ,Environmental exposure ,Critical Care and Intensive Care Medicine ,medicine.disease ,Pulmonary hypertension ,Diagnostic catheterization ,Internal medicine ,Pulmonary venoocclusive disease ,medicine ,Cardiology and Cardiovascular Medicine ,business ,Associated Pulmonary Arterial Hypertension ,Genetic testing - Abstract
Background The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade. Research Question The United States Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population. Study Design and Methods Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data. Results Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 [48%]), associated PAH (APAH; n = 256 [51%]), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 [1%]) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m2, and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH. Interpretation Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH.
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- 2021
8. Hepatoma‐derived growth factor is associated with pulmonary vascular remodeling and PAH disease severity and survival
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Jun Yang, Anjira S. Ambade, Melanie Nies, Megan Griffiths, Rachel Damico, Dhananjay Vaidya, Stephanie Brandal, Michael W. Pauciulo, Katie A. Lutz, Anna W. Coleman, William C. Nichols, Eric D. Austin, Dunbar Ivy, Paul M. Hassoun, and Allen D. Everett
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Pulmonary and Respiratory Medicine - Abstract
Hepatoma-derived growth factor (HDGF) was previously shown to be associated with increased mortality in a small study of idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH). In this study, we measured serum HDGF levels in a large multicenter cohort (total 2017 adult PAH-Biobank enrollees), we analyzed the associations between HDGF levels and various clinical measures using linear or logistic regression models. Higher HDGF levels were found to be significantly associated with worse pulmonary hemodynamics, prostacyclin treatment; among PAH subtypes, higher HDGF levels were most associated with portopulmonary hypertension (beta = 0.469
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- 2022
9. Pediatric pulmonary hypertension: insulin-like growth factor-binding protein 2 is a novel marker associated with disease severity and survival
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Melanie Nies, Rachel L. Damico, Torie Grant, Elizabeth C. Matsui, Stephanie Brandal, Jun Yang, Eric D. Austin, Monica Williams, D. Dunbar Ivy, Katie A. Lutz, Dhananjay Vaidya, Megan Griffiths, Delphine Yung, Erika B. Rosenzweig, Allen D. Everett, Michael W. Pauciulo, Russel Hirsch, and William C. Nichols
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Lung Diseases ,Cardiac output ,medicine.medical_treatment ,Prostacyclin ,Walking ,Severity of Illness Index ,Gastroenterology ,Insulin-like growth factor-binding protein ,0302 clinical medicine ,Medicine ,Myocytes, Cardiac ,Atrial septostomy ,Cardiac Output ,Insulin-Like Growth Factor I ,Child ,biology ,Hazard ratio ,Prognosis ,Treatment Outcome ,Child, Preschool ,Cohort ,medicine.drug ,medicine.medical_specialty ,Adolescent ,Hypertension, Pulmonary ,Enzyme-Linked Immunosorbent Assay ,Article ,Young Adult ,03 medical and health sciences ,030225 pediatrics ,Internal medicine ,medicine.artery ,Humans ,Proportional Hazards Models ,business.industry ,Hemodynamics ,Infant, Newborn ,Infant ,medicine.disease ,Epoprostenol ,Pulmonary hypertension ,Asthma ,Insulin-Like Growth Factor Binding Protein 2 ,Cross-Sectional Studies ,Pediatrics, Perinatology and Child Health ,Pulmonary artery ,biology.protein ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Background Insulin-like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH. Methods Serum was analyzed by ELISA for IGF1 and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n = 175) and a cohort of asthmatic subjects (n = 46, age 0-21 years) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic and clinical variables for PAH severity. Results Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output and 6-min walk distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p Conclusions Circulating IGFBP2 is a novel marker for pediatric PAH, which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension. Impact Pediatric pulmonary hypertension is a severe disease, with poorly understood pathobiology.There are few studies looking at the pathobiology of pulmonary hypertension only in children.The IGF axis is dysregulated in pediatric pulmonary arterial hypertension.IGF axis dysregulation, with increased IGFBP2, is associated with worse clinical outcomes in pediatric pulmonary artery hypertension.IGF axis dysregulation gives new insight into the disease process and may be a mechanistic or therapeutic target.Fig. 1IGF1 AND IGFBP2 CONCENTRATION (NG/ML) IN PAH BIOBANK VERSUS CONTROLS.: a IGF1 concentration (ng/mL) in PAH Biobank versus asthmatic subjects. b IGFBP2 concentration (ng/mL) in PAH Biobank versus asthmatic subjects.Fig. 2ROC CURVE OF IGF1 AND IGFBP2 IN PAH BIOBANK VERSUS CONTROLS.: a ROC curve of IGF1 in PAH Biobank subjects versus controls. AUC 0.82. Cut point for IGF1 of 177 ng/mL gives a sensitivity of 73.9% and a specificity of 78.3%. b ROC curve of IGFBP2 in PAH Biobank subjects versus controls. AUC 0.80. Cut point for IGFBP2 of 185 ng/mL gives a sensitivity of 72.2% and a specificity of 80.4%.Fig. 3IGFBP2 CONCENTRATIONS IN PAH SUBJECTS BY MEDICATION COMBINATION.: a IGFBP2 concentration in PAH subjects on a PDE5 inhibitor, a PDE5 inhibitor and an ERA, a PDE5 inhibitor and IV/SQ PCA, or a combination of PDE5 inhibitor, ERA, and IV/SQ PCA. b IGFBP2 concentrations in PAH subjects on an IV/SQ PCA and any other therapy versus subject not on IV/SQ PCA and any other therapy.Fig. 4Kaplan-Meier curve showing time to death, transplant, or palliative shunt (Pott's shunt or atrial septostomy) dichotomized by the median IGFBP2 level.
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- 2020
10. Noninvasive Prognostic Biomarkers for Left-Sided Heart Failure as Predictors of Survival in Pulmonary Arterial Hypertension
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Jun Yang, William C. Nichols, Melanie Nies, Catherine E. Simpson, Eric D. Austin, Rachel L. Damico, Paul M. Hassoun, R. Dhananjay Vaidya, Lisa J. Martin, Allen D. Everett, Michael W. Pauciulo, Stephanie Brandal, and D. Dunbar Ivy
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Enzyme-Linked Immunosorbent Assay ,Critical Care and Intensive Care Medicine ,Ventricular Function, Left ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Humans ,030212 general & internal medicine ,Protein Precursors ,Survival analysis ,Original Research ,Heart Failure ,Pulmonary Arterial Hypertension ,business.industry ,Hazard ratio ,Stroke Volume ,Middle Aged ,Prognosis ,Brain natriuretic peptide ,medicine.disease ,Interleukin-1 Receptor-Like 1 Protein ,Pulmonary hypertension ,Peptide Fragments ,United States ,Survival Rate ,medicine.anatomical_structure ,030228 respiratory system ,Heart failure ,Cardiology ,Vascular resistance ,Biomarker (medicine) ,Female ,Cardiology and Cardiovascular Medicine ,business ,Heart failure with preserved ejection fraction ,Biomarkers - Abstract
BACKGROUND: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models. METHODS: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models. RESULTS: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity. CONCLUSIONS: ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH.
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- 2020
11. Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension
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Vineet Nair, Tae Hwi Schwantes-An, Haiyang Tang, Rebecca Vanderpool, Roham T. Zamanian, Jason B. Giles, Franz Rischard, Jason X.-J. Yuan, Michael W. Pauciulo, Rick A. Kittles, Abhishek Chaturvedi, Balaji Natarajan, Vinicio A. de Jesus Perez, Ankit A. Desai, Katie A. Lutz, Ken Batai, William C. Nichols, Jason H. Karnes, Joe G.N. Garcia, Jeffrey Yu, Anna W. Coleman, Raymond L. Benza, Andrew J. Sweatt, Hemant K. Tiwari, Howard W. Wiener, Heidi E. Steiner, Maryam Hosseini, Amit Arora, and Jeremy Feldman
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Respiratory System ,Ethnic group ,Hispanic american ,Genetic admixture ,Critical Care and Intensive Care Medicine ,survival ,Medical and Health Sciences ,White People ,Race (biology) ,Humans ,Medicine ,Lung ,Aged ,health disparities ,Pulmonary Arterial Hypertension ,business.industry ,Native american ,Native American ,Hispanic or Latino ,Middle Aged ,United States ,Health equity ,Survival Rate ,Black or African American ,Hispanic American ,Good Health and Well Being ,Female ,business ,Demography - 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.
