Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension
| Autor: | Gerhard A. Coetzee, Shinwu Jeong, Janet L. Davis, Harry W. Flynn, Carmen A. Puliafito, Hussein Wafapoor, Tatsuo Itakura, Robert L. Avery, Dennis J. Hazelett, Hooman Allayee, Pei Chang Wu, Alexander M. Eaton, Mathew T. Pletcher, Pablo Argüeso, Naoto Keicho, Nitin Patel, Minako Hijikata, David V. Conti, Christopher K. Edlund, Geeta A. Lalwani, Jaana Hartiala, Stephen G. Schwartz, Xiaoyi Gao, M. Elizabeth Fini |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male medicine.medical_specialty Intraocular pressure Candidate gene genetic structures Genotype Glaucoma Ocular hypertension Biology Triamcinolone Trabecular Meshwork Ophthalmology medicine Genetics Humans RNA Messenger Glucocorticoids Dexamethasone Intraocular Pressure Mucins Middle Aged medicine.disease eye diseases medicine.anatomical_structure Gene Expression Regulation Female Ocular Hypertension sense organs Trabecular meshwork Glucocorticoid Hormone medicine.drug Follow-Up Studies Genome-Wide Association Study |
| Popis: | Glaucoma is a leading cause of irreversible blindness, presently affecting approximately 70 million people worldwide.1,2 The most common form is primary open-angle glaucoma (POAG), which accounts for approximately 90% of all cases. Ocular hypertension (OH) is the major risk factor for POAG and lowering IOP is the only effective treatment.3 However, many patients remain refractory to existing IOP-lowering interventions and eventually may become blind, underscoring the unmet medical need for novel approaches to control IOP. Intraocular pressure is a product of the rate of aqueous humor production, resistance to outflow, and episcleral venous pressure.3,4 The aqueous outflow pathways in the angle of the eye are composed of a spongy tissue called the trabecular meshwork (TBM), which leads into Schlemm's canal. Much of the resistance to outflow resides within the TBM, putatively within 7 to 14 μm of the inner wall of Schlemm's canal in a region known as the juxtacanalicular or cribriform region.5–,8 Primary open-angle glaucoma is caused by an increase in outflow resistance9,10 due to poorly understood defects in this region.11–,14 Ocular hypertension in POAG has been associated with dysregulated intracellular signaling pathways controlled by IL-1/NF-κB,15 TGF-β superfamily,16 and Wnt.17,18 The pathophysiology of OH leading to POAG shares many features with a secondary form of OH caused by treatment with glucocorticoids (GCs).19–,25 Glucocorticoids are a class of steroid hormones released in response to stress. As part of the natural feedback mechanism that turns down the inflammatory response, they are useful for treating a wide variety of diseases.26 Complicating this, however, is the considerable interindividual variability and tissue-specific GC sensitivity among individuals, which can cause a variety of systemic side effects.27–,31 Treatment with steroids, such as dexamethasone or triamcinolone acetonide (TA), in the eye causes elevated IOP in predisposed individuals. It has been documented that approximately 40% of the normal population develops an IOP increase > 6 mm Hg above baseline following topical administration of GCs, 4 times a day for 4 to 6 weeks.32 When GCs are administered intravitreally, IOP may increase by 30% or more in up to half of patients.33 These individuals are considered to be “steroid responders.” Interestingly, almost all POAG patients are steroid responders25,32,34–,40; conversely, steroid-responders who do not have POAG are at much higher risk of developing POAG compared to nonresponders.37–,41 A better understanding of genetic and molecular mechanisms underlying individual variation in the response to steroids could shed light on our understanding of steroid-induced OH and OH leading to POAG. That being said, mechanisms of steroid-induced OH and OH leading to POAG also show distinct differences; therefore, studying the genetics of steroid-induced OH specifically could lead to discovery of genes involved in IOP regulation that could not have been revealed any other way. The genome-wide association study (GWAS) represents an agnostic approach for prioritization of genes that are associated with a disease process, and makes it possible to discover novel genes that could not otherwise be identified. In the current study, we performed a pharmaco-GWAS for this purpose, using a cohort enrolled from patients treated with off-label intravitreal TA (IVTA) for various retinal indications, and followed up with an independent candidate gene study. We identified two independent quantitative trait loci (QTLs) at chromosomal locus 6p21.33 associated with the novel mucin gene HCG22. |
| Databáze: | OpenAIRE |
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