Dry Eye Syndrome

Background

Dry eye syndrome, also known as keratoconjunctivitis sicca, is a common, chronic, and often progressive multifactorial disease of the ocular surface. It is characterized by a loss of homeostasis of the tear film, accompanied by ocular symptoms such as discomfort, visual disturbance, and tear film instability, with potential damage to the ocular surface. This condition affects millions of people worldwide, with prevalence increasing with age and in certain environmental or lifestyle contexts.

Biological Basis

The tear film, essential for ocular health, comprises three main layers: a lipid layer that prevents evaporation, an aqueous layer providing moisture and nutrients, and a mucin layer that helps spread the tears evenly over the eye surface. Dry eye syndrome can result from either insufficient tear production, known as aqueous deficient dry eye, or excessive tear evaporation, termed evaporative dry eye, or a combination of both. Inflammation plays a significant role in the pathogenesis of dry eye, leading to a self-perpetuating cycle of ocular surface damage and discomfort. While environmental and lifestyle factors contribute, there is a recognized genetic predisposition to dry eye syndrome, with research ongoing to identify specific genes and pathways involved in tear film regulation and ocular surface health.

Clinical Relevance

The diagnosis of dry eye syndrome typically involves evaluating patient symptoms, conducting clinical tests to assess tear film quantity and quality (such as Schirmer’s test and tear break-up time), and examining the ocular surface for signs of damage or inflammation using vital dyes. Management strategies range from artificial tears and lubricating eye drops to anti-inflammatory medications, punctal plugs to retain tears, and lifestyle modifications. Untreated or poorly managed dry eye can lead to significant complications, including corneal damage, increased risk of ocular infections, and persistent impairment of vision, impacting daily activities.

Social Importance

Dry eye syndrome carries considerable social and economic importance due to its widespread prevalence and significant impact on quality of life. Individuals suffering from dry eye often experience chronic discomfort, which can interfere with daily activities such as reading, driving, using computers, and performing work-related tasks, leading to reduced productivity and overall well-being. The condition also imposes a substantial economic burden, encompassing healthcare costs for diagnosis and treatment, as well as indirect costs associated with lost productivity. As populations age and screen use becomes more pervasive, the public health concern related to dry eye syndrome continues to grow.

Limitations

Methodological and Statistical Constraints

Genetic studies of complex traits, including dry eye syndrome, often face inherent methodological and statistical challenges that can influence the interpretation of findings. A common limitation arises from sample size, where smaller cohorts may lack the statistical power to detect variants with modest effect sizes, leading to missed associations or an overestimation of effects in initial discovery phases.^[1] Furthermore, the use of diverse genotyping platforms across different cohorts within a meta-analysis, even with rigorous quality control and imputation to a common reference panel like HapMap CEU, can introduce subtle biases and variability. ^[2]The reliance on simplified genetic models, such as the additive model, may also overlook more complex genetic architectures, including dominant, recessive, or epistatic interactions, which could play significant roles in the etiology of dry eye syndrome.^[2]

Another critical aspect involves the handling of relatedness within family-based cohorts, where failing to account for shared genetic information can inflate false-positive rates in association tests. ^[3] While methods exist to mitigate this, their application and effectiveness are crucial for data integrity. Moreover, the stringent genome-wide significance thresholds applied in large-scale studies, often based on Bonferroni correction, while necessary to control for multiple testing, can be overly conservative and potentially obscure genuine genetic signals with smaller p-values but true biological relevance. ^[2] The observed phenomenon of some identified variants failing to replicate across independent cohorts further highlights the challenges in distinguishing robust associations from false positives or those with context-specific effects. ^[4]

Phenotypic Complexity and Measurement Challenges

The accurate and consistent characterization of complex phenotypes like dry eye syndrome presents significant limitations. Variability in diagnostic criteria and measurement protocols across different studies can introduce heterogeneity, complicating meta-analyses and the synthesis of results. For instance, even for quantitative traits like central corneal thickness, the use of different measurement devices (e.g., Tomey SP 2000 vs. DGH Technology pachymeters) across cohorts can lead to systematic differences in recorded values.^[3] Similarly, assessments of other ocular parameters, such as retinal vascular calibers, have demonstrated varying levels of inter- and intragrader reliability across different study sites, indicating potential for measurement error and inconsistency. ^[2]

Beyond instrumental differences, biological factors such as diurnal variation can influence measurements, necessitating strict protocols (e.g., measuring at the same time of day) to minimize bias. ^[3]If such environmental or temporal confounders are not uniformly controlled, they can obscure genetic effects or introduce noise into the data. The inherent complexity of dry eye syndrome, which can manifest with a range of symptoms and underlying pathologies, further complicates its precise phenotyping, making it challenging to define a homogeneous trait for genetic analysis and potentially masking distinct genetic etiologies within a broadly defined condition.