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- 2020
12. Abstract 12319: 16alpha-Hydroxyestrone Downregulates SOX17 During the Development of Pulmonary Arterial Hypertension
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Shreya Sangam, Tae-Hwi Schwantes-An, John Zagorski, Yinan Shi, Seth Morrisroe, Todd Cook, Amanda Fisher, Andrea Frump, Anna Coleman, Haiyang Tang, Howard Crawford, Katie Lutz, Michael W Pauciulo, Ketul R Chaudhary, Duncan J Stewart, Tim Lahm, William C Nichols, and Ankit A Desai
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Sexual dimorphism in pulmonary arterial hypertension (PAH) is attributed, in part, to estrogen signaling. 16α-hydroxyestrone (16αOHE) is considered a major contributor to PAH pathogenesis. Recent genetic studies have also suggested that deficiency of SOX17, an endothelial cell (EC)-specific transcription factor, contributes to PAH risk. While functional studies of SOX17 are absent, we hypothesized that 16αOHE contributes to PAH, in part, via, SOX17 downregulation. Methods/Results: Sox17 expression was reduced in 3 animal PAH models and in human pulmonary artery ECs (HPAECs) isolated from patients with PAH (vs controls). Inducible Tie2-specific Sox17 knockout ( Sox17 EC-/- ) mice exhibited increased right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and PA wall thickness (PAWT) after chronic hypoxia (CH) (Fig 1A). Inducible Tie2- Sox17 transgenic overexpressing ( Sox17 Tg ) mice attenuated CH-induced PH (Fig 1B). While not evident across murine sex, Sox17 expression was increased in baseline lungs from male compared to female rats. Supporting in silico evidence of estrogen response elements (ERE) on the SOX17 promoter, HPAECs exposed to 16αOHE reduced SOX17 expression and promoter luciferase activity via ERα, which was partly negated by serial ERE mutagenesis (Fig 1C ) . Lungs from ERα loss-of-function mutant rats (vs control) confirmed in vivo reductions of Sox17 expression. Sox17 Tg mice attenuated 16αOHE-mediated PH after CH (Fig 1D). To translate these data, we identified a functional coding SNP in the ESR1 gene (encoding ERα), rs746432, previously shown to reduce transcriptional activity of ERα. The SNP was associated with reduced pulmonary vascular resistance in patients with PAH (n=702, Fig 1E) in adjusted analyses. Conclusion: Validating genetic studies, SOX17 deficiency augments preclinical PAH. 16αOHE mediates PH development via downregulation of SOX17, linking SOX17 genetics with the observed sexual dimorphism.
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- 2021
13. Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study
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Miranda J. Munoz, Fabian J. David, Mitra Afshari, Jay L. Shils, William C. Nichols, Sepehr Sani, Leo Verhagen Metman, Daniel M. Corcos, Michael W. Pauciulo, Gian Pal, and Philip T. Hale
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medicine.medical_specialty ,Parkinson's disease ,Deep brain stimulation ,medicine.medical_treatment ,Aggressive disease ,Disease ,Internal medicine ,subthalamic nucleus beta power ,Medicine ,RC346-429 ,Beta (finance) ,Original Research ,GBA mutation carriers ,Resting state fMRI ,business.industry ,medicine.disease ,nervous system diseases ,deep brain stimulation ,local field potential (LFP) ,surgical procedures, operative ,nervous system ,Neurology ,Mutation (genetic algorithm) ,Cardiology ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,business ,therapeutics ,Glucocerebrosidase - Abstract
Introduction: Up to 27% of individuals undergoing subthalamic nucleus deep brain stimulation (STN-DBS) have a genetic form of Parkinson's disease (PD). Glucocerebrosidase (GBA) mutation carriers, compared to sporadic PD, present with a more aggressive disease, less asymmetry, and fare worse on cognitive outcomes with STN-DBS. Evaluating STN intra-operative local field potentials provide the opportunity to assess and compare symmetry between GBA and non-GBA mutation carriers with PD; thus, providing insight into genotype and STN physiology, and eligibility for and programming of STN-DBS. The purpose of this pilot study was to test differences in left and right STN resting state beta power in non-GBA and GBA mutation carriers with PD.Materials and Methods: STN (left and right) resting state local field potentials were recorded intraoperatively from 4 GBA and 5 non-GBA patients with PD while off medication. Peak beta power expressed as a ratio to total beta power (peak beta ratio) was compared between STN hemispheres and groups while co-varying for age, age of disease onset, and disease severity.Results: Peak beta ratio was significantly different between the left and the right STN for the GBA group (p < 0.01) but not the non-GBA group (p = 0.56) after co-varying for age, age of disease onset, and disease severity.Discussion: Peak beta ratio in GBA mutation carriers was more asymmetric compared with non-mutation carriers and this corresponded with the degree of clinical asymmetry as measured by rating scales. This finding suggests that GBA mutation carriers have a physiologic signature that is distinct from that found in sporadic PD.
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- 2021
14. Metabolomic Profiles of Scleroderma-PAH are different than idiopathic PAH and associated with worse clinical outcomes
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Jeramie D. Watrous, Mohit Jain, Anna R. Hemnes, Alshawabkeh L, Susan Cheng, Atul Malhotra, Stephen Y. Chan, Shao J, Ankit A. Desai, Mona Alotaibi, Timothy M. Fernandes, Nichols Wc, Nick H. Kim, Jason X.-J. Yuan, Michael W. Pauciulo, Kim M. Kerr, and Long T
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chemistry.chemical_classification ,integumentary system ,biology ,business.industry ,Fatty acid ,Pharmacology ,medicine.disease ,Scleroderma ,Pathogenesis ,chemistry.chemical_compound ,Sex hormone-binding globulin ,Metabolomics ,chemistry ,Disease severity ,medicine ,biology.protein ,skin and connective tissue diseases ,business ,Nervonic acid ,Kynurenine - Abstract
The molecular signature in patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (SSc-PAH) relative to idiopathic pulmonary arterial hypertension (IPAH) remain unclear. We hypothesize that patients with SSc-PAH exhibit unfavorable bioactive metabolite derangements compared to IPAH that contribute to their poor prognosis and limited response to therapy. We sought to determine whether circulating bioactive metabolites are differentially altered in SSc-PAH versus IPAH.Plasma biosamples from 415 patients with SSc-PAH (cases) and 1115 patients with IPAH (controls) were included in the study. Over 700 bioactive metabolites were assayed in plasma samples from independent discovery and validation cohorts using liquid chromatography - mass spectrometry (LC-MS) based approaches. Regression analyses were used to identify metabolites which exhibited differential levels between SSc-PAH and IPAH and associated with disease severity.From among hundreds of circulating bioactive molecules, twelve metabolites were found to distinguish between SSc-PAH and IPAH, as well as associate with PAH disease severity. SSc-PAH patients had increased levels of fatty acid metabolites including lignoceric acid and nervonic acid, as well as kynurenine, polyamines, eicosanoids/oxylipins and sex hormone metabolites relative to IPAH. In conclusion, SSc-PAH patients 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 pathogenesis of SSc-PAH.Take Home MessageAmong patients with PAH, those with SSc-PAH suffer disproportionately worse outcomes and disease course. This study represents the most comprehensive analysis of bioactive metabolites profiling comparing two subgroups of PAH. The findings shed light on key differences between SSc-PAH and IPAH that provide important metabolic insight into the disease pathogenesis.
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- 2021
15. United States Pulmonary Hypertension Scientific Registry (USPHSR): rationale, design, and clinical implications
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Chang Yu, Katie A. Lutz, Raymond L. Benza, Wendy K. Chung, C. Gregory Elliott, Harrison W. Farber, Michael W. Pauciulo, K. Feldkircher, Eric D. Austin, J. Badlam, David B. Badesch, Adaani E. Frost, William C. Nichols, and Abby Poms
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Pulmonary and Respiratory Medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,genotype ,Genomic data ,Pulmonary capillary hemangiomatosis ,Disease ,030204 cardiovascular system & hematology ,World health ,03 medical and health sciences ,0302 clinical medicine ,Survival data ,pulmonary hypertension ,medicine ,Intensive care medicine ,lcsh:RC705-779 ,hormones ,business.industry ,toxins ,lcsh:Diseases of the respiratory system ,Leading Edge Science ,medicine.disease ,Pulmonary hypertension ,3. Good health ,Phenotype ,Increased risk ,030228 respiratory system ,lcsh:RC666-701 ,business - Abstract
Diagnostic World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) and Diagnostic Group 1' pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) are progressive and fatal disorders. Past registries provided important insights into these disorders, but did not include hormonal exposures or genomic data. The United States Pulmonary Hypertension Scientific Registry (USPHSR) will provide demographic, physiologic, anorexigen and hormone exposure, genomic, and survival data in the current therapeutic era for 499 patients diagnosed with PAH, PVOD, or PCH. The USPHSR also will explore the relationship between pharmacologic, non-pharmacologic, and dietary hormonal exposures and the increased risk for women to develop idiopathic or heritable PAH.
