Glaucoma and Genomic Medicine

Research is bringing clinicians closer to personalized treatment based on risk alleles and the interaction with biological networks and environmental factors.

By Sayoko E. Moroi, MD, PhD, and Julia E. Richards, PhD

Since Pratap Challa, MD, wrote about genetics and glaucoma for Glaucoma Today in 2003,1 investigators have expanded previously successful research to identify more genes associated with this potentially blinding disease. This article updates the ongoing search for genetic markers for glaucoma and genes that contribute to the disease's onset and progression, discusses the shift from a single-gene to a complex disease model, and suggests how genomic testing may help clinicians develop personalized treatments for their patients in the future.

Traditionally, researchers have collaborated with patients, members of patients' families, clinicians, and geneticists to identify genetic markers for diseases. This approach has led to the identification of 70 genes, chromosomal regions containing genes (ie, loci), and alleles that either cause glaucoma or are associated with syndromes encompassing glaucoma (Table 1). The highly penetrant forms of glaucoma associated with these genes include infantile-onset, juvenile-onset, and syndromic glaucoma as well as a very small proportion of the high- and normal-pressure glaucomas. These forms of the disease, however, account for only a small fraction of all the glaucomas that occur.

Studies have also identified loci that affect an individual's potential susceptibility to glaucoma2-5 or influence the severity of the disease.6-8 The "single gene, single disease" hypothesis assumes that the presence or absence of a mutation dictates whether a patient will or will not have disease. This approach, however, fails to identify genetic variations (risk alleles) that influence an individual's likelihood of developing glaucoma, the rate of the disease's progression, and how patients respond to treatment. Clearly, we need to shift from a simple monogenic to a complex multigenic model if we want to understand the genetic complexity of glaucoma2,9 (see The Complex Disease Model of Glaucoma).

The complex genetic model of glaucoma focuses on "nature via nurture,"10 the process by which interactions between biological networks (nature) and the environment (nurture) influence a disease's clinical features and risk factors. These interactions can have variable effects along a disease's continuum depending on when they occur during an individual's life (ie, embryogenesis, organogenesis, development, and senescence).

In complex models of disease, some measurable clinical risk factors are quantitative traits. A well-known and frequently studied quantitative trait of glaucoma is IOP.11-16 Familial studies have demonstrated a high correlation17 and concordance18 between IOP within families. In addition, population studies have shown that IOP is heritable based on familial relationships,20-22 and researchers have identified several loci (by genome-wide association methods)23-26 for higher IOP.

The link between genetics and IOP is not simple, however, because IOP is a complex trait determined by the production of aqueous humor, uveoscleral and trabecular outflow, and episcleral venous pressure. Recently, our colleagues and demonstrated that individuals who have a higher flow of aqueous humor in the morning also have a relatively higher flow at night. These same individuals, however, still maintain a normal circadian rhythm of decreased flow at night. The finding of individual concordance has direct implications for fluctuations in IOP (a known risk factor for glaucomatous progression).27

The challenges we researchers must overcome to expand our knowledge of the genetic basis of glaucoma include (1) adopting a complex disease model and (2) designing and implementing studies that can help us develop personalized treatments.

A greater understanding of glaucoma will no doubt lead to new tests28 that will help us diagnose specific types of the disease and provide more information about its clinical course and prognosis. We could also benefit from tests that identify risk factors, genetic modifiers, and markers that affect individuals' responses to specific treatments (ie, efficacy and unwanted side effects).

Despite the lessons we have learned from clinical trials11-16 as well as a growing understanding of ocular genomics, pharmacology, and the dynamics of aqueous humor, glaucoma continues to blind patients.29,30 We therefore need to improve our ability to detect and treat the disease31 and to expand patients' access to healthcare. Genomics may help us to achieve these goals by facilitating the development of personalized medical treatments.

For the past few years, oncologists have used personalized therapy to improve the early detection and treatment of certain types of breast cancer.32 Their success is the direct result of an interdisciplinary assault that comprised population-based studies, clinical resources, and the translation of basic research into clinical strategies.

Ocular medicine is at the cusp of a similar shift toward personalized therapies. Some novel treatments include antivascular endothelial growth factors,33 gene replacement for specific inherited dystrophies,34 and the delivery of targeted growth factors with encapsulated cell technology.35

Approximately 50% of cases of age-related macular degeneration are attributed to single nucleotide polymorphisms in the complement factor H (CFH),36 LOC387715,37 component 2,38 factor B,38 and HTRA139 genes. Investigators have also identified environmental factors that appear to offer protection against (eg, the use of specific micronutrients40,41) or contribute to (eg, smoking42,43 and increased body mass index43) the disease's progression. Based on these discoveries, ophthalmologists have begun to recommend individualized treatments for certain retinal diseases and to advise patients how they can modify their behavior to reduce the effects of specific environmental risks. Much work remains to be done before we can offer patients similar treatments for glaucoma.

