レンズ上皮細胞恒常性調節遺伝子における遺伝子多型とデッドバッグ症候群 - パート2

To investigate genetic variants associated with the dysregulation of lens epithelial cell (LEC) homeostasis in patients diagnosed with Dead Bag Syndrome (DBS).

Cataract and IOL Research Centre.

Laboratory study.

Genomic DNAs from 37 cases and 33 controls were subjected to whole-exome sequencing. Exome wide rare variants association by Chi-square test followed by gene wide cumulative rare variant burden analysis using optimal unified sequence kernel association test were performed. The effect size and the directionality of the genetic variants associated with DBS was assessed by logistic regression analysis.

12 genes showed a significant (P < 0.05) and positive (OR > 1.0) association with DBS, of which 9 (APC2, CD320, MSLN, TJP1, TNS1, TRPM5, USPL1, ZFHX3) were expressed in LECs, involving 3 key pathways crucial for LEC homeostasis. Notably, 97.3% (36/37) of cases, versus 54.5% (18/33) of controls, harboured at least one variant in these 9 genes. Additionally, 83.8% (31/37) of cases had variants in ≥2 genes compared to only 6.1% (2/33) of controls, suggesting an increased risk of DBS in those with multiple affected genes (OR = 80.1; 95% CI, 15.0-428.0; p < 0.0001).

Our study highlights a set of rare genetic variants affecting genes involved in RNA processing (GEMIN4, USPL1), epithelial integrity (TJP1, MSLN), and metabolic homeostasis (APC2, CD320, TNS1, TRPM5, ZFHX3) -three key pathways crucial for LEC homeostasis. It further supports a multigenic risk model and highlights the potential use of these genes as predictive markers for DBS manifestation.