Generalizability and Environmental Influences

Generalizability of genetic findings for dry eye syndrome is often constrained by the demographic characteristics of study populations, particularly ancestry and cohort composition. Many large-scale genetic studies have historically focused on populations of European descent, which limits the applicability of findings to other ancestral groups and can lead to biased interpretations.^[5] Population structure, if not adequately accounted for, can result in inflated test statistics and false-positive associations, especially when the phenotype itself is stratified along axes of genetic differentiation. ^[1] For example, studies with predominantly female cohorts may not accurately reflect genetic associations or effect sizes in male populations. ^[3]

Furthermore, the imputation of genetic data to reference panels like HapMap CEU, while standard, assumes genetic similarity between the study population and the reference, which may not hold true for diverse or admixed populations, potentially affecting the accuracy of imputed genotypes. ^[2]Beyond genetic factors, environmental influences and gene-environment interactions are critical confounders that are often difficult to fully capture and model. Lifestyle factors, climate, and other external exposures can significantly modulate the expression of genetic predispositions to dry eye syndrome, and without comprehensive data on these interactions, a complete understanding of disease risk remains elusive.

Unexplained Genetic Variance and Knowledge Gaps

Despite advances in identifying genetic associations, a substantial portion of the heritability for complex traits like dry eye syndrome often remains unexplained, a phenomenon referred to as “missing heritability”.^[6] The variants identified in genome-wide association studies typically explain only a small fraction of the overall phenotypic variance, with individual loci contributing very modest effect sizes. ^[4]This suggests that dry eye syndrome, similar to other complex diseases, likely involves a highly polygenic architecture, where numerous common variants, each with a minute effect, collectively contribute to risk, alongside rare variants and structural variations that are less readily detected by standard GWAS approaches.

Moreover, the complexity of linkage disequilibrium (LD) patterns can make it challenging to pinpoint the exact causal variants within associated genomic regions, as multiple correlated single nucleotide polymorphisms (SNPs) may reside within the same LD block.^[7]This means that an associated SNP may merely be a marker for the true causal variant, which could be located within the same gene, a regulatory region, or even a distant gene. Future research needs to bridge these knowledge gaps by exploring alternative genetic architectures, gene-gene and gene-environment interactions, and integrating multi-omic data to unravel the intricate molecular etiology of dry eye syndrome.^[3]

Variants

Variants within genes crucial for neuronal function and cellular signaling pathways may contribute to the complex etiology of dry eye syndrome. For instance, single nucleotide polymorphismrs10972394 is located within the UNC13B gene, which plays a vital role in the regulation of neurotransmitter release. ^[4] Alterations in UNC13B activity could impact the neural control of tear secretion from the lacrimal glands or affect corneal nerve function, both of which are critical for maintaining ocular surface health and preventing dry eye symptoms. ^[2] Similarly, rs77969016 is associated with the CNTN1 gene, encoding Contactin 1, a cell adhesion molecule essential for nervous system development and axon guidance. Genetic variations in CNTN1 might influence corneal nerve density or regeneration, which are often compromised in individuals with severe dry eye, leading to reduced corneal sensation and impaired reflex tearing. ^[8] Another variant, rs75791291 , is found within SLIT3, a gene involved in axon guidance, cell migration, and inflammation. Dysregulation of SLIT3 could affect processes like corneal wound healing, nerve reinnervation, or the inflammatory responses on the ocular surface, all of which are relevant to the progression and severity of dry eye. ^[9]

Cellular integrity and stress response mechanisms are also key factors in dry eye pathogenesis. The variant rs9692250 is located within the DNAJB6 gene, which codes for a heat shock protein involved in protein folding and preventing protein aggregation. ^[10] Proper protein folding is essential for the function of lacrimal gland cells and corneal epithelial cells; thus, variations in DNAJB6 could lead to cellular stress and dysfunction, contributing to reduced tear production or compromised corneal barrier function. Similarly, rs2524181 is associated with TMPOP1 (Transmembrane Protein, Optic Nerve 1), a gene likely involved in maintaining cell membrane integrity or facilitating specific signaling pathways within ocular tissues. ^[11] Dysfunctional transmembrane proteins can impair cellular communication and nutrient transport, potentially affecting the health and function of the tear film-producing glands and the ocular surface, thereby increasing susceptibility to dry eye conditions.

