Genetic variants on chromosome 1q41 influence ocular axial length and high myopia.

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, ß = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

Molecular Basis of Transglutaminase-2 and Muscarinic Cholinergic Receptors in Experimental Myopia: A Target for Myopia Treatment.

Myopia, a prevalent refractive error disorder worldwide, is characterized by the elongation of the eye, leading to visual abnormalities. Understanding the genetic factors involved in myopia is crucial for developing therapeutic and preventive measures. Unfortunately, only a limited number of genes with well-defined functionality have been associated with myopia. In this study, we found that the homozygous TGM2-deleted gene in mice protected against the development of myopia by slowing down the elongation of the eye. The effectiveness of gene knockdown was confirmed by achieving a 60 percent reduction in TGM-2 transcript levels through the use of TGM-2-specific small interfering RNA (siRNA) in human scleral fibroblasts (SFs). Furthermore, treating normal mouse SFs with various transglutaminase inhibitors led to the down-regulation of TGM-2 expression, with the most significant reduction observed with specific TGM-2 inhibitors. Additionally, the study found that the pharmacological blockade of muscarinic receptors also slowed the progression of myopia in mice, and this effect was accompanied by a decrease in TGM-2 enzyme expression. Specifically, mice with homozygous mAChR5, mAChR1, and/or mAChR4 and knockout mice exhibited higher levels of TGM-2 mRNA compared to mice with homozygous mAChR2 and three knockout mice (fold changes of 5.8, 2.9, 2.4, -2.2, and -4.7, respectively; p < 0.05). These findings strongly suggest that both TGM-2 and muscarinic receptors play central roles in the development of myopia, and blocking these factors could potentially be useful in interfering with the progression of this condition. In conclusion, targeting TGM-2 may have a beneficial effect regarding myopia, and this may also be at least partially be the mechanism of anti-muscarinic drugs in myopia. Further studies should investigate the interaction between TGM-2 and muscarinic receptors, as well as the changes in other extracellular matrix genes associated with growth during the development of myopia.

Fluvastatin downregulates VEGF-A expression in TNF-α-induced retinal vessel tortuosity.

PURPOSE: To investigate the effect of tumor necrosis factor alpha (TNF-α) on the mouse retinal vasculature, function, and expression of vascular endothelial growth factor-A (VEGF-A) in the retina and retinal pigment epithelium (RPE) and to evaluate the protective effect of statin therapy (fluvastatin) on retinal vascular and functional changes. METHODS: A single intravenous injection of murine TNF-α (8 µg/kg body weight) was administered to one group of mice (TNF group). In the second group of mice (TNF+Statin group), a single dose of TNF-α was followed by 28 days oral medication of fluvastatin (10 mg/kg/d), and an equivalent volume of saline was administered to the third group (Control group). After 28 days, electroretinography (ERG) and fundus photography were performed. Eyes were collected for cell and molecular studies. Transcript levels of VEGF-A in retina and RPE were quantified using real-time polymerase chain reaction, and protein expression was analyzed by Western blot and immunostaining. RESULTS: TNF-α-injected mice showed retinal vessel tortuosity, structural change, and altered retinal function. Fluvastatin-treated mice exhibited retinal vascular, structural, and functional changes almost similar to those of the control group. VEGF-A expression was significantly upregulated in the retina and RPE of TNF-α-injected mice, and this was significantly downregulated in fluvastatin-treated mice. CONCLUSIONS: This study shows that the TNF-α-induced inflammatory process results in the alteration of retinal microvasculature and function, and fluvastatin could be a potential therapy for treating/preventing retinal microvascular or inflammatory complications.