Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

multiple genes, results in a high degree of variability in phenotypic expression and disease severity that makes linkage analysis extremely challenging. To date, linkage studies on families with COAG provide strong evidence for genetic heterogeneity. At least 11 loci have been identified, along with three genes (myocilin, optineurin, and WDR36) (Table 8.1).

Additional evidence for genetic susceptibility comes from polymorphisms of genes suspected of playing a role in glaucoma. Polymorphisms in the genes coding for the ß-adrenergic receptors ADRB1 and ADRB2 expressed in the trabecular meshwork and ciliary body have been examined and may influence the pathophysiology of COAG in both COAG and normal-tension glaucoma in Japanese patients (7). However, the ADRB2 gene does not appear to be a “ca usative” COAG genetic risk, as shown in an appropriately powered study comparing controls and COAG cases among white individuals and persons of African ancestry (8). There may also be susceptibility genes that are essential to permit other genes or environmental factors to lead to glaucoma. For example, the OPA1 gene and apolipoprotein E gene have been associated with normal-tension glaucoma and COAG, respectively (9, 10). It remains to be seen what role these diseaseassociated polymorphisms will play in patients with glaucoma.

Angle-Closure Glaucoma

There have been a growing number of investigators who have explored the familial basis of angleclosure glaucoma using both traditional Mendelian study design approaches and application of ocular biometry for quantitative trait design approach. In certain regions of the world, angle-closure glaucoma is the most common form of glaucoma, so it is important to understand the genetic mechanisms involved in this condition, which can be amenable to treatment with laser approaches.

Using a combination of a genetic approach applied to an epidemiology study, Hu found a sixfoldincreased risk for angle-closure glaucoma among persons with any family history of angle-closure glaucoma in his population-based survey in Shunyi County, Beijing, which supports a genetic factor (11). Using a quantitative trait approach, a study of axial anterior chamber depth in twins (without angleclosure glaucoma) indicated that about 70% of the variance in dizygotic twins could be attributable to a genetic component (12). A biometric study showed a relatively shallow anterior chamber depth in siblings, children, nephews, nieces, and grandchildren of angle-closure

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glaucoma probands (13). A heritability of 70% was found in this study, indicating that about two thirds of the ageand sexindependent variation of anterior chamber depth is inherited. Furthermore, Lowe has suggested that inheritance of a shallow anterior chamber is polygenic with a threshold effect so that the action of a large number of grouped or independently inherited genes results in varying degrees of anterior chamber shallowing (14). A Chinese study of families with angle-closure glaucoma and shallow anterior chambers concluded that the inheritance of a shallow anterior chamber may be a genetically heterogeneous trait and influenced by sex with autosomaldominant inheritance in subgroups (15).

Table 8.1 Summary of Genes and Loci Associated with Glaucomaa

factor-related genes: PITX2, PITX3, and FOXC1. Pigmentary Glaucoma

Several investigators have demonstrated autosomal-dominant inheritance for the pigment dispersion syndrome (PDS) (19, 20 and 21). In 1997, Andersen and colleagues described four autosomaldominant PDS families and reported localization of a gene to chromosome 7q35-36 (22). The disorder is genetically heterogeneous, and further studies are under way to determine whether additional loci exist and to find the gene (or genes) involved. DBA/2J mice appear to develop a form of pigmentary glaucoma caused by mutations in the glycoprotein (transmembrane) nmb gene, Gpnmb, and the tyrosinase-related protein 1 gene, Tyrp1. As both genes encode melanosomal proteins, it has been hypothesized that these mutations permit toxic intermediates of pigment production to leak from melanosomes (23). A study examining glaucoma patients with PDS for DNA sequence variants in TYRP1 did not find an association (24).

Exfoliation Syndrome

Evidence supports the concept that exfoliation is an inherited microfibrillopathy involving transforming growth factor-1, oxidative stress, and impaired cellular protection mechanisms as key factors (Fig. 15.12). In a study in the Icelandic and Swedish populations, a common genetic variant was identified as a major risk factor for exfoliation syndrome and glaucoma (25). Polymorphisms in the coding region of the gene lysyl oxidase-like 1 (LOXL1), located on chromosome 15q24, are associated with exfoliation and exfoliative glaucoma in these and other populations. The disease-associated polymorphisms are found in virtually all individuals with exfoliation within populations studied to date.