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- 2019
16. Hypoxia-induced Pulmonary Hypertension in Different Mouse Strains: Relation to Transcriptome
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Timothy D. Le Cras, Nupur Dasgupta, William C. Nichols, Patricia A. Pastura, Manoj K. Pandey, Kahori T. Ikeda, Michael W. Pauciulo, and Philip T. Hale
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Male ,Pulmonary and Respiratory Medicine ,RHOA ,Hypertension, Pulmonary ,T cell ,Clinical Biochemistry ,Gene mutation ,Pathogenesis ,Transcriptome ,Mice ,medicine ,Animals ,Hypoxia ,Molecular Biology ,biology ,Gene Expression Profiling ,Cell Biology ,Hypoxia (medical) ,medicine.disease ,Molecular biology ,Pulmonary hypertension ,BMPR2 ,MicroRNAs ,medicine.anatomical_structure ,Gene Expression Regulation ,biology.protein ,medicine.symptom ,Biomarkers ,Signal Transduction - Abstract
Patients with pulmonary arterial hypertension (PAH) can harbor mutations in several genes, most commonly in BMPR2. However, disease penetrance in patients with BMPR2 mutations is low. In addition, most patients do not carry known PAH gene mutations, suggesting that other factors determine susceptibility to PAH. To begin to identify additional genomic factors contributing to PAH pathogenesis, we exposed 32 mouse strains to chronic hypoxia. We found that the PL/J strain has extremely high right ventricular systolic pressure (RVSP; 86.58 mm Hg) but minimal lung remodeling. To identify potential genomic factors contributing to the high RVSP, RNAseq analysis of PL/J lung mRNAs and microRNAs (miRNAs) after hypoxia was performed, and it demonstrated that 4 of 43 upregulated miRNAs in the Dlk1-Dio3 imprinting region are predicted to target T cell marker mRNAs. These target mRNAs, as well as the numbers of T cells were downregulated. In addition, C5a and its receptor, C5AR1, were increased. Analysis of Rho-associated protein kinase (Rock) 2 mRNA expression, in the RhoA/Rock pathway, demonstrated a significant increase in PL/J. Inhibition of Rock2 ameliorated a portion of the elevated RVSP. In addition, we identified miR-150-5p as a potential regulator of Rock2 expression. In conclusion, we identified two possible pathways contributing to the hypoxia pulmonary hypertension phenotype of extreme RVSP elevation: aberrant T cell expression driven by hypoxia-induced miRNAs and increased expression of C5a and C5AR1. We suggest that the PL/J mouse will be a good model for seeking mechanism(s) of RVSP elevation in hypoxia-induced PAH.
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- 2019
17. Abstract 14979: Endostatin as a Predictor of Severity and Survival in Pediatric Congenital Heart Disease Associated Pulmonary Hypertension
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Allen D. Everett, Melanie Nies, Eric D. Austin, Rachel L. Damico, Jun Yang, Bill Nichols, Michael W. Pauciulo, D. Dunbar Ivy, Megan Griffiths, and Caroline Daly
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medicine.medical_specialty ,Heart disease ,business.industry ,Vascular disease ,High mortality ,medicine.disease ,Pulmonary hypertension ,Physiology (medical) ,Internal medicine ,medicine ,Cardiology ,Endostatin ,Cardiology and Cardiovascular Medicine ,business - Abstract
Introduction: Pediatric pulmonary arterial hypertension (PAH) is a multifactorial pulmonary vascular disease with high mortality. Endostatin (ES), an angiogenic inhibitor, is associated with disease severity and mortality in adults with PAH and poor lung growth in children. Hypothesis: Increased ES is associated with worse disease severity and outcomes in pediatric PAH. Methods: Serum ES levels were measured in two cohorts of pediatric PAH (IPAH, FPAH and APAH) patients; the cross-sectional CCHMC PAH Biobank (PAHB, N=175) and a longitudinal cohort from Children’s Hospital of Colorado (CHC, N=61). Outcomes included medical therapy, functional and hemodynamic measures, and survival (death, transplant, palliative shunt). Adjusted logistic and linear regressions and Kaplan-Meier analysis were used to assess the relationship between ES and clinical outcomes. Results: In both cohorts, ES was significantly higher in PAH associated with congenital heart disease (APAH-CHD, PAHB n=70, p=0.002; CHC n=29, p=0.007) and was highest in those with a ventricular shunt (n=24, p=0.001). In APAH-CHD, ES was associated with a decreased 6MWD (-108m, -187- -30, p=0.01) and increased mean right atrial pressure (mRAP 1.8mmHg, 0.3-3.3, p=0.02). Longitudinally, in the APAH-CHD subgroup when adjusted for age, sex, and multiple time points, higher ES was associated with increased PVRi and mPAP (PVRi 2.5WU*m 2 , 0.7-4.3, p=0.007; mPAP 10mmHg, 4.5-15, p Conclusions: ES was associated with worse functional measures, pulmonary vascular hemodynamics, and survival in pediatric APAH-CHD. These observations suggest that serum ES could act as a pulmonary vascular specific biomarker to identify those who are at increased risk of developing PAH and predict poor outcomes in APAH-CHD.
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- 2020
18. New rare variant associations with distinct phenotypes in patients with pulmonary arterial hypertension revealed with Bayesian inference
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Emilia Świetlik, Katie A Lutz, Daniel Greene, Michael W Pauciulo, Tobias Tilly, Divya Pandya, Na Zhu, Marcella Cogliano, Carrie L Welch, Anna W Coleman, N.I.H.R Bioresource Rare Diseases Consortium, Yufeng Shen, Andrew Swift, Wendy Chung, William C Nichols, Nick W Morrell, and Stefan Graf
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Oncology ,medicine.medical_specialty ,biology ,business.industry ,VEGF receptors ,Age at diagnosis ,Disease ,Mitochondrial respiration ,Phenotype ,Internal medicine ,medicine ,biology.protein ,In patient ,Family history ,business - Abstract
Background: Up to 25% of idiopathic and > 70% of cases with familial pulmonary arterial hypertension (PAH) can be explained by rare deleterious variants in established PAH risk genes. We hypothesised that integrating deep phenotyping with whole-genome sequencing (WGS) data will reveal additional disease variants that are ultra-rare and/or have a unique phenotypic signature. Methods: We analysed WGS data from 1,148 PAH patients and 11,889 controls enrolled in the NIHR BioResource-Rare Diseases study. We used a Bayesian model comparison method (BeviMed) to test for genotype-phenotype associations. Case-control labels were defined by diagnostic groupings and KCO and age strata. Competing models were fitted to identify associations between labels and rare variants under the dominant and recessive mode of inheritance and different variant consequence types. Results: We discovered a strong association between the protein-truncating variants (PTV) in KDR, which encodes VEGFR2, and PAH with low KCO (posterior probability (PP)=0.99) and older age at diagnosis (PP=0.91). Lung CT scans of patients harbouring PTV in KDR revealed a range of mild parenchymal abnormalities. One KDR subject had a family history of PAH. KCO stratification also highlighted an association between IDH3G and moderately reduced KCO in patients with PAH (PP=0.92). The US PAH Biobank was used to validate these findings and identified 4 additional PAH cases with PTVs in KDR and 3 in IDH3G. Conclusions: The smart study design allowed the discovery of new PAH risk, which further implicate central roles for the endothelium and alterations in mitochondrial respiration in PAH
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- 2020
19. Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH
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Heritable Pah, Yufeng Shen, Emilia M. Swietlik, Nicholas W. Morrell, Michael W. Pauciulo, William C. Nichols, Yicheng Guo, Katie A. Lutz, Erika B. Rosenzweig, Jacob J. Hagen, Pah Biobank Enrolling Centers’ Investigators, Divya Pandya, Johannes Karten, Stefan Gräf, Claudia Gonzaga-Juaregiu, Tobias Tilly, Allan Lawrie, Carrie L. Welch, Richard C. Trembath, Xueya Zhou, Anna W. Coleman, Wendy K. Chung, Martin R. Wilkins, Na Zhu, and Usha Krishnan
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Genetics ,Candidate gene ,Right ventricular hypertrophy ,business.industry ,Heart failure ,medicine ,Disease ,Age of onset ,medicine.disease ,business ,Gene ,Genome ,Exome sequencing - Abstract
BackgroundGroup 1 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. Recent high-throughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases.MethodsTo identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource – Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101 unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzedde novovariants in 124 pediatric trios.ResultsSeven genes with rare deleterious variants were significantly associated (false discovery rate BMPR2,GDF2, andTBX4), two recently identified candidate genes (SOX17,KDR), and two new candidate genes (FBLN2, fibulin 2;PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene,ACVRL1, showed association with APAH. Predicted deleteriousde novovariants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carryingde novovariants have plausible roles in lung/heart development.ConclusionsRare variant analysis of a large international consortium identifies two new candidate genes -FBLN2andPDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained byde novovariants.