A significant number of identified variants reside within long non-coding RNA (lncRNA) genes, highlighting their emerging role in ocular health. For example, rs534921742 and rs555072311 are found in LINC01809, an lncRNA that can regulate the expression of nearby or distant genes. ^[12] Similarly, rs139167636 is located in LINC00574, and rs112017655 in LINC01876, both of which are lncRNAs with potential roles in modulating gene networks involved in immune responses, cell differentiation, and tissue repair within the eye. ^[13] Dysregulation of these lncRNAs due to genetic variants could lead to an imbalance in gene expression, affecting the proper development and function of lacrimal glands or the ocular surface epithelium, thereby contributing to dry eye. Furthermore, rs371565191 is found in DLX2-DT, an antisense RNA that specifically regulates the expression of the DLX2 gene, a transcription factor involved in development. Variations in DLX2-DT could alter DLX2activity, potentially impacting the development or maintenance of ocular structures crucial for tear production and distribution, further increasing the risk for dry eye syndrome.^[3]

Key Variants

RS ID	Gene	Related Traits
rs10972394	UNC13B	dry eye syndrome
rs9692250	DNAJB6	dry eye syndrome
rs2524181	MICC - TMPOP1	dry eye syndrome
rs534921742	DHFRP3 - LINC01809	dry eye syndrome
rs139167636	LINC00574 - RPL12P23	dry eye syndrome
rs75791291	SLIT3	dry eye syndrome
rs555072311	DHFRP3 - LINC01809	dry eye syndrome
rs112017655	RNU6-546P - LINC01876	dry eye syndrome
rs77969016	CNTN1 - PDZRN4	dry eye syndrome
rs371565191	DLX2-DT	dry eye syndrome

Classification, Definition, and Terminology

Causes

Acquired Conditions and Medication Effects

Dry eye syndrome can develop as a sequela of severe systemic conditions and adverse drug reactions. For instance, cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a critical condition characterized by extensive mucosal involvement, which frequently includes the ocular surface.^[9]The profound damage to the conjunctiva and other vital ocular structures resulting from SJS/TEN often precipitates chronic ocular surface disease, a primary underlying cause of persistent and severe dry eye. Research indicates that genetic factors, such as variants within theIKZF1 gene, can influence an individual’s susceptibility to such severe drug-induced reactions, thereby implicating a genetic predisposition in these acquired forms of ocular surface damage that lead to dry eye. ^[9]

Biological Background

Ocular Surface Homeostasis and Structural Integrity

The maintenance of a healthy ocular surface is critically dependent on the structural integrity of the cornea and the proper function of its constituent cells. Central corneal thickness (CCT) is a vital indicator of ocular health, with genetic variants near the ZNF469 locus, associated with Brittle Cornea Syndrome, influencing this characteristic. ^[3] The COL5A1 gene, responsible for encoding type V collagen, also significantly impacts CCT. ^[3] Disruptions in type V collagen, a key structural component of connective tissues, are linked to conditions like Ehlers-Danlos Syndrome, which often manifest with extremely thin corneas. ^[3] These genetic influences on corneal architecture highlight the fundamental role of structural proteins in preserving ocular surface integrity and function.

Beyond structural components, cellular mechanisms are crucial for ocular surface homeostasis. The FOXC1 gene, which acts as a transcription factor, is essential for maintaining cell viability and enhancing resistance to oxidative stress within the eye, partly through its transcriptional regulation of FOXO1A. ^[14] Oxidative stress can lead to cellular damage on the ocular surface, disrupting the stability of the tear film and compromising corneal health, thereby contributing to the development of dry eye. Thus, the correct functioning of regulatory genes like FOXC1 is vital for protecting ocular cells from environmental insults and ensuring a healthy ocular surface.