LOXL1 is one of many enzymes essential for the formation of elastin fibers: It plays a role in modifying tropoelastin, the basic building block of elastin, and catalyzes the process for monomers to cross-link and form elastin. Although LOXL1 is a major risk factor for exfoliation syndrome and exfoliative glaucoma, evidence suggests that additional genetic or environmental factors will be identified that influence disease expression and severity. One example is a study of white persons in Australia with a ninefold-lower lifetime incidence of exfoliative glaucoma compared with Scandinavian populations that demonstrated a similar allelic architecture at the LOXL1 locus (26). This suggests that unidentified genetic or environmental factors independent of LOXL1 strongly influence the phenotypic expression of the syndrome.

The disease-associated LOXL1 variant is extremely common and is found in up to 90% of affected and unaffected individuals worldwide. For this reason, genetic testing is of limited clinical value at this time (27).

Revisiting Case 2

The discovery of the variants in the LOXL1 gene has the potential to lead to more exact diagnosis, better monitoring of glaucoma suspects, improved knowledge of pathogenesis, and eventually more effective treatment. Despite the importance of the identification of LOXL1 as a major contributor to exfoliation syndrome and exfoliative glaucoma, given the high frequency of disease-associated polymorphisms in the population, DNA testing is not clinically useful at this time.

Systemic Diseases Associated with Glaucoma

A number of ocular disorders that have been linked are associated with open-angle forms of glaucoma as part of their phenotype. These are listed in Table 8.1. In addition, a number of systemic disorders are associated with open-angle forms of glaucoma (e.g., nail-patella syndrome and Marfan syndrome), and those for which the gene has been localized or identified are listed in Table 8.1.

GENETICS AND INSIGHTS INTO DISEASE MECHANISMS

After identifying genes that are causative for glaucoma and genes that contribute to risk factors for glaucoma, we will elucidate disease mechanisms for glaucoma. This will also involve well-established mouse-model systems for glaucoma that will allow studies on specific biochemical pathways that ultimately cause glaucoma (28). To reach an in-depth understanding of role of these genes among these pathways, however, it will be essential to combine the tools of genomics, molecular biology, developmental biology, bioinformatics, and computational biology. This should ultimately lead to a better understanding of the normal physiology of the trabecular meshwork, optic nerve, ganglion cells,

and other glaucoma-relevant tissues. Improved understanding of the state of the eye in disease and health will facilitate the rational development of drugs tailored to specific subtypes of glaucoma. PHARMACOGENETICS, PHARMACOGENOMICS, AND THE PROMISE OF “PERSONALIZED MEDICINE”

Although all this information on genetics may appear daunting to the clinician, it is important to put this genomic technology in perspective. All of this genomic information, and the anticipated proteomic and metabolomic information, will not substitute for solid clinical history-taking skills, observation, assessment, and development of a treatment plan for the individual patient. However, at present, using our clinical acumen, our treatment approach is a trial-and-error approach by recommending a medication, laser, or surgery with an expected optimal treatment outcome. There is great optimism that genetic profiling will help target patients with glaucoma to individualized treatments on the basis of validated disease-risk alleles, validated pharmacogenetic markers, and specific behavioral modification. Thus, one may view these newer technology advances to take the guesswork out of the treatment plan, with

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the expectation of improved efficacy because the optimal treatment is specified for certain individual profiles and for decreased adverse events to treatment because it will not be recommended in a susceptible individual.

It is important to remember, however, that genes merely represent the blueprint to uncover genetic variants in common diseases, and they will not provide “the answer” to the question “What causes glaucoma?” Considerable strides are needed to fully understand factors that affect gene expression, such as DNA methylation, gene repair, copy-number variation, and telomerase action. In addition, proteomics is arguably just as crucial to genomics when looking at normal physiology and disease. For instance, posttranslational modifications, such as glycosylation, adenosine diphosphateribosylation, and phosphorylation, that affect cell function may also contribute to differences in an individual's disease manifestation and response to treatment.

