Corneal Hysteresis
Background
Corneal hysteresis (CH) is a biomechanical property of the cornea that quantifies its ability to absorb and dissipate energy during deformation. This viscoelastic property is a crucial indicator of the cornea's stiffness and elasticity. As the eye's primary refracting element, the cornea's biomechanical integrity, including its hysteresis, is fundamental for maintaining clear vision and overall ocular health. [1] Studies, including those on twins, have demonstrated that these biomechanical properties are highly heritable. [2]
Biological Basis
The structural characteristics and biomechanical behavior of the human cornea are largely determined by its extracellular matrix, predominantly composed of uniformly arranged type I collagen fibrils. [3] Type VI collagen is also recognized as a significant component of the human cornea. [4] Genetic research has advanced the understanding of corneal biomechanics, with genome-wide association studies identifying over 200 loci associated with these properties, offering insights into the genetic underpinnings of various ocular diseases. [5] Gene-set enrichment analyses further underscore the importance of collagen pathways in influencing CH. [5] Within the cornea, keratocytes, a specialized type of fibroblast, are abundant and contribute to the tissue's biomechanical regulation. [5]
Clinical Relevance
Corneal hysteresis holds significant clinical importance due to its association with several ocular pathologies. Notably, lower CH is recognized as a risk factor for the progression of glaucoma, a leading cause of irreversible blindness. Research indicates that reduced CH is linked to more rapid glaucomatous visual field progression and an increased loss of retinal nerve fiber layer. [6] Abnormal corneal biomechanics are also implicated in various corneal disorders. Corneal thinning, for example, is a characteristic feature of rare Mendelian connective tissue disorders such as Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and brittle cornea syndrome. [3] Extreme thinning is particularly evident in keratoconus, a condition where genetic variants affecting biomechanical properties may confer susceptibility. [7] Furthermore, diseases like Fuchs' corneal dystrophy, a major cause of corneal transplant surgery, are associated with altered corneal biomechanical properties. [8]
Social Importance
The implications of corneal hysteresis extend to significant public health and social impact, particularly concerning conditions that lead to severe visual impairment and blindness. Glaucoma affects approximately 3.5% of the population over 40 years of age and represents a major global cause of irreversible blindness. [9] Keratoconus is the leading indication for corneal transplants worldwide, while Fuchs' endothelial corneal dystrophy also contributes substantially to the global need for corneal transplant procedures. [3] Macular corneal dystrophy (MCD), though rare globally, accounts for a considerable proportion of corneal transplantations in specific populations, such as in Iceland, due to founder effects. [9] A deeper understanding and improved measurement of corneal hysteresis can facilitate earlier diagnosis and lead to more effective management strategies for these sight-threatening diseases, thereby potentially preserving vision and reducing the global burden of blindness and the demand for corneal transplantation.
