Systemic sclerosis & Raynaud's
Gain of function NOTCH4 variants disrupt angiogenesis in systemic sclerosis
Authors' conclusion
NOTCH4 variants are associated with SSc pathogenesis and vasculopathy, partly explaining the increased prevalence of SSc in AAs.
Study context
- Population
- African American patients with systemic sclerosis (SSc) with more severe vascular phenotypes and poorer outcomes
- Outcome
- NOTCH4 association with SSc and severe vascular disease (gene-based testing, exome-wide significance)
Methodological detailsgenetics, single-cell RNA sequencing, functional assays, mouse model
- Genetics
- Single-cell RNA sequencing
- Functional assays
- Mouse model
Main finding
As reported in the abstract
- NOTCH4 association with SSc
- P = 1.6 × 10-7
- NOTCH4 association with severe vascular disease
- P = 3.5 × 10-7
- Risk haplotype (c.2824C>T missense, c.-117G>A promoter) enriched in African American (AAs) with SSc vs controls
- 11%
- Population attributable risk due to the haplotype in AAs with SSc (52-fold higher than in European Americans)
- 2.6%
Original publication
Gain of function NOTCH4 variants disrupt angiogenesis in systemic sclerosis. Ann Rheum Dis. Published 4 February 2026. doi:10.
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