Pharmacogenomic studies could reveal genetic factors that predispose to poor IOP response (Fig. 8.6) as well as to higher-than-average risk for an adverse response—for example, the development of elevated IOP in response to corticosteroid therapy.

The new challenges of genomics, and for the expected technological advances with proteomics and metabolomics, are to determine whether we can predict disease risk, disease progression, and treatment outcome. Despite the intricate biological and physiologic interactions among expression of drug target genes, drug-metabolizing enzymes, and disease genes, an approach to identify genetic markers of “poor IOP responders” has the potential to target patient s with disease to more appropriate treatment, such as surgery, to lower IOP more effectively, thus minimizing progressive optic nerve damage and visual field loss.

The promise of personalized medicine is new abilities to improve on clinical decision making regarding individualized treatment regimens based on the patient's genetic profile. It is equally as important to consider health behaviors—that is, adherence with t reatments—while conducting appropriately designed studies. Lifestyle factors, such as diet, exercise, cigarette smoking, and alcohol use, are all included in the individual health behaviors but have not been extensively studied for glaucoma. The genetic profile would enable the assessment of risk for disease, protective genetic factors, disease progression, and variations in treatment responses of both efficacy and toxicity.

Figure 8.6 Variations in IOP response to glaucoma medical therapy are determined by pharmacokinetic and pharmacodynamic processes (blue arrow) and interaction with the environment, disease, and pathophysiologic processes. The sequence variants among pharmacokinetic and pharmacodynamic genes are predicted to have functional consequences that contribute to the genetic component of variance in IOP response. (Modified from pharmgkb.org, with permission of PharmGKB and Stanford University.)

Revisiting Case 3

Our current knowledge can only begin to answer the patient's question. As our understanding grows about applying genomic results to this potentially blinding disease, clinicians will be expected to be informed about treatments that can be personalized for their patients. These treatments will be based on a patient's genetic profile and will incorporate information on disease risk, disease progression, and the likelihood of individual drug safety and efficacy.

Privacy and Counseling

The fear of genetic discrimination has presented an impediment to the widespread application of personalized medicine. Legislation to protect patients against this risk is essential. An example is the Genetic Information Nondiscrimination Act (GINA), was signed into law in the United States and which offers protection against discrimination based on genetic information when it comes to health insurance and employment (29).

As more widespread genetic testing becomes available, clinicians will need to safeguard these data and also ensure that appropriate genetic counseling is available. The role of the counselor is to be an informer, not an advisor. It will be important to provide the necessary facts and options, so that an informed decision can be made by the patient and his or her caregivers.

Concluding Remarks

Personalized medicine will become a reality through identification of disease and pharmacogenetic markers followed by careful study of how to employ this information for improving

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treatment outcomes. With advances in genomic technologies, research has shifted from the simple monogenic disease model to a complex multigenic and environmental disease model. Our challenges lie in developing risk models incorporating genegene interactions, gene copy-number variations,

environmental interactions, treatment effects, and clinical covariates.

Future approaches to glaucoma therapeutics encompass identification of genetic markers for “non-IOP responders”; problematic wound healing, which affec ts surgical outcomes; and incorporation of the utility of growth factors, stem cells, and other non-pressure-based mechanisms to decrease glaucoma neuropathy.

KEY POINTS

Genetic studies have the ability to

identify risk alleles for disease and predict the chance of developing disease,

identify genetic modifiers of age of onset,

identify genetic modifiers for disease progression,

identify genetic markers of treatment response to glaucoma medications, and

assist with disease classification.

The glaucomas are a complex group of diseases with considerable genetic heterogeneity. Genetic variations have been found that cause glaucoma or are associated with syndromes that include glaucoma, and loci have been identified that affect an individual's potential susceptibility to glaucoma.

There are a large number of mapped locations for COAG, and three genes have been identified (MYOC, OPTN, and WDR36). However, the vast majority of the genetic contribution to this form of glaucoma and angle-closure glaucoma remains to be determined.