Methodological and Statistical Challenges
Many genetic association studies investigating corneal hysteresis and related corneal biomechanical properties face limitations due to insufficient sample sizes, particularly for identifying variants with small effects. Even large-scale meta-analyses, pooling results from tens of thousands of subjects, have sometimes struggled to achieve genome-wide statistical significance for specific loci, highlighting that the individual effects of many contributing variants are often subtle This collagen contributes significantly to the cornea's tensile strength and biomechanical resilience. Rare loss-of-function variants in COL6A1 have been shown to have substantial effects on corneal resistance factor (CRF), a property highly correlated with corneal hysteresis. [10] Similarly, ADAMTS8 (A disintegrin and metalloproteinase with thrombospondin motifs 8), through its variant rs56009602, belongs to a family of enzymes essential for organizing and remodeling the ECM. The ADAMTS family is closely involved in regulating ECM function and has associations with corneal curvature, implying that variations affecting ADAMTS8 activity could alter the structural integrity and biomechanics of the cornea, thereby influencing corneal hysteresis. [11]
Cellular processes, including cell cycle regulation and transcription factor activity, also play a vital role in maintaining corneal health and biomechanics. ANAPC1 (Anaphase-Promoting Complex Subunit 1), with variants like rs1044864 and rs202110867, is a core component of the anaphase-promoting complex/cyclosome (APC/C), a master regulator of the cell cycle and mitosis. [12] Proper cell cycle control is essential for the proliferation and health of corneal endothelial cells, which are crucial for maintaining corneal hydration and transparency. [9] Disruptions in ANAPC1 can influence corneal endothelial cell density and overall eye development, impacting the cornea's biomechanical properties. The TCF4 gene, associated with rs11659764, encodes a transcription factor critical for numerous developmental pathways, including Wnt signaling, which is important for cell differentiation and tissue maintenance. The variant rs11659764 has been directly linked to corneal hysteresis (CH) and corneal resistance factor (CRF), as well as Fuchs endothelial corneal dystrophy (FECD), indicating its significant role in corneal cell function and biomechanics. [13]
Long non-coding RNAs (lncRNAs) and other transcription factors contribute to corneal hysteresis by regulating gene expression. LncRNAs such as LINC02182 (rs28526212, rs12448211, rs35193497), LINC01235 - LINC00583 (rs34944131, rs1831902, rs66720556), and LINC01415 (part of the TCF4 - LINC01415 locus) are known to modulate gene expression, affecting cellular processes like differentiation and proliferation that are vital for corneal development and maintenance. Variations in these lncRNAs could alter the expression of genes involved in corneal structure or function, indirectly influencing corneal hysteresis. FOXO1 (Forkhead Box Protein O1), encompassing variants rs2755238 and rs2721051, is a transcription factor regulating genes involved in cellular metabolism, stress response, and apoptosis, all crucial for corneal cell survival and function. Variants near FOXO1 can impact its regulatory activity, affecting the resilience and regenerative capacity of corneal cells and influencing corneal biomechanical properties. [10] The lncRNA ZBTB44-DT, associated with rs56009602, also likely plays a regulatory role in gene expression, potentially affecting proteins essential for maintaining corneal structure and function.
Finally, genes involved in metabolic and signaling pathways are also implicated in corneal hysteresis. ABCA6 (rs77542162) and ABCA10 (rs8070232) belong to the ATP-binding cassette (ABC) transporter family, which are integral to transporting various molecules, including lipids, across cell membranes. Proper lipid metabolism and membrane integrity are essential for the health and function of corneal cells, affecting corneal transparency and biomechanical strength. Variations in these transporters could therefore influence corneal hysteresis. FST (Follistatin), associated with rs27323 (part of the RPL13AP13 - FST locus), is a glycoprotein that modulates the activity of growth factors within the TGF-beta superfamily, such as BMPs. [11] These growth factors are critical for extracellular matrix synthesis and eye development. [11] Variants affecting FST could disrupt the delicate balance of these signaling pathways, impacting corneal development, ECM remodeling, and ultimately, its biomechanical properties.