What Now? What Next?
Which risk alleles contribute to the common forms of glaucoma?
This question will be answered by appropriately designed, genome-wide studies of healthy controls and patients with glaucoma. Similar population-based studies helped researchers identify the CFH Y402H allele for age-related macular degeneration.50-51 Individual groups are independently exploring the link between risk alleles and glaucoma, but no collaborative, multicenter, clinical studies are currently underway.

Do genetic modifiers affect the age of onset for various types of glaucoma?
At least two studies have identified a gene that influences the age at which people develop glaucoma. For example, patients with infantile glaucoma appear to have two mutated copies of CYP1B1, an autosomal recessive gene associated with a form of glaucoma that causes high IOP in infants.52 The underlying mechanism of this genetic form of glaucoma is not presently known. A person who has one defective copy of CYP1B1 may be more likely to develop juvenile- and adult-onset open-angle glaucoma at an earlier age than someone who does not have the mutated gene.4

Do genetic modifiers affect the severity of glaucoma?
The ability to determine if patients carry a specific genetic modifier would help clinicians identify the individuals who have the highest risk of developing glaucoma and who would benefit from earlier intervention. Conversely, careful monitoring would likely be appropriate for patients who did not have the marker.

Researchers have found that a mutated tyr gene is associated with the dysgenesis of ocular drainage structures in Cyp1b1-/-transgenic mice.53 This finding in a mouse model is not directly applicable to humans because the same gene modifier has not been found in Saudi Arabian families who carry nonpenetrant CYP1B1.54

Do genetic markers influence the outcome of glaucoma treatments?
Our current approach to treating glaucoma is based on the disease's severity, the presence of comorbidities, the patient's compliance with therapy, the efficacy and adverse effects of drugs, and the cost of treatment. If medical therapy is appropriate, then we evaluate whether a patient is a "responder" or "nonresponder" and monitor him for adverse reactions after an initial trial of the chosen drug. It may be possible to streamline this process by performing pharmacogenomic association studies and using the results to test patients for genetic markers that affect their response to glaucoma medications.55 The technology that could make this possible is the genotyping microarray, also known as a DNA chip.

In 2005, the FDA cleared a DNA microchip for genotyping certain cytochrome P450 alleles known to alter the body's ability to metabolize drugs.56 Altered drug metabolism directly affects therapeutic drug levels that correlate with efficacy and toxicity. For example, increased blood levels of absorbed timolol due to decreased metabolism can lead to cardiac side effects in susceptible individuals.57

Genetic markers may also affect the complex process of wound healing and thus the outcomes of glaucoma surgery.58 It may be possible to test patients for alleles that raise their risk of delayed wound healing, increased scarring, or sensitivity to antifibrotic drugs. Markers associated with wound healing are unlikely to be found on the same genes as risk alleles for glaucoma.59,60 The identification of markers that predict the outcomes of various treatments could, however, take the empiric guesswork out of determining the optimal glaucoma treatment for a given patient59,60 and minimize the complications of glaucoma surgery.61,62

Quigley and Broman project that 60.5 million people worldwide will have glaucoma in 2010, and they estimate that the number of affected individuals will increase to 79.6 million by 2020.30 They also extrapolate that the number of people with bilateral blindness from glaucoma will increase from 8.4 million in 2010 to 11.2 million in 2020.30 These numbers necessitate improvements in clinicians' ability to diagnose glaucoma as well as the development of novel treatments to delay the disease's onset and decrease its severity (Figure 1).

Several caveats apply to the research efforts described herein. Genomic testing platforms must be (1) sensitive and accurate, (2) applicable to common forms of glaucoma across different subpopulations, (3) cost effective, and (4) able to provide valid predictive information about glaucoma's progression, its severity, and the outcomes of treatment.28,63 If we researchers could develop a genomic diagnostic panel that met all of these requirements, we could use its results to develop personalized medical treatment for glaucoma. The large-scale implementation of such therapy might decrease the burden of glaucomatous visual impairment on public health.

The authors acknowledge the assistance of David Murrel for designing the figures in this article.

Sayoko E. Moroi, MD, PhD, is Associate Professor, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor. She may be reached at (734) 763-3732;

Julia E. Richards, PhD, is Professor, Department of Ophthalmology and Visual Sciences and Department of Epidemiology, University of Michigan, Ann Arbor. She may be reached at (734) 936-8966;


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