ArticleAnnals of the rheumatic diseases2026
Gain of function NOTCH4 variants disrupt angiogenesis in systemic sclerosis.
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Article in Annals of the rheumatic diseases, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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57 authors.
Urvashi KaundalScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Pei-Suen TsouUniversity of Michigan Scleroderma Program, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Mousumi SahuScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Mengqi HuangDivision of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Steven E BoydenUtah Center for Genetic Discovery, Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Curtis M WoodfordLaboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
Daniel ShrinerCenter for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Emilee StensonScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Sarah Ayla SafranScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Yuechen ZhouDivision of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Taylor A TalleyScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Kaavya GudapatiScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Xuetao ZhangLaboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
Yosuke KunishitaScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Janet WangScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Ami A ShahJohns Hopkins University, Division of Rheumatology, Baltimore, MD, USA.
Maureen D MayesHouston McGovern Medical School, University of Texas, Houston, TX, USA.
Ayo P DoumateyCenter for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Amy R BentleyCenter for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Robyn DomsicDivision of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Thomas A MedsgerDivision of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Paula S RamosDivision of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Division of Rheumatology, Department of Medicine, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
Richard M SilverDivision of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Virginia SteenSchool of Medicine, Georgetown University, Washington, DC, USA.
John VargaUniversity of Michigan Scleroderma Program, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Vivien HsuDepartment of Medicine, Rutgers- RWJ Medical School, Rheumatology Division, New Brunswick, NJ, USA.
Lesley Ann SaketkooNew Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, Louisiana State University and Tulane University Medical Schools, New Orleans, LA, USA.
Elena SchiopuDivision of Rheumatology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
Jessica K GordonDivision of Rheumatology, Hospital for Special Surgery and New York Presbyterian-Weill Cornell Medical College, New York, NY, USA.
Lindsey A CriswellGenomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Heather GladueArthritis & Osteoporosis Consultants of the Carolinas, Charlotte, NC, USA.
Chris DerkDivision of Rheumatology, University of Pennsylvania, Philadelphia, PA, USA.
Elana J BernsteinDivision of Rheumatology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
S Louis BridgesDivision of Rheumatology, Hospital for Special Surgery and New York Presbyterian-Weill Cornell Medical College, New York, NY, USA.
Victoria ShanmugamOffice of Autoimmune Disease Research, Office of Research on Women's Health, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
Lorinda ChungDivision of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto VA Health Care System, Palo Alto, CA, USA.
Suzanne KafajaDivision of Rheumatology, University of California, Los Angeles, CA, USA.
Reem JanSection of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
Marcin TrojanowskiDepartment of Rheumatology, Boston University School of Medicine, Boston, MA, USA.
Avram GoldbergDivision of Rheumatology, NYU Langone Health, Lake Success, New York, NY, USA.
Benjamin D KormanDivision of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA.
James MullikinNIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
James W ThomasNIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Stefania Dell'OrsoGenomic Technology Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Davide RandazzoLight Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Adebowale AdeyemoCenter for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Elaine F RemmersMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Pamela L SchwartzbergCell Signaling and Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Ivona AksentijevichMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Charles RotimiCenter for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Fredrick M WigleyJohns Hopkins University, Division of Rheumatology, Baltimore, MD, USA.
Rong A WangLaboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
Francesco BoinDivision of Rheumatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Dinesh KhannaUniversity of Michigan Scleroderma Program, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Robert LafyatisDivision of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Daniel L KastnerMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Pravitt GourhScleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Novartis Biomedical Research, Novartis Campus, Basel 4002, Switzerland. Electronic address: pravitt@gmail.com.
Funding
Inter- and Intra-Species Comparative SequencingZIBHG000196 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI THOMAS, JAMES · 2009 to 2025
$177.6MGenetic epidemiology of complex diseasesZIAHG200362 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI ROTIMI, CHARLES · 2009 to 2025
$54.7MGenetic Analysis of Complex Inflammatory DisordersZIAHG200371 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI KASTNER, DANIEL · 2011 to 2024
$18.8MResource CoreP30AR072582 · NIAMS · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI JAMES C OATES · 2017 to 2026
$8.5MGenomic studies of Systemic Lupus ErythematosusZIAHG200416 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI CRISWELL, LINDSEY · 2021 to 2025
$7.0MGenetics and Pathogenesis of SclerodermaZIAAR041209 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI GOURH, PRAVITT · 2019 to 2024
$6.3MNotch Signaling in Mouse Arterial-Venous SpecificationR01HL075033 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WANG, RONG · 2005 to 2015
$3.7MVasculopathy and Systemic Sclerosis-Associated Interstitial Lung DiseaseR01HL164758 · NHLBI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Elana J. Bernstein · 2022 to 2026
$3.5MNIMHD Adjunct Investigator ProgramZIJMD000010 · NIMHD · NATIONAL INSTITUTE ON MINORITY HEALTH AND HEALTH DISPARITIES · PI CHOI, KELVIN · 2017 to 2025
$3.4MMolecular Pathogenesis of Brain Arteriovenous MalformationR01NS067420 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WANG, RONG · 2010 to 2018
$2.3MMolecular Pathogenesis of Hereditary Hemorrhagic TelangiectasiaR01NS113429 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WANG, RONG · 2020 to 2024
$2.3MScreening Chest CT to Detect Interstitial Lung Disease in Systemic SclerosisK23AR075112 · NIAMS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BERNSTEIN, ELANA · 2019 to 2023
$794kIntramural NIH HHS ZIA AR041209Intramural NIH HHS ZIA HG200362Intramural NIH HHS ZIA HG200371Intramural NIH HHS ZIA HG200416Intramural NIH HHS ZIB HG000196Intramural NIH HHS ZIJ MD000010NHLBI NIH HHS R01 HL075033NHLBI NIH HHS R01 HL164758NIAMS NIH HHS K23 AR075112NIAMS NIH HHS P30 AR072582NINDS NIH HHS R01 NS067420NINDS NIH HHS R01 NS113429NINDS NIH HHS R56 NS067420
Abstract
objectivesVasculopathy and fibrosis are central to the pathogenesis of systemic sclerosis (SSc) and their genetic underpinnings are largely unknown. Here, we sought to examine the aetiology of severe vascular phenotypes and poorer outcomes in African American (AA) patients with SSc.
methodsThe study focuses on AA patients with SSc who have more severe vascular phenotypes and poorer outcomes and combines genetics, single-cell RNA sequencing, functional assays, and a mouse model to explore the role of NOTCH4 in SSc vasculopathy and the potential for NOTCH4-directed therapies.
resultsGene-based testing identified NOTCH4 association at an exome-wide significance with SSc (P = 1.6 × 10
conclusionsNOTCH4 variants are associated with SSc pathogenesis and vasculopathy, partly explaining the increased prevalence of SSc in AAs. The study highlights the need for further research and clinical trials in the inhibition of the NOTCH4 pathway as a strategy to treat the vascular and fibrotic manifestations of SSc.
Indexed as
AngiogenesisNeovascularization, PathologicReceptor, Notch4Scleroderma, SystemicAdultAnimalsBlack or African AmericanDisease Models, AnimalEndothelial-Mesenchymal TransitionFemaleGenetic Predisposition to DiseaseHaplotypesHumansMaleMiceMiddle AgedNOTCH4 protein, humanNotch4 protein, mouseReceptor, Notch4
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