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- 2020
20. Mutation of the Epigenetic Regulatortet2 Is Associated with Increased Inflammation in Pulmonary Arterial Hypertension
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Elina K. Cook, Michael W. Pauciulo, William C. Nichols, Stephen L. Archer, Wendy K. Chung, Michael J. Rauh, François Potus, and Paul M. Hassoun
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business.industry ,Mutation (genetic algorithm) ,Cancer research ,Medicine ,Inflammation ,Epigenetics ,medicine.symptom ,business - Published
- 2020
21. Did Anorexigens Contribute to the Increased Ratio of Women to Men Diagnosed with Idiopathic Pulmonary Arterial Hypertension in the United States from 2011-2017?
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Harrison W. Farber, K. Feldkircher, Michael W. Pauciulo, Chang Yu, J. Badlam, Katie A. Lutz, Eric D. Austin, Wendy K. Chung, W.C. Nichols, Raymond L. Benza, David B. Badesch, Adaani E. Frost, A. Poms, and C.G.G. Elliott
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medicine.medical_specialty ,business.industry ,Internal medicine ,Idiopathic Pulmonary Arterial Hypertension ,medicine ,Cardiology ,business - Published
- 2020
22. Matrix Metalloproteinase 9 (MMP-9) as a Novel Diagnostic Biomarker in Portopulmoanry Hypertension
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William C. Nichols, Michael W. Pauciulo, C. Gandhi, Katie A. Lutz, A. Jose, and Jean M. Elwing
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business.industry ,Cancer research ,Diagnostic biomarker ,Medicine ,Matrix metalloproteinase 9 ,Matrix metalloproteinase ,business - Published
- 2020
23. Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival
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Rachel L. Damico, William C. Nichols, D. Dunbar Ivy, Allen D. Everett, Dhananjay Vaidya, Eric D. Austin, Catherine E. Simpson, Michael W. Pauciulo, Todd M. Kolb, Megan Griffiths, Melanie Nies, Xueting Tao, Stephanie Brandal, Paul M. Hassoun, Jun Yang, and Stephen C. Mathai
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0301 basic medicine ,Male ,medicine.medical_specialty ,Survival ,medicine.medical_treatment ,lcsh:Medicine ,Insulin-like growth factor binding protein 2 ,030204 cardiovascular system & hematology ,Insulin-like growth factor-binding protein ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Western blot ,Internal medicine ,medicine.artery ,medicine ,Humans ,Aged ,Pulmonary Arterial Hypertension ,Lung ,medicine.diagnostic_test ,biology ,business.industry ,Growth factor ,lcsh:R ,General Medicine ,Biomarker ,Middle Aged ,medicine.disease ,Prognosis ,Pulmonary hypertension ,Survival Analysis ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Case-Control Studies ,Pulmonary artery ,Cohort ,biology.protein ,Biomarker (medicine) ,Female ,business ,Biomarkers ,Research Article - Abstract
Background Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival. Methods Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis. Results In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p p Conclusions IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.
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- 2020
24. Novel Mutations and Decreased Expression of the Epigenetic Regulator
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François, Potus, Michael W, Pauciulo, Elina K, Cook, Na, Zhu, Alexander, Hsieh, Carrie L, Welch, Yufeng, Shen, Lian, Tian, Patricia, Lima, Jeffrey, Mewburn, Christine L, D'Arsigny, Katie A, Lutz, Anna W, Coleman, Rachel, Damico, Brooke, Snetsinger, Ashley Y, Martin, Paul M, Hassoun, William C, Nichols, Wendy K, Chung, Michael J, Rauh, and Stephen L, Archer
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Adult ,Male ,Mice, Knockout ,Pulmonary Arterial Hypertension ,Gene Expression ,Middle Aged ,Dioxygenases ,Epigenesis, Genetic ,Cohort Studies ,DNA-Binding Proteins ,Mice ,Case-Control Studies ,Proto-Oncogene Proteins ,Mutation ,Animals ,Humans ,Female ,Aged - Abstract
Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations inTo test for a role ofWe observed an increased burden of rare, predicted deleterious germline variants inPAH is the first human disease related to potential
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- 2020
25. United States Pulmonary Hypertension Scientific Registry: Baseline Characteristics
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Jessica B, Badlam, David B, Badesch, Eric D, Austin, Raymond L, Benza, Wendy K, Chung, Harrison W, Farber, Kathy, Feldkircher, Adaani E, Frost, Abby D, Poms, Katie A, Lutz, Michael W, Pauciulo, Chang, Yu, William C, Nichols, C Gregory, Elliott, and Murali M, Chakinala
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Adult ,Male ,Adolescent ,Hypertension, Pulmonary ,Middle Aged ,United States ,Cohort Studies ,Young Adult ,Pulmonary and Cardiovascular: Original Research ,Mutation ,Humans ,Female ,Registries ,Symptom Assessment ,Gonadal Steroid Hormones ,Reproductive History ,Aged - Abstract
BACKGROUND: The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade. RESEARCH QUESTION: The United States Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population. STUDY DESIGN AND METHODS: Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data. RESULTS: Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 [48%]), associated PAH (APAH; n = 256 [51%]), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 [1%]) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m(2), and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH. INTERPRETATION: Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH.
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- 2020
26. Phenotype-Agnostic Molecular Subtyping of Neurodegenerative Disorders: The Cincinnati Cohort Biomarker Program (CCBP)
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Alberto J. Espay, Peixin Lu, Elizabeth G. Keeling, Joaquin A. Vizcarra, Andrew P. Duker, Lily L Wang, Max A. Little, Caroline M. Tanner, Benjamin D. Wissel, Alok Dwivedi, Andrea Sturchio, Long J. Lu, Ronan M. T. Fleming, Benjamin Stecher, Daniel W. Hagey, Emily J. Hill, Luca Marsili, David B. Haslam, Samir El Andaloussi, Achala Vagal, Matthew J. Robson, Marcelo Andrés Kauffman, Kariem Ezzat, and Michael W. Pauciulo
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0301 basic medicine ,Aging ,Cognitive Neuroscience ,Parkinson's disease ,Genomics ,Disease ,Computational biology ,Neurodegenerative ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,Methods ,Genetics ,Medicine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Repurposing ,screening and diagnosis ,drug repurposing ,business.industry ,Prevention ,Human Genome ,neurodegeneration ,Neurosciences ,biomarkers ,cohort ,Alzheimer's disease ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,Clinical trial ,Detection ,030104 developmental biology ,Good Health and Well Being ,bioassay ,Pharmacogenomics ,Cohort ,Parkinson’s disease ,Biomarker (medicine) ,Cognitive Sciences ,Patient Safety ,Biochemistry and Cell Biology ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Cohort study ,Neuroscience - Abstract
Ongoing biomarker development programs have been designed to identify serologic or imaging signatures of clinico-pathologic entities, assuming distinct biological boundaries between them. Identified putative biomarkers have exhibited large variability and inconsistency between cohorts, and remain inadequate for selecting suitable recipients for potential disease-modifying interventions. We launched the Cincinnati Cohort Biomarker Program (CCBP) as a population-based, phenotype-agnostic longitudinal study. While patients affected by a wide range of neurodegenerative disorders will be deeply phenotyped using clinical, imaging, and mobile health technologies, analyses will not be anchored on phenotypic clusters but on bioassays of to-be-repurposed medications as well as on genomics, transcriptomics, proteomics, metabolomics, epigenomics, microbiomics, and pharmacogenomics analyses blinded to phenotypic data. Unique features of this cohort study include (1) a reverse biology-to-phenotype direction of biomarker development in which clinical, imaging, and mobile health technologies are subordinate to biological signals of interest; (2) hypothesis free, causally- and data driven-based analyses; (3) inclusive recruitment of patients with neurodegenerative disorders beyond clinical criteria-meeting patients with Parkinson's and Alzheimer's diseases, and (4) a large number of longitudinally followed participants. The parallel development of serum bioassays will be aimed at linking biologically suitable subjects to already available drugs with repurposing potential in future proof-of-concept adaptive clinical trials. Although many challenges are anticipated, including the unclear pathogenic relevance of identifiable biological signals and the possibility that some signals of importance may not yet be measurable with current technologies, this cohort study abandons the anchoring role of clinico-pathologic criteria in favor of biomarker-driven disease subtyping to facilitate future biosubtype-specific disease-modifying therapeutic efforts.