Immune Dysregulation and Inflammatory Pathways

Dry eye syndrome, particularly in its more severe forms, is frequently associated with systemic immune dysregulation. Sjögren’s syndrome, a prevalent autoimmune disease, is characterized by its typical presentation of keratoconjunctivitis sicca, which refers to dry eyes, alongside xerostomia or dry mouth.^[15] This direct connection illustrates how an overactive or misdirected immune system can attack and damage the lacrimal glands, leading to reduced tear production and chronic inflammation of the ocular surface.

Genetic studies have revealed specific loci that confer susceptibility to autoimmune conditions affecting ocular health. For example, variants at multiple genetic loci involved in both innate and adaptive immune responses are strongly linked to Sjögren’s syndrome. ^[15] Similarly, genetic variants within the MHC class I region, along with genes such as IL10 and the IL23R-IL12RB2regions, are associated with Behçet’s disease, another autoimmune disorder known for its significant ocular manifestations.^[12] These genetic predispositions underscore the complex role of immune signaling molecules and regulatory networks in the development of dry eye, where persistent inflammation on the ocular surface is a defining feature. Additionally, other inflammatory conditions can profoundly affect the ocular surface; for instance, IKZF1 is a susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis, a severe mucocutaneous reaction that often causes extensive mucosal damage. ^[9] Such widespread mucosal involvement can lead to severe and lasting damage to the conjunctiva and cornea, impairing tear film integrity and resulting in chronic dry eye.

Genetic Predisposition and Regulatory Mechanisms

The genetic basis of dry eye syndrome involves several genes that are crucial for ocular development, structural integrity, and cellular regulation. As previously mentioned,ZNF469 and COL5A1 are key genes that influence central corneal thickness, with mutations in ZNF469 being a cause of Brittle Cornea Syndrome, characterized by exceptionally thin corneas. ^[3] Furthermore, the transcription factor PAX6 serves as a multifunctional regulator in both embryonic and adult neurogenesis, which is essential for the development and maintenance of ocular tissues, including the corneal innervation vital for the tear reflex. ^[16] These genes highlight the importance of precise genetic programming for a healthy and functional ocular surface.

Variations in an individual’s genetic code, including single nucleotide polymorphisms, can significantly impact gene expression and the function of proteins, thereby predisposing individuals to dry eye. For example, common genetic variants located near theZNF469 locus directly affect central corneal thickness, a risk factor for blinding diseases, indicating that even subtle genetic alterations can compromise the structural integrity of the eye. ^[3] The transcription factors FOXC1 and FOXO1A form a critical regulatory network where FOXC1 controls the expression of FOXO1A, influencing cellular viability and resistance to oxidative stress in the eye. ^[14] Disruptions within these intricate regulatory networks can lead to impaired cellular function and an increased susceptibility to dry eye.

Tissue Interactions and Systemic Consequences

Dry eye is often not merely an isolated condition of the eye but can frequently manifest as a symptom of broader systemic diseases, illustrating the profound interconnectedness of the body’s systems. Autoimmune disorders, such as Sjögren’s syndrome and Behçet’s disease, which are underpinned by distinct genetic factors, commonly present with severe dry eye symptoms. This occurs because systemic inflammation impacts the tear-producing glands and the delicate tissues of the ocular surface.^[15] These systemic immune responses instigate chronic inflammation and damage within the eye, disrupting the intricate balance required for stable tear film production and corneal health.

The integrity of mucosal tissues throughout the body, including those covering the ocular surface, is paramount for overall health. Conditions like Stevens-Johnson syndrome/toxic epidermal necrolysis, which are characterized by severe and widespread mucosal damage, can have devastating and long-lasting effects on the eyes. ^[9]The extensive inflammation and scarring that can develop on the conjunctiva and eyelids severely impair the production and distribution of tears, leading to chronic, severe dry eye and potentially significant visual impairment. This exemplifies how generalized inflammatory reactions across the body can result in profound and enduring organ-specific damage to the eye.

