Study Links Genes to Common Forms of Glaucoma

ScienceDaily (Apr. 26, 2012) - Results from the largest genetic study of Glaucoma, a leading cause of blindness and vision loss worldwide, showed that two genetic variations are associated with primary open angle Glaucoma (POAG), a common form of the disease. The identification of genes responsible for this disease is the first step toward the development of gene-based disease detection and treatment.

About 2.2 million people in the U.S. have Glaucoma. POAG is often associated with increased eye pressure but about one-third of patients have normal pressure Glaucoma (NPG). Currently, no curative treatments exist for NPG.

Researchers including lead author Janey Wiggs, M.D., Ph.D., and Lou Pasquale, M.D., Co-Directors of the Harvard Glaucoma Center of Excellence, analyzed DNA sequences of 6,633 participants, half of whom had POAG. Participants were part of two NIH-funded studies: GLAUGEN (Glaucoma Genes and Environment) and NEIGHBOR (NEI Glaucoma Human genetics collaBORation), conducted at 12 sites in the United States. Dr. Pasquale is Director of the Glaucoma Service at Mass. Eye and Ear.

The results, reported online in PLoS Genetics (April 26, 2012), found that two variations were associated with POAG, including NPG. These are the first variants commonly associated with NPG. One variant is in a gene located on chromosome 9 called CDKN2BAS whereas the other variant is in a region of chromosome 8 where it may affect the expression of genes LRP12 or ZFPM2. These genes may interact with transforming growth factor beta (TGF-beta), a molecule that regulates cell growth and survival throughout the body. Previous studies have also implicated TGF-beta in Glaucoma.

"This research has provided important new insights into the disease pathogenesis and will make future studies focused on translating this information into the clinic possible. Ultimately we hope to prevent blindness caused by this very common eye disease," said lead author Dr. Wiggs.

"This study has identified an important molecular pathway in the development of POAG. Control of TGF-beta might lead to more effective therapies for this blinding disease," said Dr. Hemin Chin, associate director for Ophthalmic Genetics at the National Eye Institute.

Funding sources for this research include the National Eye Institute, National Human Genome Research Institute, Lions Eye Research Fund, Glaucoma Center of Excellence, the Margolis Fund, and Research To Prevent Blindness.

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Glaucoma as Neurologic Disorder Rather Than Eye Disease?

ScienceDaily (Mar. 7, 2012) - A new paradigm to explain Glaucoma is rapidly emerging, and it is generating brain-based treatment advances that may ultimately vanquish the disease known as the "sneak thief of sight." A review now available in Ophthalmology, the journal of the American Academy of Ophthalmology, reports that some top researchers no longer think of Glaucoma solely as an eye disease. Instead, they view it as a neurologic disorder that causes nerve cells in the brain to degenerate and die, similar to what occurs in Parkinson disease and in Alzheimer's. The review, led by Jeffrey L Goldberg, M.D., Ph.D., assistant professor of ophthalmology at the Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, describes treatment advances that are either being tested in patients or are scheduled to begin clinical trials soon.

Glaucoma is the most common cause of irreversible blindness worldwide. For many years, the prevailing theory was that vision damage in Glaucoma patients was caused by abnormally high pressure inside the eye, known as intraocular pressure (IOP). As a result, lowering IOP was the only goal of those who developed surgical techniques and medications to treat Glaucoma. Creating tests and instruments to measure and track IOP was crucial to that effort. Today, a patient's IOP is no longer the only measurement an ophthalmologist uses to diagnose Glaucoma, although it is still a key part of deciding how to care for the patient. IOP-lowering medications and surgical techniques continue to be effective ways to protect Glaucoma patients' eyes and vision. Tracking changes in IOP over time informs the doctor whether the treatment plan is working.

But even when surgery or medication successfully lowers IOP, vision loss continues in some Glaucoma patients. Also, some patients find it difficult to use eye drop medications as prescribed by their physicians. These significant shortcomings spurred researchers to look beyond IOP as a cause of Glaucoma and focus of treatment.

The new research paradigm focuses on the damage that occurs in a type of nerve cell called retinal ganglion cells (RGCs), which are vital to the ability to see. These cells connect the eye to the brain through the optic nerve.