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- 2020
27. Elevated Interleukin-6 Levels Predict Clinical Worsening in Pediatric Pulmonary Arterial Hypertension
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Stephanie Brandal, D. Dunbar Ivy, Melanie Nies, Rachel L. Damico, Eric D. Austin, Russel Hirsch, Delphine Yung, R. Dhananjay Vaidya, Jenny Y. Chen, Katie A. Lutz, Allen D. Everett, Megan Griffiths, Erika B. Rosenzweig, Jun Yang, Catherine E. Simpson, Michael W. Pauciulo, and William C. Nichols
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Male ,medicine.medical_specialty ,Composite score ,Adolescent ,Hemodynamics ,Prostacyclin ,Enzyme-Linked Immunosorbent Assay ,Article ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Pulmonary Wedge Pressure ,Longitudinal cohort ,Interleukin 6 ,Child ,Pulmonary Arterial Hypertension ,Lung ,biology ,business.industry ,Interleukin-6 ,Prognosis ,medicine.anatomical_structure ,Cross-Sectional Studies ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,biology.protein ,Vascular resistance ,Disease Progression ,Female ,business ,Biomarkers ,medicine.drug ,Follow-Up Studies - Abstract
Objective To assess whether circulating interleukin-6 (IL-6) is associated with measures of disease severity and clinical worsening in pediatric pulmonary arterial hypertension (PAH). Study design IL-6 was measured by enzyme-linked immunosorbent assay in serum samples from a cross-sectional cohort from the National Heart, Lung, and Blood Institute Pulmonary Arterial Hypertension Biobank (n = 175) and a longitudinal cohort from Children's Hospital Colorado (CHC) (n = 61). Associations between IL-6, disease severity, and outcomes were studied with regression and Kaplan–Meier analysis. Results In analyses adjusted for age and sex, each log-unit greater IL-6 was significantly associated in the Pulmonary Arterial Hypertension Biobank cohort with greater pulmonary vascular resistance indices, lower odds of having idiopathic PAH or treatment with prostacyclin, and greater odds of having PAH associated with a repaired congenital shunt. In the CHC cohort, each log-unit greater IL-6 was significantly associated with greater mean pulmonary arterial pressure over time. Kaplan–Meier analysis in the CHC cohort revealed that IL-6 was significantly associated with clinical worsening (a composite score of mortality, transplant, or palliative surgery) (P = .037). Conclusions IL-6 was significantly associated with worse hemodynamics at baseline and over time and may be associated with clinical worsening. IL-6 may provide a less-invasive method for disease monitoring and prognosis in pediatric PAH as well as a potential therapeutic target.
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- 2019
28. Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension
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Karyn Megy, William C. Nichols, Chung K. Wendy, Jonathan Stephens, Nicholas W. Morrell, Christopher J. Penkett, Stefan Gräf, Tobias Tilly, Richard C. Trembath, Michael W. Pauciulo, Divya Pandya, Carrie L. Welch, Carmen M. Treacy, Allan Lawrie, Smitha Rajaram, Martin R. Wilkins, Yufeng Shen, Emilia M. Swietlik, Andrew J. Swift, Laura Southgate, Marcella Cogliano, Na Zhu, Heritable Pah, Katie A. Lutz, Daniel Greene, US Pah Biobank Enrolling Centers' Investigators, and Jennifer M. Martin
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Genetics ,0303 health sciences ,Candidate gene ,Kinase insert domain receptor ,Biology ,Bayesian inference ,medicine.disease ,Phenotype ,Pulmonary hypertension ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Missing heritability problem ,030220 oncology & carcinogenesis ,Rare mutations ,medicine ,Gene ,030304 developmental biology - Abstract
BackgroundApproximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics.MethodsWe analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 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.ResultsHeterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics.ConclusionsThe Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
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- 2019
29. Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension
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William C. Nichols, Katie A. Lutz, Pah Biobank Enrolling Centers’ Investigators, Yufeng Shen, Anna W. Coleman, Claudia Gonzaga-Jauregui, Michael W. Pauciulo, Lisa J. Martin, Wendy K. Chung, Hua He, Na Zhu, Carrie L. Welch, Joseph M. Grimes, and Jiayao Wang
- Subjects
0301 basic medicine ,Male ,Exome sequencing ,PAH Biobank Enrolling Centers’ Investigators ,lcsh:Medicine ,Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,Pulmonary arterial hypertension ,Cardiovascular ,Whole Exome Sequencing ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Exome ,Age of Onset ,Aetiology ,Lung ,Genetics (clinical) ,Middle Aged ,3. Good health ,Case-control association testing ,Molecular Medicine ,Female ,Adult ,lcsh:QH426-470 ,Clinical Sciences ,Gamma-glutamyl carboxylase ,03 medical and health sciences ,Rare Diseases ,Right ventricular hypertrophy ,Clinical Research ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Aged ,business.industry ,Research ,Gene Expression Profiling ,lcsh:R ,Human Genome ,Hemodynamics ,Genetic Variation ,medicine.disease ,Human genetics ,lcsh:Genetics ,030104 developmental biology ,Heart failure ,business ,Biomarkers ,Rare disease ,Genome-Wide Association Study - Abstract
Background Group 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. Methods To 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. Results Tissue 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. Conclusions We 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.
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- 2019
30. Serum endostatin as a genetically-influenced biomarker in PAH
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Catherine E. Simpson, Eric D. Austin, Rachel L. Damico, Jun Yang, Stephanie Brandal, Allen D. Everett, Melanie Nies, William C. Nichols, Michael W. Pauciulo, D. Dunbar Ivy, Paul M. Hassoun, R. Dhananjay Vaidya, and Lisa J. Martin
- Subjects
medicine.medical_specialty ,business.industry ,Single-nucleotide polymorphism ,Quantitative trait locus ,Gastroenterology ,medicine.anatomical_structure ,Internal medicine ,Vascular resistance ,medicine ,Biomarker (medicine) ,SNP ,Missense mutation ,Endostatin ,business ,Genotyping - Abstract
Endostatin (ES) is an angiostatic peptide encoded by Col18a1. Our group has shown that a single nucleotide polymorphism (SNP) resulting in a missense mutation in Col18a1 is associated with altered disease severity and survival in PAH. We hypothesized that associations would exist between circulating serum ES levels and 1) clinical metrics of PAH severity, including survival and 2) SNPs in Col18a1. Serum samples and clinical data were obtained from 2,017 adult subjects in the PAH Biobank. Serum ES was measured with an electrochemiluminescent immunosorbent assay. Statistical associations between ES and clinical variables were examined with regression models. Genotyping was performed for protein quantitative trait loci (pQTL) analysis. Each log-unit increase in ES was associated with higher right atrial pressure (1.8 mmHg, 95% CI 1.3-2.3), higher mean pulmonary arterial pressure (2.0 mmHg, 95% CI 0.7 to 3.2), higher pulmonary vascular resistance (1.0 Wood unit, 95% CI 0.4 to 1.5), and lower 6 minute walk distance (-53.5m, 95 % CI -70.7 to -36.2). Mortality doubled for each log-unit increase in ES (2.3, 95% CI 1.6 to 3.4). In pQTL analysis, 4 SNPs in Col18a1 were associated with differences in circulating ES levels (Figure). Increased ES levels are associated with disease severity and survival in PAH, and several SNPs in Col18a1 are associated with differences in circulating ES levels. ES is a genetically-influenced determinant of disease severity in PAH.
