Faculty, Staff and Student Publications

Language

English

Publication Date

2-4-2026

Journal

Annals of the Rheumatic Diseases

DOI

10.1016/j.ard.2025.12.015

PMID

41644364

Abstract

Objectives: Vasculopathy 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.

Methods: The 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.

Results: Gene-based testing identified NOTCH4 association at an exome-wide significance with SSc (P = 1.6 × 10-7) and patients with severe vascular disease (P = 3.5 × 10-7). The risk haplotype defined by the missense (c.2824C>T) and promoter (c.-117G>A) variants was enriched in AAs with SSc (11%) vs controls, and the population attributable risk due to this haplotype in AAs with SSc was 2.6%, which was 52-fold higher than in European Americans. The SSc-associated NOTCH4 variants increased NOTCH4 expression and signalling, leading to decreased angiogenesis and increased endothelial-to-mesenchymal transition (EndoMT). Nailfold capillary abnormalities, decreased angiogenesis, and fibrosis of the vascular lumen are commonly seen in SSc. Genetic, chemical, antibody, or Food and Drug Administration-approved drug inhibition of NOTCH4 signalling rescued angiogenesis and returned EndoMT to baseline.

Conclusions: NOTCH4 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.

Published Open-Access

yes

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