Definition and Biomechanical Characterization
Corneal hysteresis (CH) is a quantitative indicator of the cornea's biomechanical properties, specifically reflecting its viscoelastic dampening capabilities and viscosity. It represents the cornea's ability to absorb and dissipate energy during deformation. This unique characteristic is distinct from simple elasticity, which only describes a material's ability to return to its original shape. [5] The operational definition of CH is derived from the difference between two applanation pressures, measured by a specialized non-contact tonometer called the Ocular Response Analyzer (ORA). [5] Specifically, CH is calculated as the difference between p1, the inward applanation pressure at which the cornea flattens as an air pulse is applied, and p2, the outward applanation pressure at which applanation reoccurs after the air pressure is released. [10] All these biomechanical metrics, including CH, are typically expressed in millimeters of mercury (mmHg). [10]
Clinical Significance and Associated Ocular Conditions
Corneal hysteresis serves as a crucial biomarker in ophthalmology due to its association with the susceptibility and progression of various ocular diseases. Research indicates that corneas with reduced dampening capabilities, reflected by lower CH values, are more vulnerable to several ocular pathologies. [5] Notably, lower corneal hysteresis has been identified as a significant risk factor for glaucoma progression and is associated with more rapid glaucomatous visual field deterioration. [14] While not a primary diagnostic criterion for disease classification itself, CH provides valuable prognostic information. Its quantitative nature allows for a dimensional approach to assessing corneal health, contributing to the understanding of conditions like keratoconus, where altered corneal biomechanics play a central role. [7]
Related Biomechanical Parameters and Measurement Considerations
Beyond corneal hysteresis, the Ocular Response Analyzer (ORA) also quantifies other related biomechanical parameters, such as the Corneal Resistance Factor (CRF). CRF is designed to reflect the cornea's overall resistance to deformation and is adjusted to be maximally associated with central corneal thickness (CCT) while minimally associated with intraocular pressure (IOP). [5] Other derived measures include Goldmann-correlated IOP (IOPg), calculated as the average of p1 and p2, and cornea-compensated IOP (IOPcc), which are linear combinations of p1 and p2 designed to minimize changes in IOP measurements following refractive surgery. [10] In research settings, rigorous diagnostic and measurement criteria are applied to ensure data accuracy and reliability; this often involves excluding participants with extreme inter-ocular differences (e.g., greater than the population mean difference plus 3 standard deviations) or those with self-reported ocular conditions, such as recent eye surgery, that could compromise the accuracy of biomechanical readings. [15]
Cellular Homeostasis and Regulation of Corneal Biomechanics
The viscoelastic properties of the cornea, reflected by corneal hysteresis, are intimately linked to the maintenance of cellular homeostasis, particularly within the corneal endothelium. These cells, forming the innermost layer of the cornea, are generally considered non-mitotic after birth, remaining arrested in the G1 phase of the cell cycle. [9] Their primary role involves an ion pump function that regulates corneal hydration, preventing edema and maintaining the precise spacing of collagen fibrils necessary for transparency. [9] This delicate balance of cell number and function is challenged by factors such as contact inhibition, the presence of negative growth factors in the anterior chamber, and the accumulation of reactive oxygen species, which collectively promote a state of stress-induced senescence. [9]
Genetic factors significantly influence this cellular equilibrium, with variations in genes like ANAPC1 accounting for a notable portion of the variability in corneal endothelial cell density. [9] ANAPC1 is a critical component of the Anaphase-Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that orchestrates cell cycle progression, especially during mitosis. [12] Disruptions in Apc1 homologs have been observed to impair normal eye development by interfering with G1 cell cycle arrest and progression through mitosis. [16] Thus, the intricate regulation of cell division, survival, and stress responses directly impacts the structural integrity and viscoelastic behavior of the cornea.
Extracellular Matrix Dynamics and Structural Integrity
Corneal hysteresis is profoundly influenced by the dynamic composition and organized architecture of the extracellular matrix (ECM), predominantly within the corneal stroma. The stroma's unique biomechanical properties derive from its high content of collagen fibrils, whose precise arrangement and lamellar spacing are crucial for maintaining both corneal transparency and its mechanical strength. [9] Genome-wide association studies have revealed a significant enrichment for collagen pathways, indicating that numerous collagen-coding genes are fundamental determinants of corneal biomechanical properties. [5] For instance, Type VI collagen constitutes a major structural component of the human cornea, and the COL8A1 gene, encoding a key alpha chain of type VIII collagen, further contributes to the cornea's robust framework. [4]
Beyond collagens, other ECM constituents play essential roles in modulating corneal biomechanics. Laminins are significant in the context of corneal dystrophies and contribute to epithelial cell adhesion and migration. [13] Small leucine-rich proteoglycans such as Keratocan and Lumican are vital for regulating collagen fibril assembly and spacing; Keratocan-deficient mice exhibit altered corneal structure, and Lumican deficiency can lead to corneal opacity. [17] Additionally, elastic fibers, whose integrity can be affected by genes like FBN1 (associated with conditions like Marfan syndrome and thicker corneas), contribute to the cornea's viscoelasticity. [18] The complex interplay and regulated synthesis, assembly, and turnover of these diverse ECM proteins are central to defining the cornea's ability to deform and recover, thereby dictating its hysteresis.