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- 2019
31. Circulating Serum ST2 as a Biomarker of Disease Severity and Survival in Pulmonary Arterial Hypertension
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Jun Yang, Melanie Nies, Megan Griffiths, Eric D. Austin, Catherine E. Simpson, Rachel L. Damico, Allen D. Everett, Dhananjay Vaidya, D. Dunbar Ivy, Michael W. Pauciulo, W.C. Nichols, Stephanie Brandal, and Paul M. Hassoun
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medicine.medical_specialty ,Disease severity ,business.industry ,Internal medicine ,medicine ,Biomarker (medicine) ,business ,Gastroenterology - Published
- 2019
32. Sorting Nexin 29 (SNX29) as a Novel Biomarker for Vasoresponsive Pulmonary Arterial Hypertension
- Author
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Ankit A. Desai, Richard Kittles, Jason X.-J. Yuan, T. Thayer, Ken Batai, Katie A. Lutz, S. Halladay, Jason H. Karnes, Anna W. Coleman, William C. Nichols, Evan L. Brittain, Michael W. Pauciulo, Mark W. Geraci, Joe G. N. Garcia, Robert S. Stearman, James West, Anna R. Hemnes, and Amit Arora
- Subjects
Sorting nexin ,Cancer research ,Biomarker (medicine) ,Biology - Published
- 2019
33. Genomic Test Results May Improve REVEAL Risk Calculation Results from the United States Pulmonary Hypertension Scientific Registry (USPHSR)
- Author
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William C. Nichols, Y. Chang, C.G.G. Elliott, J. Badlam, David B. Badesch, Eric D. Austin, Wendy K. Chung, Adaani E. Frost, A. Poms, Michael W. Pauciulo, K. Feldkircher, Harrison W. Farber, Katie A. Lutz, and Raymond L. Benza
- Subjects
medicine.medical_specialty ,business.industry ,Emergency medicine ,Medicine ,Risk assessment ,business ,medicine.disease ,Pulmonary hypertension ,Test (assessment) - Published
- 2019
34. DNMT3A and TET2 Mutations: Linking Genetics and Epigenetics in Pulmonary Arterial Hypertension
- Author
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Paul M. Hassoun, William C. Nichols, Yufeng Shen, Carrie L. Welch, Wendy K. Chung, Stephen L. Archer, Michael J. Rauh, Patricia D.A. Lima, Lian Tian, François Potus, Christine L. D’Arsigny, Elina K. Cook, Michael W. Pauciulo, Na Zhu, and Alexander Hsieh
- Subjects
Genetics ,business.industry ,Medicine ,Epigenetics ,business - Published
- 2019
35. Identification of Insulin-Like Growth Factor Binding Protein-2 (IGFBP2) as a Novel Biomarker for Pulmonary Arterial Hypertension Severity and Survival
- Author
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Megan Griffiths, Jun Yang, D. Dunbar Ivy, Melanie Nies, William C. Nichols, Rachel L. Damico, Michael W. Pauciulo, Dhananjay Vaidya, Allen D. Everett, and Eric D. Austin
- Subjects
biology ,business.industry ,biology.protein ,Cancer research ,Medicine ,Biomarker (medicine) ,Identification (biology) ,business ,Insulin-like growth factor-binding protein - Published
- 2019
36. Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension
- Author
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Claudia Gonzaga-Jauregui, William C. Nichols, Yufeng Shen, Carrie L. Welch, Pah Biobank, Hua He, Jiayao Wang, Michael W. Pauciulo, Wendy K. Chung, Anna W. Coleman, Joseph M. Grimes, Na Zhu, Lisa J. Martin, and Katie A. Lutz
- Subjects
0303 health sciences ,business.industry ,Inflammation ,Disease ,030204 cardiovascular system & hematology ,medicine.disease ,Bioinformatics ,Gamma-glutamyl carboxylase ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Right ventricular hypertrophy ,Heart failure ,Medicine ,medicine.symptom ,business ,Gene ,Exome sequencing ,030304 developmental biology ,Rare disease - Abstract
Group 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. To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH. By statistical association of rare deleterious variants, we found tissue kallikrein 1 and gamma glutamyl carboxylase as new candidate risk genes for idiopathic PAH associated with a later age-of-onset and relatively moderate disease phenotype compared to bone morphogenetic receptor type 2. 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
37. Phenotype characterisation of
- Author
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Csaba, Galambos, Mary P, Mullen, Joseph T, Shieh, Nicolaus, Schwerk, Matthew J, Kielt, Nicola, Ullmann, Renata, Boldrini, Irena, Stucin-Gantar, Cristina, Haass, Manish, Bansal, Pankaj B, Agrawal, Joyce, Johnson, Donatella, Peca, Cecilia, Surace, Renato, Cutrera, Michael W, Pauciulo, William C, Nichols, Matthias, Griese, Dunbar, Ivy, Steven H, Abman, Eric D, Austin, and Olivier, Danhaive
- Subjects
Adult ,Male ,Heterozygote ,Adolescent ,DNA Copy Number Variations ,Hypertension, Pulmonary ,Infant, Newborn ,Genetic Variation ,Infant ,Young Adult ,Phenotype ,Child, Preschool ,Mutation ,Humans ,Female ,Vascular Resistance ,Child ,T-Box Domain Proteins ,Lung ,Gene Deletion ,Lung Transplantation - Abstract
Rare variants in the T-box transcription factor 4 gene (
- Published
- 2018
38. Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension
- Author
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D. Dunbar Ivy, Rachel L. Damico, Stephanie Brandal, Jun Yang, Eric D. Austin, Catherine E. Simpson, Katie A. Lutz, Anna W. Coleman, Paul M. Hassoun, Allen D. Everett, Jenny Y. Chen, R. Dhananjay Vaidya, Lisa J. Martin, Michael W. Pauciulo, Megan Griffiths, Melanie Nies, and William C. Nichols
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Myocytes, Smooth Muscle ,Pulmonary Artery ,030204 cardiovascular system & hematology ,Gastroenterology ,Article ,Vascular remodelling in the embryo ,03 medical and health sciences ,0302 clinical medicine ,medicine.artery ,Internal medicine ,medicine ,Humans ,Interleukin 6 ,Pulmonary Arterial Hypertension ,biology ,Interleukin-6 ,business.industry ,Hazard ratio ,Endothelial Cells ,Interleukin ,medicine.disease ,Phenotype ,Cytokine ,030228 respiratory system ,Pulmonary artery ,biology.protein ,Biomarker (medicine) ,Portal hypertension ,business - Abstract
The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (pIL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups.
- Published
- 2020
39. The relationship between obsessive-compulsive symptoms andPARKINgenotype: The CORE-PD study
- Author
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Madeleine Sharp, Maritza Arroyo, Cheryl Waters, Joseph H. Friedman, Elan D. Louis, Martha Orbe Reilly, Lucien J. Cote, Haydeh Payami, Kevin Novak, William C. Nichols, Carmen Serrano, Caroline M. Tanner, Michael W. Pauciulo, Llency Rosado, Ronald F. Pfeiffer, Blair Ford, Lorraine N. Clark, John G. Nutt, Michael Rezak, Elise Caccappolo, Ming X. Tang, Cynthia L. Comella, Karen Marder, Stuart A. Factor, Stanley Fahn, Diana Ruiz, Roy N. Alcalay, Susan B. Bressman, Helen Mejia-Santana, Martha Nance, William K. Scott, and Eric Molho
- Subjects
Oncology ,medicine.medical_specialty ,Dopaminergic ,Neuropsychology ,Disease ,Asymptomatic ,Parkin ,nervous system diseases ,Loss of heterozygosity ,Neurology ,Internal medicine ,Genotype ,medicine ,Neurology (clinical) ,Age of onset ,medicine.symptom ,Psychology ,Psychiatry - Abstract
Background Few 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). Methods The 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. Results Among 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). Conclusions First, 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
- 2014
40. Tandem mass spectrometry assay of β-glucocerebrosidase activity in dried blood spots eliminates false positives detected in fluorescence assay
- Author
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Michael W. Pauciulo, Joan Keutzer, Emmaline Cullen, Wendy K. Chung, Petra Oliva, William C. Nichols, Tina Faulkner, Robert J. Pomponio, Christopher Liong, Xiwen Ma, X. Kate Zhang, Christopher Bentis, Roy N. Alcalay, Ziv Gan-Or, and Pavlina Wolf
- Subjects
0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Fluorescence assay ,Glucocerebroside ,Tandem mass spectrometry ,Biochemistry ,Fluorescence ,Article ,Cohort Studies ,03 medical and health sciences ,Glucocerebrosidase activity ,0302 clinical medicine ,Endocrinology ,Tandem Mass Spectrometry ,Genetics ,False positive paradox ,Humans ,Mass Screening ,Dried blood ,Molecular Biology ,Blood Specimen Collection ,Gaucher Disease ,Spots ,Chemistry ,Molecular biology ,030104 developmental biology ,Case-Control Studies ,Glucosylceramidase ,Biological Assay ,Dried Blood Spot Testing ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Deficiency of β-Glucocerebrosidase (GBA) activity causes Gaucher Disease (GD). GD can be diagnosed by measuring GBA activity [1] Beutler and Kuhl 1990. In this study, we assayed dried blood spots from a cohort (n=528) enriched for GBA mutation carriers (n=78) and GD patients (n=18) using both the tandem mass spectrometry (MS/MS) and fluorescence assays and their respective synthetic substrates. The MS/MS assay differentiated normal controls, which included GBA mutation carriers, from GD patients with no overlap. The fluorescence assay did not always differentiate normal controls including GBA mutation carriers from GD patients and false positives were observed. The MS/MS assay improved specificity compared to the fluorescence assay.