Pathways and Mechanisms

Immune and Inflammatory Signaling in Ocular Homeostasis

Dry eye syndrome, particularly in its autoimmune forms like Sjögren’s syndrome, involves complex immune dysregulation and inflammatory cascades that disrupt ocular surface homeostasis.^[15] This includes the activation of both innate and adaptive immune responses, where signaling pathways initiate cellular responses through receptor activation and subsequent intracellular cascades. Genetic variants in regions such as MHC class I, IL10, and IL23R-IL12RB2are associated with immune-mediated diseases like Behçet’s disease and Sjögren’s syndrome, highlighting their role in modulating immune cell function and cytokine production.^[15] The complement system, an integral part of innate immunity, also plays a role, with polymorphisms in genes like CFH influencing immune responses and potentially contributing to ocular inflammatory conditions. ^[7]

Cellular Resilience and Transcriptional Regulation

FOXC1 is a key transcription factor required for maintaining cell viability and resistance to oxidative stress within the eye, primarily through the transcriptional regulation of FOXO1A. ^[3] This mechanism represents a critical regulatory pathway where gene expression is tightly controlled to protect ocular tissues from environmental and endogenous stressors. Furthermore, IKZF1 has been identified as a susceptibility gene associated with severe mucosal involvement in conditions like Stevens-Johnson syndrome/toxic epidermal necrolysis, suggesting its broader role in mucosal health, which can include the ocular surface. ^[9]Such transcriptional and regulatory mechanisms are vital for the integrity and function of ocular surface cells, with their dysregulation contributing to disease pathology.

Microvascular Dynamics and Angiogenic Pathways

The delicate microcirculation within ocular tissues is crucial for nutrient and oxygen supply, and its regulation involves intricate systems-level integration and network interactions. ^[2] Genetic loci have been identified that influence the microcirculation in vivo, highlighting the complex regulatory mechanisms governing vascular health. ^[2] Angiogenic pathways are also critical, with proteins like Jmjd6 being essential for angiogenic sprouting and regulating the splicing of VEGF-receptor 1, a key receptor in vascular development. ^[4] Dysregulation in these microcirculatory and angiogenic pathways can impair ocular tissue perfusion, contributing to cellular stress and potentially exacerbating conditions like dry eye.

Clinical Relevance

Comorbidities and Syndromic Associations

The genetic landscape of severe systemic conditions can have profound implications for ocular health, including the development of chronic dry eye. For instance, the IKZF1 gene has been identified as a susceptibility locus for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), particularly in cases presenting with severe mucosal involvement. ^[9] Given that SJS/TEN frequently leads to debilitating ocular surface complications, such as persistent epithelial defects and severe chronic dry eye, understanding this genetic predisposition offers a crucial avenue for risk stratification. Identifying individuals at higher genetic risk for SJS/TEN could facilitate early intervention strategies to mitigate the severity of ocular sequelae, thereby improving long-term patient outcomes related to dry eye and other chronic eye morbidities. ^[9]

Environmental and Genetic Factors in Ocular Surface Health

Assessing the interplay between genetic predispositions and environmental exposures is vital for understanding and managing ocular surface conditions. Research indicates that conjunctival UV autofluorescence (CUVAF), a biomarker of ocular surface health, is influenced by both genetic factors and environmental elements, such as reported time spent outdoors. ^[17]This correlation suggests that environmental factors like UV radiation contribute to changes in conjunctival tissue, which is a critical component of the ocular surface and directly relevant to the pathogenesis of dry eye syndrome. Incorporating data on genetic susceptibility alongside environmental exposure assessments can enhance risk stratification, allowing for more personalized prevention strategies and patient counseling regarding protective measures to preserve ocular surface integrity.^[17]

Frequently Asked Questions About Dry Eye Syndrome

These questions address the most important and specific aspects of dry eye syndrome based on current genetic research.

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1. My mom has dry eyes, will I get it too?

Yes, there’s a recognized genetic predisposition to dry eye syndrome, meaning it can run in families. If your mom has it, you might have inherited some of the genetic factors that increase your likelihood of developing it. However, environmental factors and lifestyle choices also play a significant role.

2. I work on a computer all day, but my friend does too and doesn’t have dry eyes. Why me?

It’s likely a combination of your genes and environment. While prolonged screen use is a known trigger, some people are genetically more susceptible to dry eye syndrome. Your unique genetic makeup might make your eyes more vulnerable to factors like computer use, leading to symptoms even if others in similar situations don’t experience them.

3. Does getting older mean I’ll definitely get dry eyes?

While the prevalence of dry eye syndrome does increase with age, it’s not a definite outcome for everyone. Your genetic background can influence your individual risk of developing it as you get older, making some people more prone to age-related tear film changes than others.

4. I’m not European; does my background affect my dry eye risk?

Yes, your ancestral background can influence your dry eye risk. Many large-scale genetic studies have historically focused on populations of European descent, meaning different populations might have unique genetic risk factors or prevalence rates that are not yet fully understood.