Signaling Networks in Corneal Development and Remodeling
Corneal hysteresis is shaped by complex signaling networks that govern cellular processes during corneal development, maintenance, and remodeling. The Wnt/beta-catenin pathway, for example, is a key regulator of human corneal epithelial stem/progenitor cell proliferation. [19] Genetic studies have identified WNT7B as a locus influencing central corneal thickness, and its family member Wnt-7a promotes corneal epithelial cell proliferation and up-regulates MMP-12 expression during wound healing. [20] These signaling cascades are crucial for ensuring appropriate cellular density and regenerative capacity, which are indispensable for maintaining corneal integrity and biomechanical function.
Growth factors and their downstream signaling pathways are also pivotal. The platelet-derived growth factor (PDGF) system, with PDGFRA identified as a susceptibility locus for corneal astigmatism, stimulates corneal fibroblast proliferation, migration, and IL8 chemokine secretion, primarily through the JAK2-STAT3 signaling pathway. [11] Similarly, members of the transforming growth factor-beta (TGF-beta) superfamily, including TGFbeta2 and BMP7, are involved in various cellular functions such as corneal morphogenesis, cell proliferation, apoptosis, and extracellular matrix synthesis. [21] BMP7 is particularly critical for embryonic eye development, with its knockout leading to anophthalmia, highlighting its fundamental role in establishing the corneal structure that ultimately influences biomechanical properties . For instance, the tetraspanin CD151 plays a role in maintaining vascular stability by balancing cell adhesion and cytoskeletal tension, suggesting its potential involvement in regulating the biomechanical forces within corneal tissue. [6] Furthermore, the circadian clock modulates global gene expression in human corneal endothelial cells, indicating a rhythmic regulation of corneal physiology that could influence its biomechanical state. [22]
Dysregulation within these integrated pathways contributes to disease-relevant mechanisms, impacting CH and its clinical significance. A lower corneal hysteresis is recognized as a significant risk factor for glaucoma progression, correlating with more rapid visual field loss and thinning of the retinal nerve fiber layer. [14] This suggests that altered corneal biomechanics may serve as a biomarker reflecting a broader susceptibility to tissue damage in various ocular diseases. Moreover, conditions such as keratoconus and Fuchs endothelial dystrophy are associated with distinct changes in corneal biomechanics, involving factors like the downregulation of IGFBP5 in keratoconus and functional alterations in endothelial cells. [11] The loss of heparan sulfate, for example, is linked to corneal degeneration and impaired wound healing, further illustrating how specific molecular changes can compromise overall corneal integrity and function. [23] Deciphering these integrated mechanisms offers crucial insights for identifying potential therapeutic targets aimed at preserving corneal health and mitigating disease progression.
Prognostic Indicator for Glaucoma Progression
Corneal hysteresis (CH) serves as a valuable prognostic indicator for the progression of glaucoma, a leading cause of irreversible blindness worldwide. Studies have demonstrated that lower CH is significantly associated with a more rapid progression of glaucomatous visual field loss. [14] Furthermore, reduced CH has been linked to progressive retinal nerve fiber layer loss, highlighting its role in predicting structural damage to the optic nerve. [6] This biomechanical property is considered a crucial risk factor for glaucoma progression, as evidenced by prospective longitudinal studies, and its assessment can aid in identifying individuals at higher risk for disease worsening. [24] The ocular response analyzer, which measures CH, can also assess corneal resistance factor (CRF) for evaluating ocular hypertension, low tension glaucoma, and open-angle glaucoma. [25]
The interplay between corneal biomechanics and intraocular pressure (IOP) is also relevant in glaucoma management. While central corneal thickness (CCT) is associated with glaucoma development and progression, a cornea compensated IOP (IOPcc) has been shown to have a direct causal effect on corneal biomechanical properties, including CH and CRF. [3] This suggests that the inherent dampening capabilities of the cornea, as reflected by CH, influence how well the eye can withstand IOP-related stress. Additionally, changes in corneal endothelial cell density, a related corneal trait, may be observed in glaucoma patients, further emphasizing the cornea's role in the overall health of the glaucomatous eye. [26]
Diagnostic Utility and Association with Corneal Dystrophies
Corneal hysteresis and other biomechanical properties are crucial for understanding and diagnosing various corneal conditions. Corneas with reduced dampening capabilities, as indicated by lower CH, are proposed to be more susceptible to several ocular diseases. [5] For instance, Fuchs' endothelial corneal dystrophy (FECD), a common cause of corneal transplant surgery characterized by premature loss of endothelial cells, is associated with altered corneal biomechanical properties. [8] Similarly, keratoconus, a condition marked by extreme corneal thinning and irregular shape, is characterized by significantly altered biomechanics and is a leading cause of corneal transplants globally. [3]
The assessment of CH can provide insights into the overall integrity and resilience of the cornea. Beyond primary corneal diseases, altered corneal biomechanics are observed in Mendelian connective tissue disorders such as Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta, which feature corneal thinning. [3] Furthermore, external factors such as topical prostaglandin analogues, commonly used in glaucoma treatment, have been shown to affect corneal hysteresis. [27] Understanding these associations aids in comprehensive patient evaluation, treatment selection, and monitoring strategies for a range of ocular conditions.
Genetic Basis and Personalized Risk Assessment
Corneal hysteresis is a highly heritable trait, with a significant genetic component influencing its variability. [2] Extensive genome-wide association studies (GWAS) have identified over 200 genetic loci associated with corneal biomechanical properties, including CH and corneal resistance factor (CRF), offering profound insights into the genetic etiology of various ocular diseases. [5] Many of these identified polymorphisms are located within or near collagen-coding genes, and gene-set enrichment analyses have highlighted the involvement of collagen pathways and skeletal system development in determining corneal biomechanics. [5]
These genetic discoveries pave the way for more personalized medicine approaches by enabling the identification of individuals at a higher genetic risk for conditions influenced by corneal biomechanics. For example, specific genetic variants associated with corneal biomechanical properties may confer susceptibility to keratoconus. [7] While not directly CH, sequence variation at ANAPC1 also accounts for a substantial portion of the variability in corneal endothelial cell density, underscoring the broad genetic influence on corneal traits. [9] Such genetic insights can inform risk stratification, potentially allowing for earlier detection, targeted prevention strategies, and tailored management plans for patients predisposed to ocular diseases linked to altered corneal biomechanics.
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs1044864 rs202110867 |
ANAPC1 | intraocular pressure measurement leukocyte quantity corneal hysteresis |
| rs142493024 rs148766287 |
COL6A1 | corneal resistance factor central corneal thickness keratoconus corneal hysteresis |
| rs28526212 rs12448211 rs35193497 |
LINC02182 | central corneal thickness corneal hysteresis |
| rs34944131 rs1831902 rs66720556 |
LINC01235 - LINC00583 | corneal resistance factor hematocrit corneal hysteresis |
| rs11659764 | TCF4 - LINC01415 | body mass index intraocular pressure measurement corneal resistance factor urate measurement retinal vasculature measurement |
| rs2755238 rs2721051 |
LINC00598 - FOXO1 | central corneal thickness corneal resistance factor corneal hysteresis |
| rs77542162 | ABCA6 | low density lipoprotein cholesterol measurement total cholesterol measurement erythrocyte volume hematocrit hemoglobin measurement |
| rs27323 | RPL13AP13 - FST | serum IgG glycosylation measurement corneal resistance factor corneal hysteresis |
| rs8070232 | ABCA10 | corneal hysteresis corneal resistance factor body height |
| rs56009602 | ZBTB44-DT, ADAMTS8 | corneal resistance factor corneal hysteresis central corneal thickness intraocular pressure measurement |
Frequently Asked Questions About Corneal Hysteresis
These questions address the most important and specific aspects of corneal hysteresis based on current genetic research.
1. My mom has glaucoma. Am I likely to get weak corneas too?
Yes, there's a strong hereditary component. Your corneal hysteresis (CH), which measures your cornea's ability to absorb energy, is highly heritable, meaning it often runs in families. Since lower CH is a known risk factor for glaucoma progression, having a parent with glaucoma suggests you might have a genetic predisposition for similar corneal characteristics and potentially a higher risk for eye issues.
2. My eye doctor mentioned my "corneal stiffness." What does that mean for me?
That "stiffness" is likely corneal hysteresis (CH), a crucial measure of your cornea's flexibility and energy absorption. It's an important indicator of your eye's overall biomechanical health. Knowing your CH helps doctors assess your risk for various eye conditions, including glaucoma and certain corneal disorders, even if your vision seems fine.
3. I have high eye pressure. Does my eye's stiffness affect my glaucoma risk?
Absolutely, it's a significant factor. Lower corneal hysteresis (CH) is recognized as an independent risk factor for glaucoma progression, even when eye pressure is controlled. A weaker, less flexible cornea is linked to faster visual field loss and greater retinal nerve damage in glaucoma patients. Your doctor uses CH to get a more complete picture of your true glaucoma risk.
4. Can I do anything in my daily life to keep my corneas strong?
Your cornea's fundamental strength and elasticity, measured by corneal hysteresis, are largely determined by its genetic makeup and the specific types of collagen and other components in its structure. While maintaining overall eye health is always good, the article doesn't suggest that specific daily habits like diet or exercise directly alter these inherited biomechanical properties.
5. My sibling has keratoconus. Does that mean my corneas will get really thin too?
There's a genetic link, so it's a valid concern. Keratoconus, characterized by extreme corneal thinning, is associated with specific genetic variants that can increase susceptibility. While you might not develop the condition, your family history suggests a potential genetic predisposition for altered corneal biomechanics, making regular eye check-ups important.
6. Why do some people need corneal transplants but others don't?
The need for corneal transplants often comes down to underlying corneal diseases linked to biomechanical issues. Conditions like keratoconus, which causes severe thinning, and Fuchs' endothelial corneal dystrophy are major reasons for transplants worldwide. Genetic factors play a significant role in determining who develops these severe conditions that damage the cornea beyond repair.
7. Does my age increase my risk for weaker corneas or eye problems?
Yes, age can be a factor, particularly for conditions like glaucoma. While your inherent corneal strength (hysteresis) has a strong genetic basis, glaucoma, which is linked to lower corneal hysteresis, affects a significant portion of the population over 40. Regular monitoring becomes more important as you age to detect any changes early.
8. If my doctor measures my corneal strength, what does that tell me?
Measuring your corneal strength, or hysteresis, gives your doctor crucial insight into your eye's health beyond just eye pressure. It can help identify if you're at a higher risk for conditions like glaucoma progression or certain corneal disorders, even before symptoms appear. This allows for earlier diagnosis and more personalized management strategies to preserve your vision.
9. Does my ethnic background make me more prone to certain eye issues?
Yes, genetic background can influence susceptibility to certain eye conditions. For example, specific populations might have unique genetic predispositions or "founder effects" that make rare conditions, like Macular Corneal Dystrophy, more common in their community. This highlights how ancestry can play a role in your inherited risk for specific eye diseases.
10. Can having weak corneas affect my overall vision quality?
Absolutely. Your cornea's biomechanical integrity, including its hysteresis (strength and elasticity), is fundamental for maintaining clear vision. When corneal strength is compromised, it can contribute to the development or progression of serious conditions like glaucoma or keratoconus, which are major causes of irreversible vision loss and blindness.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
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