- Published
- 2017
41. Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults
- Author
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Frederick E. Dewey, Na Zhu, Jeffrey G. Reid, Rizwan Hamid, Aris Baras, Wendy K. Chung, Alejandra King, D. Dunbar Ivy, Ashley Sawle, Lijiang Ma, William C. Nichols, Claudia Gonzaga-Jauregui, John D. Overton, Michael W. Pauciulo, Usha Krishnan, Hongjian Qi, Yufeng Shen, Eric D. Austin, Carrie L. Welch, Katie A. Lutz, and Erika B. Rosenzweig
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,DNA Mutational Analysis ,Disease ,030204 cardiovascular system & hematology ,Bone Morphogenetic Protein Receptors, Type II ,Genetic analysis ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Mutation Rate ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Exome Sequencing ,medicine ,Missense mutation ,Humans ,Exome ,Familial Primary Pulmonary Hypertension ,Genetic Predisposition to Disease ,Age of Onset ,Child ,Exome sequencing ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,BMPR2 ,030104 developmental biology ,Blood pressure ,Phenotype ,Heart failure ,Mutation ,Female ,business ,T-Box Domain Proteins ,Rare disease - Abstract
Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared with adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. Although BMPR2 mutations underlie ≈70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood. Methods: We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). After screening for 2 common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing. RESULTS: We observed similar frequencies of rare, deleterious BMPR2 mutations in pediatric- and adult-onset patients: ≈55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of TBX4 mutations in pediatric- compared with adult-onset patients (IPAH: 10/130 pediatric versus 0/178 adult-onset), and TBX4 carriers had younger mean age-of-onset compared with BMPR2 carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene-damaging and predicted deleterious missense variants. Conclusions: Mutations in known PAH risk genes accounted for ≈70% to 80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in TBX4 are enriched in pediatric patients and de novo variants in novel genes may explain ≈19% of pediatric-onset IPAH cases.
- Published
- 2017
42. Genetic and Clinical Predictors of Deep Brain Stimulation in Young-Onset Parkinson's Disease
- Author
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Roy N. Alcalay, Christopher G. Goetz, William C. Nichols, Deborah A. Hall, Lucia M. Blasucci, Michael W. Pauciulo, Cynthia L. Comella, Lorraine N. Clark, Bichun Ouyang, Gian Pal, Helen Mejia-Santana, Guy A. Rouleau, Karen Marder, Amy Colcher, Ziv Gan-Or, and J. Phelps
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Deep brain stimulation ,Parkinson's disease ,medicine.medical_treatment ,Logistic regression ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,business.industry ,Odds ratio ,medicine.disease ,LRRK2 ,Confidence interval ,nervous system diseases ,surgical procedures, operative ,030104 developmental biology ,Neurology ,Dyskinesia ,Cohort ,Physical therapy ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Objective In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment. Methods Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years. The analyses presented here focus on glucocerebrosidase (GBA), leucine-rich repeat kinase 2 (LRRK2), and parkin (PRKN) mutation carriers. Mutation carrier status, demographic data, and disease characteristics in individuals who did and did not enroll in DBS were analyzed. The association between mutation status and DBS placement was assessed in logistic regression models. Results Patients who had PD with either GBA, LRRK2, or PRKN mutations were more common in the DBS group (n = 99) compared with the non-DBS group (n = 684; 26.5% vs. 16.8%, respectively; P = 0.02). In a multivariate logistic regression model, GBA mutation status (odds ratio, 2.1; 95% confidence interval, 1.0–4.3; P = 0.05) was associated with DBS surgery enrollment. However, when dyskinesia was included in the multivariate logistic regression model, dyskinesia had a strong association with DBS placement (odds ratio, 3.8; 95% confidence interval, 1.9–7.3; P < 0.0001), whereas the association between GBA mutation status and DBS placement did not persist (P = 0.25). Conclusions DBS populations are enriched with genetic mutation carriers. The effect of genetic mutation carriers on DBS outcomes warrants further exploration.
- Published
- 2016
43. Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and paediatric pulmonary hypertension
- Author
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Cecilia Surace, Csaba Galambos, Matthew J Kielt, Manish Bansal, William C. Nichols, Steven H. Abman, Nicola Ullmann, Joyce E. Johnson, Olivier Danhaive, Eric D. Austin, Joseph T. Shieh, Renato Cutrera, Mary P. Mullen, Pankaj B. Agrawal, Renata Boldrini, Donatella Peca, Nicolaus Schwerk, Matthias Griese, Michael W. Pauciulo, D. Dunbar Ivy, Cristina Haass, and Irena Stucin-Gantar
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pediatrics ,medicine.medical_specialty ,Lung ,business.industry ,medicine.medical_treatment ,medicine.disease ,Pulmonary hypertension ,Pathophysiology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Respiratory failure ,Ductus arteriosus ,medicine ,Lung transplantation ,Histopathology ,Copy-number variation ,business - Abstract
Rare variants in the T-box transcription factor 4 gene (TBX4) have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH.We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next-generation sequencing and copy number variation arrays.Variants included six 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling.TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.
- Published
- 2019
44. Parkinson disease phenotype in Ashkenazi jews with and withoutLRRK2G2019S mutations
- Author
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Mark Groves, Vicki Shanker, Diana Ruiz, Marta San Luciano, Mali Gana Weisz, Tanya Gurevich, Nir Giladi, Karen Marder, Elan D. Louis, Anat Mirelman, Ming X. Tang, Laurie J. Ozelius, Rivka Sachdev, Naomi Lubarr, Tsvyatko Dorovski, Harini Sarva, Joan Miravite, Ernest Roos, Roberto A. Ortega, Llency Rosado, Helen Mejia Santana, Deborah Raymond, Cheryl Waters, Christina Palmese, Lucien J. Cote, Kira Yasinovsky, Andres Deik, Susan Bressman, Maayan Zalis, Lawrence Severt, Blair Ford, Oren A. Levy, Lorraine N. Clark, Matthew Swan, Jeannie Soto-Valencia, Michael W. Pauciulo, Avi Orr-Urtreger, William C. Nichols, Stanley Fahn, Pietro Mazzoni, Martha Orbe-Reilly, Ann L. Hunt, Roy N. Alcalay, Avner Thaler, Jose Cabassa, Brooke Johannes, Matthew J. Barrett, Anat Bar Shira, and Rachel Saunders-Pullman
- Subjects
medicine.medical_specialty ,business.industry ,Montreal Cognitive Assessment ,Disease ,LRRK2 ,Ashkenazi jews ,nervous system diseases ,Neurology ,Internal medicine ,Genotype ,Severity of illness ,Physical therapy ,Medicine ,Geriatric Depression Scale ,Neurology (clinical) ,business ,Glucocerebrosidase - Abstract
The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P 5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.