The identification of CYP1B1 gene for PCG, responsible for up to half of cases, is a major improvement in our understanding of this devastating disorder.

Future studies in humans will provide an opportunity to correlate genotype to phenotype, while animal studies will continue to unravel the complexity of biochemical networks that cause glaucoma in its various manifestations. This may enable earlier detection, a better understanding of the pathophysiology, and thus natural history of disease, and eventually the institution of more rational, targeted therapy.

Given the five different main classes of drugs for glaucoma therapy, it is important to recognize that genetic variability among the pharmacokinetic and pharmacodynamic pathways may influence responses to these drugs.

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3.Libby RT, Smith RS, Savinova OV, et al. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science. 2003; 299:1578-1581.

4.Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open angle glaucoma. Science. 1997;275:668-670.

5.Sud A, Del Bono EA, Haines JL, et al. Fine mapping of the GLC1K juvenile primary open-angle glaucoma locus and exclusion of candidate genes. Mol Vis. 2008;14:1319-1326.

6.Damji KF, Song X, Gupta SK, et al. Childhood-onset primary open angle glaucoma in a Canadian kindred: clinical and molecular genetic features. Ophthalmic Genet. 1999;20(4):211-218.

7.Inagaki Y, Mashima Y, Fuse N, et al. Polymorphism of beta-adrenergic receptors and susceptibility to open-angle glaucoma. Mol Vis. 2006;12: 673-680.

8.McLaren N, Reed DM, Musch DC, et al. Evaluation of the beta2-adrenergic receptor gene as a candidate glaucoma gene in 2 ancestral populations. Arch Ophthalmol. 2007;125(1):105-111.

9.Aung T, Ocaka L, Ebenezer ND, et al. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum Genet. 2002;110:52-56.

10.Copin B, Brezin A P, Valtot F, et al. Apolipoprotein E-promoter single-nucleotide polymorphisms

affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene. Am J Hum Genet. 2002;70:1575-1581.

11.Hu CN. An epidemiologic study of glaucoma in Shunyi County, Beijing. Chung Hua Yen Ko Tsa Chih. 1989;25:115-119.

12.Tornquist R. Shallow anterior chambers in acute glaucoma. Acta Ophthalmol. 1953;31:1-74.

13.Alsbirk PH. Anterior chamber depth and primary angle-closure glaucoma. II. A genetic study. Acta Ophthalmol (Copenh). 1975;53:436-449.

14.Lowe RF. Primary angle-closure glaucoma. Inheritance and environment. Br J Ophthalmol. 1972;56:13-19.

15.Tu YS, Yin ZQ, Pen HM, et al. Genetic heritability of a shallow anterior chamber in Chinese families with primary angle closure glaucoma. Ophthalmic Genet. 2008;29(4):171-176.

16.Othman MI, Sullivan SA, Skuta GL, et al. Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11. Am J Hum Genet. 1998;63(5):14111418.

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21.Mandelkorn R, Hoffman M, Olander K, et al. Inheritance of the pigmentary dispersion syndrome. Ann Ophthalmol. 1983;15:577-582.

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Shields > SECTION II - The Clinical Forms of Glaucoma >

9 - Clinical Epidemiology of Glaucoma

Authors: Allingham, R. Rand

Title: Shields Textbook of Glaucoma, 6th Edition

Copyright © 2011 Lippincott Williams & Wilkins

> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 9 - Clinical Epidemiology of Glaucoma

9

Clinical Epidemiology of Glaucoma

Glaucoma affects more than 67 million persons worldwide, of whom about 10%, or 6.6 million, are estimated to be blind (1). Glaucoma is the leading cause of irreversible blindness worldwide and is second only to cataracts as the most common cause of blindness overall (1). Glaucoma is responsible for 14% of all blindness (2). In the United States, chronic open-angle glaucoma (COAG) affects more than 2.2 million persons, and this number is projected to increase to 3.4 million by 2020 (3). Over the same time period in the developing world, the prevalence of glaucoma is expected to rise even more dramatically as the population of adults older than 60 years more than doubles (2).