5. Can my healthy habits really prevent dry eyes if it runs in my family?

Absolutely. Even with a genetic predisposition, healthy habits are crucial. Lifestyle factors can significantly modulate the expression of genetic predispositions to dry eye syndrome. Maintaining good eye hygiene, staying hydrated, and managing screen time can help mitigate your inherited susceptibility.

6. My sibling doesn’t have dry eyes, but I do. Why the difference if we’re family?

Even within families, genetic inheritance isn’t always identical, and environmental influences differ. You and your sibling might have inherited different combinations of genetic risk factors, or your unique lifestyle and environmental exposures could be triggering your predisposition more strongly. Dry eye is a complex, multifactorial condition.

7. Would a genetic test tell me if I’ll get dry eyes?

Currently, genetic testing isn’t routinely used to predict individual risk for dry eye syndrome. While research is ongoing to identify specific genes and pathways involved, the condition is complex, involving many genes and environmental factors. A doctor usually diagnoses dry eye based on your symptoms and clinical tests.

8. Does what I eat affect my genetic risk for dry eyes?

While the direct link between specific foods and genetic dry eye risk isn’t fully mapped out, your diet is part of your overall lifestyle. Healthy eating habits, particularly those rich in anti-inflammatory nutrients, can support overall eye health and might help modulate the expression of genetic predispositions.

9. Can stress make my genetically-prone dry eyes worse?

Yes, stress can certainly exacerbate dry eye symptoms, even if you have a genetic predisposition. Stress can affect your body’s inflammatory responses and tear production, potentially making your genetically vulnerable eyes more symptomatic. Managing stress is a good strategy for overall eye health.

10. If dry eyes run in my family, can I really prevent it?

While you can’t change your genes, you absolutely can take steps to reduce your risk or manage symptoms if you have a family history. Proactive lifestyle modifications, like taking regular breaks from screens, maintaining good hydration, and using artificial tears, can help mitigate your genetic predisposition.

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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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[2] Ikram MK, et al. “Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.” PLoS Genet, vol. 6, no. 10, 2010, p. e1001184.

[3] Lu Y, et al. “Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness.”PLoS Genet, vol. 6, no. 5, 2010, p. e1000921.

[4] Sim X. “Genetic loci for retinal arteriolar microcirculation.” PLoS One, vol. 8, no. 6, 2013, p. e65301.

[5] Gao, X., et al. “A genome-wide association study of central corneal thickness in Latinos.” Invest Ophthalmol Vis Sci, 2013.

[6] Liu, F., et al. “Digital quantification of human eye color highlights genetic association of three new loci.” PLoS Genet, 2010.

[7] Nakano, M., et al. “Novel common variants and susceptible haplotype for exfoliation glaucoma specific to Asian population.” Sci Rep, 2014.

[8] Vitart V, et al. “New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8.” Hum Mol Genet, vol. 19, no. 21, 2010, pp. 4304-11.

[9] Ueta M, et al. “IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement.” J Allergy Clin Immunol, vol. 135, no. 3, 2015, pp. 722-30.

[10] Hou S, et al. “Identification of a susceptibility locus in STAT4 for Behçet’s disease in Han Chinese in a genome-wide association study.”Arthritis Rheum, vol. 64, no. 12, 2012, pp. 4106-15.

[11] Li Y, et al. “A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren’s syndrome at 7q11.23.” Nat Genet, vol. 45, no. 11, 2013, pp. 1368-72.

[12] Remmers EF, et al. “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease.”Nat Genet, vol. 42, no. 8, 2010, pp. 698-702.

[13] Mizuki N, et al. “Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci.”Nat Genet, vol. 42, no. 8, 2010, pp. 703-6.

[14] Berry, F. B., et al. “FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A.” Hum Mol Genet, vol. 17, no. 4, 2008, pp. 490-505.

[15] Lessard, C. J., et al. “Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome.” Nat Genet, vol. 45, no. 11, 2013, pp. 1284-92.

[16] Osumi, N., et al. “Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator.” Stem Cells, vol. 26, no. 7, 2008, pp. 1663-72.

[17] Yazar, S., et al. “Genetic and environmental factors in conjunctival UV autofluorescence.” JAMA Ophthalmology, 2015.