- Published
- 2013
45. High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension
- Author
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Laurel Mendelsohn, Vijay K. Kalra, Tomoyasu Higashimoto, Janaka Wansapura, Nambirajan Sundaram, William C. Nichols, Punam Malik, Xunde Wang, Gregory J. Kato, Anitaben Tailor, Michael W. Pauciulo, and William M. Gottliebson
- Subjects
Adult ,Hemolytic anemia ,medicine.medical_specialty ,Hypertension, Pulmonary ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,Anemia, Sickle Cell ,Pregnancy Proteins ,Biochemistry ,Cell Line ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Red Cells, Iron, and Erythropoiesis ,Internal medicine ,medicine.artery ,medicine ,Animals ,Humans ,Placenta Growth Factor ,Mice, Knockout ,Endothelin-1 ,business.industry ,Myocardium ,Respiratory disease ,Erythroid Hyperplasia ,Cell Biology ,Hematology ,medicine.disease ,Endothelin 1 ,Pulmonary hypertension ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Ventricle ,Pulmonary artery ,Hypertrophy, Left Ventricular ,business - Abstract
Pulmonary hypertension is associated with reduced nitric oxide bioavailability and early mortality in sickle cell disease (SCD). We previously demonstrated that placenta growth factor (PlGF), an angiogenic factor produced by erythroid cells, induces hypoxia-independent expression of the pulmonary vasoconstrictor endothelin-1 in pulmonary endothelial cells. Using a lentivirus vector, we simulated erythroid expression of PlGF in normal mice up to the levels seen in sickle mice. Consequently, endothelin-1 production increased, right ventricle pressures increased, and right ventricle hypertrophy and pulmonary changes occurred in the mice within 8 weeks. These findings were corroborated in 123 patients with SCD, in whom plasma PlGF levels were significantly associated with anemia, endothelin-1, and tricuspid regurgitant velocity; the latter is reflective of peak pulmonary artery pressure. These results illuminate a novel mechanistic pathway linking hemolysis and erythroid hyperplasia to increased PlGF, endothelin-1, and pulmonary hypertension in SCD, and suggest that strategies that block PlGF signaling may be therapeutically beneficial. This trial was registered at http://clinicaltrials.gov as #NCT00011648.
- Published
- 2010
46. The United States Pulmonary Hypertension Scientific Registry (USPHSR): Objectives and Preliminary Data
- Author
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Raymond L. Benza, Harrison W. Farber, J. Badlam, Chang Yu, William C. Nichols, Michael W. Pauciulo, Wendy K. Chung, K. Feldkircher, David B. Badesch, Adaani E. Frost, A. Poms, Eric D. Austin, and C.G. Elliott
- Subjects
Pulmonary and Respiratory Medicine ,Transplantation ,medicine.medical_specialty ,business.industry ,Emergency medicine ,medicine ,Surgery ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease ,Pulmonary hypertension - Published
- 2018
47. INITIAL DATA FROM THE US PULMONARY HYPERTENSION REGISTRY: GENETICS AND DEMOGRAPHICS IN NEWLY DIAGNOSED PULMONARY ARTERIAL HYPERTENSION (PAH)
- Author
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Harrison Farber, Kathy Feldkircher, Abby M. Poms, Wendy Chung, Greg Elliott, David Badesch, Jessica Badlam, Eric D. Austin, Raymond Benza, Chang Yu, William C. Nichols, Adaani Frost, and Michael W. Pauciulo
- Subjects
medicine.medical_specialty ,Demographics ,business.industry ,Female preponderance ,Genomic data ,Internal medicine ,Medicine ,Observational study ,Newly diagnosed ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease ,Pulmonary hypertension - Abstract
Prior US registries PAH have demonstrated changing demographics with, increasing female preponderance but have not included genomic data or hormonal information. USPHSR is a multicenter observational study to characterize demographics(with an emphasis on hormonal history), genomics, and clinical
- Published
- 2018
48. Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations
- Author
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Tatiana Foroud, Karen Marder, William C. Nichols, Alice Rudolph, Ronald F. Pfeiffer, Michael W. Pauciulo, Diane Kissell, Cheryl Halter, and Nathan Pankratz
- Subjects
Adult ,Genetic Markers ,Male ,Adolescent ,Genotype ,Ubiquitin-Protein Ligases ,DNA Mutational Analysis ,Gene Dosage ,Biology ,Parkin ,Young Adult ,Exon ,Gene Frequency ,Risk Factors ,Humans ,Point Mutation ,Genetic Predisposition to Disease ,Genetic Testing ,Age of Onset ,Allele ,Aged ,Aged, 80 and over ,Genetics ,Base Sequence ,Point mutation ,Parkinson Disease ,Articles ,Middle Aged ,nervous system diseases ,Haplotypes ,Mutation ,Mutation (genetic algorithm) ,Female ,Neurology (clinical) ,Age of onset ,Haploinsufficiency ,Gene Deletion - Abstract
Objective: Mutations in both alleles of parkin have been shown to result in Parkinson disease (PD). However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for PD. Methods: We performed comprehensive dosage and sequence analysis of all 12 exons of parkin in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single parkin mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 parkin mutations. Results: We identified 55 independent patients with PD with at least 1 parkin mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, p = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at ≤45 years) compared with those with no parkin mutations (10%, p = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at ≤45 years, p = 0.06). Conclusions: Parkin haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset.
- Published
- 2009
49. Alpha-synuclein and familial Parkinson's disease
- Author
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Ronald F. Pfeiffer, Michael W. Pauciulo, William C. Nichols, Joanne Wojcieszek, V. E. Elsaesser, Nathan Pankratz, Alice Rudolph, Diane K. Marek, Cheryl Halter, and Tatiana Foroud
- Subjects
Genetics ,Linkage disequilibrium ,Neurology ,Polymorphism (computer science) ,Haplotype ,Genotype ,Single-nucleotide polymorphism ,Neurology (clinical) ,Age of onset ,Allele ,Biology ,Allele frequency - Abstract
Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3' region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3' region of SNCA. The four SNPs were in high LD (r(2) > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3' haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3' haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3' region of SNCA convey an increased risk for PD.
- Published
- 2009
50. Variation in GIGYF2 is not associated with Parkinson disease
- Author
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Diane Kissell, Kristi A. Clark, Tatiana Foroud, Ronald F. Pfeiffer, V. E. Elsaesser, Alice Rudolph, William C. Nichols, Joanne Wojcieszek, Cheryl Halter, Michael W. Pauciulo, and Nathan Pankratz
- Subjects
Male ,Parkinson's disease ,Genotype ,Genetic Linkage ,DNA Mutational Analysis ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Open Reading Frames ,Degenerative disease ,Genetic linkage ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Aged ,Genetic testing ,Genetics ,Linkage (software) ,Base Sequence ,medicine.diagnostic_test ,Chromosome Mapping ,Genetic Variation ,Parkinson Disease ,Middle Aged ,medicine.disease ,Pedigree ,Chromosomes, Human, Pair 2 ,Mutation ,Chromosomal region ,Female ,Neurology (clinical) ,Carrier Proteins - Abstract
Objective: A recent study reported that mutations in a gene on chromosome 2q36-37, GIGYF2 , result in Parkinson disease (PD). We have previously reported linkage to this chromosomal region in a sample of multiplex PD families, with the strongest evidence of linkage obtained using the subset of the sample having the strongest family history of disease and meeting the strictest diagnostic criteria. We have tested whether mutations in GIGYF2 may account for the previously observed linkage finding. Methods: We sequenced the GIGYF2 coding region in 96 unrelated patients with PD used in our original study that contributed to the chromosome 2q36-37 linkage signal. Subsequently, we genotyped the entire sample of 566 multiplex PD kindreds as well as 1,447 controls to test whether variants in GIGYF2 are causative or increase susceptibility for PD. Results: We detected three novel variants as well as one of the previously reported seven variants in a total of five multiple PD families; however, there was no consistent evidence that these variants segregated with PD in these families. We also did not find a significant increase in risk for PD among those inheriting variants in GIGYF2 ( p = 0.28). Conclusions: We believe that variation in a gene other than GIGYF2 accounts for the previously reported linkage finding on chromosome 2q36-37. GDS = Geriatric Depression Scale; MMSE = Mini-Mental State Examination; NCRAD = National Cell Repository for Alzheimer’s Disease; PD = Parkinson disease; PSG = Parkinson Study Group; UPDRS = Unified Parkinson’s Disease Rating Scale.
- Published
- 2009
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