The social and economic impact of glaucoma is enormous but difficult to quantify. Economic data on the cost of glaucoma are also limited. The total direct cost per case of treating newly diagnosed COAG or ocular hypertension for 2 years was estimated to average $2109 in the United States and $2160 in Sweden in 1998 (4). Costs have been shown to be greater for more advanced cases and uncontrolled disease and to increase following trabeculectomy (5, 6). The annual direct costs of glaucoma and ocular hypertension in the United States were estimated at $3.9 billion in 2001 (7); a separate estimate from 1991 put the direct costs of glaucoma (excluding ocular hypertension) at $1.9 billion (8). National per capita estimates are similar for Canada but lower for Sweden and the United Kingdom (5, 9, 10). FUNCTIONAL LIMITATIONS ASSOCIATED WITH GLAUCOMATOUS VISION LOSS

From the perspective of those whose visual function has been severely affected by glaucoma, the impact of the disease can be profound and may include difficulty with reading and writing, activities of daily living (cooking and eating, dressing and bathing, medication management, money management), mobility with increased risk of falls, ability to drive, vocational challenges, social isolation, and depression (11, 12, 13, 14, 15 and 16). As individuals age, the impact of visual dysfunction can be amplified if comorbidities are present. These include hearing loss, arthritis, head tremors, and cognitive impairment. The impact of glaucoma can be quantified by using various vision-targeted and generic health-related quality-of-life measures, but is difficult to predict on the basis of visual function measurements alone. Many factors such as physical health, psychological state, visual demands of daily living, values, adaptability, and social and cultural milieu shape the changing impact of glaucoma on individuals (17). This may explain in part the low correlation between visual field loss in glaucoma and vision-targeted and generic measurements of health-related quality of life (18, 19). Vision-targeted measures of health-related quality of life have found lower scores in glaucoma suspects than in healthy controls and have been successively lower in those with early and moderate and advanced visual field changes (20, 21, 22, 23 and 24); general health-related quality-oflife scores also have been shown to be decreased in persons with glaucoma (20, 21 and 22, 25). In general, these findings support the notion that glaucoma, as the ‘sneak thief’ of vision, caus es subtle symptoms and modestly affects health-related quality of life until the disease is advanced. Interestingly, visual changes associated with glaucoma are often not interpreted as symptoms of a visual problem until after a diagnosis has been made (17). An important consideration in the treatment of glaucoma is that therapy can itself adversely affect quality of life (26, 27). Therapies may be inconvenient or expensive, cause discomfort, or lead to significant ocular and systemic complications.

It has been suggested that strategies aimed at improving an individual's function be tied to socially meaningful outcomes (28). Examples include maintaining functional independence; sustaining meaningful relationships; enhancing one's psychosocial well-being; and being able to access transportation, pursue leisurely activities, and maintain employment and economic productivity. PREVALENCE, INCIDENCE, AND GEOGRAPHIC DISTRIBUTION OF GLAUCOMA

The prevalence of glaucoma has been studied extensively (Table 9.1), but the case definition of glaucoma has varied widely and clinical classification has been inconsistent among studies (52). Intraocular pressure (IOP), the appearance of the optic nerve head, and visual field abnormalities have

all been used in varying combinations to define glaucoma; the status of the iridocorneal angle and the presence or absence of secondary causes are typically used to determine the clinical classification of glaucoma. These differences make it difficult to directly compare the prevalence findings of different studies. There is, however, growing acceptance of the concept that glaucoma is a progressive optic neuropathy characterized by a typical damage to the optic nerve head (cupping) and associated visual dysfunction. Glaucomatous damage to the optic nerve appears to be the final common pathway to a diverse assortment of etiologic factors and clinical subtypes.

There is some discussion in the literature about the value of distinguishing between normal-tension glaucoma and

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COAG on the basis of IOP at presentation. In population-based studies, normal-tension glaucoma has been far more common than expected, accounting for between 40% and 75% of individuals with newly diagnosed COAG based on screening IOP (44, 50, 53). These entities are likely part of a spectrum of disease in which IOP plays an important role, and other factors such as vascular, apoptotic, or connective tissue factors are increasingly important at lower IOP levels (54); they less likely represent distinct varieties of glaucoma.