Omics · study · 2026
Granzyme B links CFH Genetic Risk to Vitronectin Loss in Macular Degeneration
Listed in NCBI GEO
The complement factor H (CFH) Y402H polymorphism is a leading genetic risk factor for age-related macular degeneration (AMD).
Description
However, the molecular mechanisms connecting this risk variant to retinal degeneration remain unclear. Here, we identify extracellular granzyme B (GzmB) as a crucial mediator connecting complement dysregulation to structural pathology in AMD.
We found that patients with dry AMD exhibited significantly elevated plasma GzmB levels. Strikingly, in clinically healthy human donor eyes, the high-risk CFH genotype was associated with increased GzmB-positive choroidal mast cells and enhanced membrane attack complex (MAC) deposition. Notably, these eyes displayed a distinct redistribution of vitronectin, characterized by loss in the inner choroid and accumulation in sub-RPE deposits.
Read the rest (2 more)
Mechanistically, we demonstrate that complement fragment C5a triggers GzmB secretion and pro-inflammatory signaling in retinal pigment epithelium (RPE) cells, leading to zonula occludens-1 (ZO-1) disruption. Furthermore, GzmB-deficient mice displayed preserved choroidal vitronectin compared with wild-type controls, supporting a role for GzmB in the cleavage of this terminal complement inhibitor. RNA sequencing of GzmB-treated RPE cells confirmed transcriptomic signatures of barrier dysfunction and cellular stress.
These findings delineate a pathogenic C5a-GzmB pathway that compromises extracellular matrix integrity, establishing extracellular GzmB as a critical link between genetic risk and early AMD onset.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE322nnn/GSE322497 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE322497 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1430216 ncbi.nlm.nih.gov/bioproject/PRJNA1430216 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- RNA sequencing 75% · Sequencing 75%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE322497 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |