Corneal Endothelial Cell Attribute
The cornea is the transparent, outermost layer of the eye, essential for focusing light and protecting the inner structures. It is composed of several layers, with the innermost layer being the corneal endothelium. This attribute refers to various characteristics of these specialized cells, which are crucial for maintaining corneal health and clarity.
Biological Basis
The corneal endothelium consists of a single layer of hexagonal cells lining the posterior surface of the cornea. These cells are unique because they have a limited capacity for regeneration in humans. Their primary biological function is to actively pump fluid out of the corneal stroma, a process known as the "pump function." This active transport of ions and water maintains the cornea in a relatively dehydrated state, known as deturgescence, which is vital for its transparency. Without a properly functioning endothelium, the cornea would swell with fluid (edema), leading to cloudiness and impaired vision.
Clinical Relevance
Attributes of corneal endothelial cells, such as their density, morphology (shape and size), and overall health, are of significant clinical importance. A healthy endothelium with a sufficient number of well-functioning cells is critical for clear vision. Damage to these cells, which can occur due to aging, trauma, inflammation, certain eye surgeries (like cataract surgery), or genetic predispositions, can lead to a reduction in cell density and function. This can result in corneal edema, a condition where the cornea swells and becomes cloudy, severely impacting vision. Conditions like Fuchs' endothelial dystrophy are characterized by progressive loss and dysfunction of these cells. Assessing endothelial cell attributes is a routine part of ophthalmic examinations, especially before and after intraocular surgeries, and is crucial for determining suitability for corneal transplantation procedures such as Descemet's Stripping Endothelial Keratoplasty (DSEK) or Descemet's Membrane Endothelial Keratoplasty (DMEK).
Social Importance
The health of corneal endothelial cells has substantial social importance, as visual impairment due to corneal endothelial dysfunction can significantly affect an individual's quality of life, independence, and ability to participate in daily activities. Corneal diseases, including those affecting the endothelium, are a leading cause of blindness and visual impairment globally. Understanding the genetic and environmental factors that influence corneal endothelial cell attributes can lead to improved diagnostic tools, preventative strategies, and more effective treatments, ultimately reducing the burden of corneal blindness and enhancing public health outcomes worldwide.
Limitations
The study of complex traits like corneal endothelial cell attribute, particularly through genome-wide association studies (GWAS), inherently faces several methodological and interpretative limitations. While research efforts aim to uncover genetic underpinnings, a comprehensive understanding requires acknowledging the constraints in study design, phenotype assessment, population representation, and the intricate nature of genetic and environmental influences.
Methodological and Statistical Constraints
The power to identify robust genetic associations for a complex corneal attribute is often constrained by the sample sizes available in individual cohorts. Even when studies combine data through meta-analysis, the contribution of smaller cohorts can limit the overall statistical power, making it challenging to detect genetic variants with subtle effects. [1] This limitation can lead to effect-size inflation in initial discovery phases, where detected associations might appear stronger than their true biological impact, necessitating rigorous replication in independent and often larger samples for confirmation. [2] Consequently, some genuine genetic signals may remain below the threshold of detection, contributing to an incomplete catalog of associated loci.
Furthermore, the stringent statistical thresholds required for genome-wide significance (e.g., P < 5 × 10−8) mean that associations identified with less conservative criteria in discovery cohorts may not achieve this level of significance in individual replication cohorts. [2] This tiered approach, while crucial for reducing false positives, can result in "suggestive" associations that require even larger meta-analyses to reach definitive genome-wide significance. [3] Such gaps in replication and the need for continually expanding sample sizes underscore the ongoing challenge in fully validating all potential genetic contributors to corneal endothelial cell attribute.
Phenotypic Definition and Measurement Challenges
Defining and accurately measuring complex phenotypes like corneal endothelial cell attribute presents a significant challenge that can impact genetic studies. For traits that are continuous, such as corneal astigmatism, categorizing individuals into "cases" and "controls" using arbitrary thresholds (e.g., ≥0.75D) can lead to misclassification, particularly for individuals whose values fall close to the cutoff. [1] While sensitivity analyses can explore the robustness of findings to different thresholds, the inherent subjectivity in these definitions can influence the observed associations and their clinical relevance.
Beyond categorical definitions, the precision and consistency of quantitative measurements are paramount. Technical variations in ophthalmic instrumentation and protocols across different study sites or even within a single study can introduce measurement error, which effectively reduces the statistical power to detect true genetic associations. Although strategies like averaging measurements from both eyes can enhance power [1] subtle inconsistencies can still contribute to heterogeneity between cohorts or obscure weaker genetic signals. Therefore, achieving highly standardized phenotyping across all participating studies is crucial for minimizing measurement variability and ensuring the reliability of genetic findings.
Population Specificity and Generalizability
A significant limitation in genetic studies of corneal endothelial cell attribute is the potential for findings to be specific to the populations in which they were discovered, limiting their generalizability across diverse ancestries. Genetic architecture, including allele frequencies and linkage disequilibrium patterns, can vary considerably among ethnic groups. [1] While meta-analyses that include multiple populations are designed to broaden applicability, the predominant representation of certain ancestral groups can introduce cohort bias, making it challenging to extrapolate results globally without further validation in underrepresented populations.
Moreover, despite the application of advanced statistical methods like principal component analysis to adjust for population stratification, residual confounding due to subtle population substructure might persist. [1] In some instances, the stringent application of these adjustments, particularly for relatively rare complex diseases, could inadvertently reduce the statistical power to identify genuine disease-associated regions. [4] Navigating this balance between adequately controlling for population structure and preserving statistical power remains a complex methodological consideration, especially in studies involving cohorts with mixed ancestries.
Incomplete Understanding of Etiology
Even with the identification of robust genetic loci, the current understanding of the genetic etiology of complex corneal attributes like corneal endothelial cell attribute remains incomplete. The identified genetic variants typically explain only a small fraction of the overall heritability of these traits [1] a phenomenon often referred to as "missing heritability." This suggests that a multitude of other genetic factors, including rare variants, structural variations, or complex gene-gene interactions (epistasis), which are not fully captured by common SNP-based GWAS, likely contribute to the trait.
Furthermore, genetic studies often struggle to fully account for the complex interplay between genetic predispositions and environmental factors. Environmental exposures, lifestyle choices, and other external influences can significantly modulate the expression of corneal attributes, and gene-environment interactions are likely to play a substantial, yet often unmeasured, role in the overall etiology. The absence of comprehensive environmental data or the challenges in modeling these intricate interactions means that identified genetic variants represent only one component of a larger, multifaceted biological system, leaving considerable knowledge gaps regarding the complete pathways involved in the development and maintenance of corneal endothelial cell attribute.
Variants
Variants in genes involved in cell cycle regulation, immune response, and gene expression play a significant role in determining corneal endothelial cell attributes, which are crucial for maintaining corneal transparency and function. For instance, variants in genes like ANAPC1 (Anaphase Promoting Complex Subunit 1) and its pseudogene ANAPC1P6 (Anaphase Promoting Complex Subunit 1 Pseudogene 6), including rs78658973, rs201205018, rs200632716, and rs147701520, may influence the precise control of cell division and proliferation. ANAPC1 is a core component of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that regulates progression through mitosis and the G1 phase of the cell cycle. Proper regulation of cell division is essential for the regeneration and maintenance of corneal endothelial cell density, as these cells have limited proliferative capacity in adults. [5] The extracellular matrix protein Fibulin 7, encoded by FBLN7, contributes to tissue architecture and integrity, and its variant rs113858761 could impact the structural stability of the cornea.
Other variants affect genes involved in immune regulation and cellular signaling pathways critical for corneal health. The MERTK (Mer Receptor Tyrosine Kinase) gene, with variants such as rs112977309 and rs35594851, encodes a receptor tyrosine kinase that is vital for the clearance of apoptotic cells and the resolution of inflammation. Efficient removal of cellular debris and controlled inflammatory responses are paramount for preventing damage to corneal endothelial cells and maintaining a clear cornea. Furthermore, the intergenic variant rs36153567 located between MERTK and TMEM87B (Transmembrane Protein 87B) may influence the expression or regulation of these genes, potentially impacting related cellular processes. [1] Variants in the IL1A-IL1B (Interleukin 1 Alpha - Interleukin 1 Beta) locus, exemplified by rs4849124, are particularly relevant as IL-1 beta is a potent pro-inflammatory cytokine known to modulate cytokine and receptor expression in human corneal and limbal fibroblasts. [1] Alterations in these inflammatory pathways can significantly impact corneal endothelial cell function and overall corneal transparency.
Finally, variants affecting non-coding RNAs and gene regulatory regions can have broad implications for corneal endothelial cell attributes. The variants rs71413012 and rs796772920 within the CENPNP1-LINC01955 locus, where LINC01955 is a long intergenic non-coding RNA, may modulate gene expression critical for corneal development and function. Similarly, the variant rs4849748 in MIR4435-2HG (MIR4435 Host Gene) could affect the production or regulation of microRNAs, which are key post-transcriptional regulators of gene expression. Pseudogenes like BMS1P19 (BMS1 Ribosome Biogenesis Factor Homolog Pseudogene 19) and SRSF3P6 (Serine And Arginine Rich Splicing Factor 3 Pseudogene 6), with variant rs546476261, and the intergenic variant rs2323458 between HS3ST3B1 (Heparan Sulfate D-Glucosaminyl 3-O-Sulfotransferase 3B1) and RPS18P12 (Ribosomal Protein S18 Pseudogene 12) may also play regulatory roles, influencing the complex gene networks that govern corneal cell biology. Recurrent ocular abnormalities in disease phenotypes underscore the importance of such regulatory elements for normal structural development of the eye. [4]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs78658973 rs201205018 rs200632716 |
ANAPC1 | corneal endothelial cell attribute intraocular pressure measurement |
| rs71413012 rs796772920 |
CENPNP1 - LINC01955 | corneal endothelial cell attribute |
| rs147701520 | ANAPC1P6 | corneal endothelial cell attribute |
| rs112977309 rs35594851 |
MERTK | corneal endothelial cell attribute |
| rs113858761 | FBLN7 | corneal endothelial cell attribute |
| rs4849748 | MIR4435-2HG | corneal endothelial cell attribute serum albumin amount |
| rs36153567 | MERTK - TMEM87B | corneal endothelial cell attribute |
| rs4849124 | IL1A - IL1B | corneal endothelial cell attribute interleukin-1 beta measurement |
| rs546476261 | BMS1P19 - SRSF3P6 | corneal endothelial cell attribute |
| rs2323458 | HS3ST3B1 - RPS18P12 | corneal endothelial cell attribute |
Corneal Architecture and Extracellular Matrix Regulation
The cornea, a transparent outer layer of the eye, is crucial for vision, acting as a protective barrier and the primary refractive surface. Its structural integrity is maintained by a complex extracellular matrix, primarily composed of collagens, and regulated by various cellular components, including the corneal endothelium, epithelium, and stromal fibroblasts. Central corneal thickness (CCT) is a highly heritable characteristic, with studies indicating a heritability of up to 95 percent, and serves as an important clinical indicator of overall corneal health . [5], [6] Deviations in CCT are observed in various corneal diseases, such as dystrophies, keratoconus, and herpes simplex keratitis. [5]
Key biomolecules and their encoding genes play a significant role in establishing and maintaining corneal structure. For instance, genes encoding Type I collagens, COL1A1 and COL1A2, and Type V collagens, COL5A1 and COL5A2, are implicated in corneal thickness and integrity. Mutations in these genes are associated with connective tissue disorders like osteogenesis imperfecta and Ehlers-Danlos syndrome, where extremely thin corneas are a common finding . [5], [7] Additionally, the gene ZNF469 is associated with brittle cornea syndrome and influences CCT, while RAB3GAP1 is expressed in corneal tissue and is essential for the normal structural development and function of the eye, with defects leading to ocular abnormalities . [3], [4], [5], [8]
Growth Factor Signaling in Corneal Cell Biology
Growth factors and their signaling pathways are fundamental in regulating corneal cellular functions, including proliferation, differentiation, migration, and tissue remodeling, processes that directly impact corneal endothelial cell attributes. The platelet-derived growth factor receptor alpha (PDGFRA), located on chromosome 4q12, is a critical component in these regulatory networks. PDGFRA binds to various forms of platelet-derived growth factor (PDGF-AA, AB, and BB) and is expressed across different corneal layers, including the corneal epithelium, stromal fibroblasts, and endothelium . [1], [9], [10], [11] This widespread expression underscores its role in mediating diverse biological processes such as embryonic development, angiogenesis, and cell growth. [1]
In the cornea, PDGF and its receptors, in concert with other cytokines like epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α) and -beta (TGF-β), orchestrate crucial cellular functions. These include mediating corneal fibroblast migration, facilitating extracellular matrix remodeling, and playing a vital role in corneal wound healing . [1], [4], [12], [13], [14] The administration of PDGF has been shown to induce keratocyte elongation in corneal stroma, further illustrating its influence on corneal cell morphology and function . [1], [10] The JAK2-STAT3 signaling pathway is specifically involved in PDGF-driven proliferation, migration, and chemokine secretion in human corneal fibroblasts, highlighting the complex molecular cascades that govern corneal cellular responses. [13]
Genetic Determinants of Corneal Shape and Thickness
Corneal shape and thickness are complex traits influenced by a range of genetic mechanisms and gene expression patterns. Corneal astigmatism, characterized by an uneven corneal curvature that distorts light focus, and corneal curvature, which describes the steepness of the cornea, are both highly heritable ocular parameters . [1], [15], [16] Genetic variants within the PDGFRA gene have been identified as a susceptibility locus for corneal astigmatism, with specific single nucleotide polymorphisms (SNPs) such as rs7677751 conferring an increased risk and explaining a portion of the variation in corneal cylinder power. [1] Furthermore, variants in PDGFRA are also associated with corneal curvature, suggesting a pleiotropic effect of this gene on different corneal biometrics . [1], [17]
Beyond PDGFRA, other genes contribute to the genetic architecture of corneal traits. Central corneal thickness (CCT) is influenced by genes involved in extracellular matrix organization, such as COL5A1 and ZNF469, which have been identified through genome-wide association studies (GWAS) . [3], [5] Other candidate genes like PAX6, associated with aniridia and linked to myopia, and FOXC1, involved in abnormal ocular development, also play roles in determining corneal and anterior chamber morphology . [5], [18], [19] These genetic insights highlight the intricate regulatory networks that govern corneal development and shape, impacting a range of ocular conditions.
Corneal Attributes in Ocular Health and Disease
The attributes of the cornea, including its shape and thickness, have significant pathophysiological implications for overall ocular health. Corneal astigmatism, by fragmenting light rays, impairs the eye's ability to focus light onto a single point, leading to blurry or distorted vision. [1] Extreme variations in corneal curvature, such as excessively flatter corneas, can be associated with conditions like cornea plana, resulting in high hyperopia and potentially leading to angle-closure glaucoma. [1] These conditions underscore the importance of precise corneal biometrics for optimal visual function and ocular well-being.
Central corneal thickness (CCT) is a critical prognostic indicator for the development of primary open-angle glaucoma (OAG), one of the leading causes of irreversible blindness worldwide, with thinner corneas correlating with an increased risk. [5] While OAG has a complex molecular etiology, the gene MYOCILIN has been identified as a major contributor . [5], [20] Corneal diseases like keratoconus, characterized by progressive thinning and protrusion of the cornea, are also linked to specific genetic factors, such as defects in RAB3GAP1, which are crucial for normal eye development and function. [4] Understanding these tissue and organ-level effects provides insight into the systemic consequences of altered corneal attributes and the molecular pathways involved in ocular pathologies.
Growth Factor Signaling and Cellular Homeostasis in the Cornea
Corneal cell attributes, including proliferation, migration, and differentiation, are intricately regulated by a complex network of growth factor signaling pathways. Platelet-derived growth factor (PDGF) and its receptor, PDGFRA, are widely expressed in corneas and exert significant effects on various corneal cell types. [9] Activation of the PDGFRA pathway, particularly in human corneal fibroblasts, can drive proliferation, migration, and the secretion of chemokines like IL8, often mediated through the JAK2-STAT3 signaling pathway. [13] Furthermore, PDGFRA is expressed in corneal myofibroblasts in situ, highlighting its role in corneal remodeling and response to injury. [12]
Beyond PDGF, other growth factors such as epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and interleukin-1 beta (IL-1 beta) differentially regulate the expression of cytokines and their receptors in human corneal and limbal fibroblasts. [21] These factors collectively influence corneal keratocyte differentiation and migration within the corneal matrix. [10] The tight regulation of these signaling cascades is crucial for maintaining corneal clarity, wound healing, and overall structural integrity.
Genetic Regulation and Corneal Development
The genetic architecture underlying corneal attributes involves specific gene regulation mechanisms that govern cell function and development. The human alpha-platelet-derived growth factor receptor gene, PDGFRA, has been extensively characterized for its structure, organization, and transcription units. [11] Variants within PDGFRA are associated with corneal curvature, demonstrating a direct link between genetic predisposition and corneal morphology. [17]
Another critical gene, RAB3GAP1, is expressed in the cornea, with its transcript identified in both mouse cornea and human keratoconus cornea libraries. [4] Defects in RAB3GAP1 lead to recurrent ocular abnormalities, underscoring the requirement of Rab3 proteins for normal structural development and function of the eye. [4] Additionally, the forkhead box protein FOXC1 is essential for ocular cell viability and resistance to oxidative stress through its transcriptional regulation of FOXO1A. [22] Mutations in FOXC1 can result in developmental defects of the anterior chamber, suggesting a gene dosage mechanism for these pathologies. [23]
Inter-Pathway Communication and Network Integration
Corneal cell behavior is not dictated by isolated pathways but rather by an integrated network of interacting signals. For instance, corneal fibroblast chemotaxis, a critical process in wound healing and remodeling, is influenced by the interplay of PDGF, IL-1alpha, and bone morphogenetic protein 2/4 (BMP2/4). [24] This demonstrates a clear crosstalk where multiple growth factors converge to orchestrate a specific cellular response.
At a broader systems level, the genomic response of hypoxic Muller cells in the eye involves the very low density lipoprotein receptor (VLDLR) as part of an angiogenic network. [25] While described in Muller cells, this highlights how specific receptors and their associated networks contribute to complex physiological processes in ocular tissues. Such integrated networks ensure robust control over corneal attributes, adapting to physiological demands and environmental stresses.
Molecular Mechanisms in Corneal Pathologies
Dysregulation of these intricate pathways contributes significantly to various corneal pathologies. Genetic variants in PDGFRA have been identified as a susceptibility locus for corneal astigmatism [1] indicating that altered PDGF signaling can lead to structural changes in the cornea. Similarly, the presence of RAB3GAP1 transcripts in keratoconus cornea and the ocular abnormalities associated with its defects suggest a mechanistic role for its dysregulation in this blinding disease. [4]
Therapeutic interventions targeting specific pathways also underscore their pathological significance. Topical anti-transforming growth factor-beta treatments have been shown to impact corneal stromal haze [14] positioning TGF-beta signaling as a potential therapeutic target for mitigating post-surgical complications or fibrotic conditions. Furthermore, deleterious mutations in the zinc-finger gene ZNF469 cause brittle cornea syndrome [8] illustrating how genetic defects impacting structural proteins or regulatory factors can severely compromise corneal integrity.
Risk Assessment and Prognostication in Ocular Health
Central corneal thickness (CCT) serves as a critical prognosticator for various ocular conditions, particularly open-angle glaucoma (OAG), a leading cause of irreversible blindness worldwide. Studies indicate that individuals with a thin CCT have a substantially increased risk of developing OAG and associated visual loss, making CCT a valuable quantitative trait for understanding the genetic underpinnings of this complex disease. [5] Similarly, genetic factors contribute to the risk of corneal astigmatism, with the T-allele of the rs7677751 variant within the PDGFRA gene conferring a 26% higher risk for the condition and explaining a portion of the variation in corneal cylinder power. [1] Furthermore, genome-wide association studies have identified a potential novel gene locus linked to keratoconus, a condition frequently necessitating corneal transplantation. [4]
Clinical Applications and Personalized Management Strategies
The assessment of corneal attributes holds significant diagnostic utility and informs personalized treatment approaches. CCT, for instance, is an essential measure in determining a person's suitability for laser refractive surgery, impacting treatment selection and patient outcomes. [5] Genetic insights into conditions like corneal astigmatism can facilitate improved risk stratification; studies have shown that the association of specific genetic variants with astigmatism remains robust across different clinical definitions and thresholds, indicating their potential for personalized risk assessment and monitoring strategies. [1] Such genetic information may contribute to identifying high-risk individuals and tailoring preventative or early intervention strategies.
Comorbidities and Genetic Associations with Corneal Structure
Corneal attributes are often associated with broader systemic conditions and exhibit complex genetic relationships. For example, extremely thin corneas are a common finding in Ehlers-Danlos Syndrome (EDS), a connective tissue disorder, and the COL5A1 gene, encoding type V collagen, is associated with CCT, highlighting the phenotypic link between EDS and abnormal CCT values. [5] The PDGFRA gene, identified as a susceptibility locus for corneal astigmatism, also demonstrates a weak correlation with corneal curvature, suggesting a potential pleiotropic role in different ocular outcomes. [1] The Platelet-Derived Growth Factor (PDGF) system, including its receptor PDGFRA, plays a crucial role in corneal biology by influencing the proliferation, migration, and differentiation of corneal and limbal fibroblasts. [1]
Frequently Asked Questions About Corneal Endothelial Cell Attribute
These questions address the most important and specific aspects of corneal endothelial cell attribute based on current genetic research.
1. My vision seems fuzzier as I age; is it normal?
It's common for vision to change with age, and yes, your corneal cells can naturally decline over time. This can reduce their ability to keep your cornea clear, sometimes leading to cloudiness. Regular eye check-ups are important to monitor this and catch any issues early.
2. My grandma had cloudy vision; will I get that too?
There's a chance, yes. Conditions like Fuchs' endothelial dystrophy, which causes progressive cloudy vision, can run in families due to genetic predispositions. If you have a family history, it's wise to discuss it with your eye doctor so they can monitor your corneal health closely.
3. I'm having cataract surgery; will it permanently affect my eye clarity?
While cataract surgery is generally safe, it can sometimes cause stress or damage to the corneal cells. In some cases, this might lead to temporary or even permanent corneal swelling and cloudiness. Your eye doctor will assess your cell health before surgery to minimize this risk.
4. Could an old eye injury make my vision cloudy later?
Yes, it's possible. Trauma to the eye, even from years ago, can damage the delicate corneal cells. Because these cells don't regenerate easily, that damage could potentially lead to reduced cell function and corneal cloudiness developing later in life.
5. Can I do anything daily to keep my eye cells healthy?
While genetics play a role, maintaining overall eye health through a balanced diet, protecting your eyes from injury, and regular check-ups can help. Limiting inflammation and managing conditions that affect eye health are also beneficial, as environmental factors interact with your genetic makeup.
6. Sometimes my vision is blurry in the morning; is that a bad sign?
It could be. Morning blurriness that clears up can sometimes be an early sign of your corneal cells not effectively pumping fluid out overnight. If this is happening, it's a good idea to see an eye doctor to have your corneal health checked, especially if it's new or worsening.
7. Is it important to get special eye cell checks regularly?
Yes, especially if you have risk factors like a family history of eye disease or are considering eye surgery. Routine ophthalmic exams often include assessing your corneal cells. These checks are crucial for detecting problems early and planning treatments like corneal transplants if needed.
8. Does my ethnic background affect my risk for eye cloudiness?
Yes, it can. Genetic factors that influence corneal cell health can vary significantly among different ethnic groups. This means your ancestry might predispose you to a higher or lower risk for certain corneal conditions. It's an important consideration for personalized eye care.
9. If my eye cells get damaged, can they ever grow back?
Unfortunately, no, not really. In humans, these specialized corneal cells have a very limited capacity for regeneration. Once they are lost or damaged, they don't easily grow back, which is why maintaining their health is so crucial for clear vision.
10. Why do some people never get cloudy vision, even when old?
It's a combination of luck with their genetic makeup and environmental factors. Some individuals are genetically predisposed to have more resilient corneal cells or are less susceptible to age-related decline or damage. Their lifestyle and lack of trauma also play a significant role.
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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