RGC-targeted Glaucoma treatments now in clinical trials include: medications injected into the eye that deliver survival and growth factors to RGCs; medications known to be useful for stroke and Alzheimer's, such as cytidine-5-diphosphocholine; and electrical stimulation of RGCs, delivered via tiny electrodes implanted in contact lenses or other external devices. Human trials of stem cell therapies are in the planning stages.

"As researchers turn their attention to the mechanisms that cause retinal ganglion cells to degenerate and die, they are discovering ways to protect, enhance and even regenerate these vital cells," said Dr. Goldberg. "Understanding how to prevent damage and improve healthy function in these neurons may ultimately lead to sight-saving treatments for Glaucoma and other degenerative eye diseases."

If this neurologically-based research succeeds, future Glaucoma treatments may not only prevent Glaucoma from stealing patients' eyesight, but may actually restore vision. Scientists also hope that their in-depth exploration of RGCs will help them determine what factors, such as genetics, make some people more vulnerable to Glaucoma.

http://www.sciencedaily.com/releases/2012/03/120307094659.htm

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Detecting Glaucoma Before It Blinds

Early detection and diagnosis of open angle Glaucoma important so that treatment can be used in the early stages of the disease developing to prevent or avoid further vision loss. Writing in a forthcoming issue of the International Journal of Medical Engineering and Informatics, researchers in the US have analyzed and ranked the various risk factors for open angle Glaucoma so that patients can be screened at an earlier stage if they are more likely to develop the condition.

Glaucoma is one of the main leading causes of blindness; it is a progressive and irreversible disease. Of the various forms of Glaucoma, open angle Glaucoma (OAG) is the most common and can cause the most damage. Unfortunately, unless a patient is undergoing regular screening from about the age of 40 years because of a family history, it is otherwise difficult to detect until substantial and irreversible vision loss has occurred. Glaucoma is the third leading cause of blindness worldwide and the second leading cause of blindness in the USA.

Now, Duo Zhou and colleagues at the University of Medicine and Dentistry of New Jersey, Newark, have used statistical collinearity analysis to evaluate risk factors for OAG, and logistic regression models to identify a minimum set of such risk factors for prognosis and diagnosis of the disease. Their study was based on more than 400 patients with subtle or severe vision problems who attended hospital. It reveals the relative risk of being a smoker, age, visual "field test" results, presence of a localized notch or thinning of the neuroretinal rim identified during standard eye examination, cup to disk ratio (a measure of restriction of the optic nerve at the back of the eye) and other factors.

The data are complex and separating out predictors from diagnostic factors was difficult, the team admits. However, they suggest that family history, medical history, current medications, geographic location, visual field test and ocular examination must all be considered in diagnosis and prognosis for OAG. They have excluded certain factors from the OAG prognosis: gender, race, family history of Glaucoma, diabetes mellitus, hypercholesterolemia, thyroid disease, migraine, Reynaud's disease and myopia as these have no direct effect on OAG development.

As revealed in the analyses, the odds of developing OAG will be increased by 91% with an increase in the Cup-to-Disc ratio of 0.1. Risk increases by 3% annually by age but decreases by 31% for every dB increase of mean deviation of Humphrey visual field. The odds of developing OAG will be 4.36 higher for patients with abnormal Humphrey visual filed overall test, 7.19 higher in patients with localized notch or thinning of the neuroretinal rim. Interestingly, patients with a smoking history seem to be less likely to develop OAG as compared to those with smoking history; although there are many smokers with OAG. Oddly, because of the location of the study, the team can also say that patients living in Atlantic/Quebec will be 73% less likely to develop OAG compared to their fellow Canadians in Ontario.

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New Glaucoma Test Allows Earlier, More Accurate Detection

Cumbersome Glaucoma tests that require a visit to the ophthalmologist could soon be history thanks to a home test developed by a UA engineer.

Phoenix ophthalmologist Dr. Gholan Peyman demonstrates a prototype Glaucoma test instrument that's noninvasive and simpler to use than current procedures. It can also be used in situations that are difficult or impossible with current tests. (Credit: Image courtesy of University of Arizona College of Engineering)

The self-test instrument has been designed in Eniko Enikov's lab at the UA College of Engineering. Gone are the eye drops and need for a sterilized sensor. In their place is an easy-to-use probe that gently rubs the eyelid and can be used at home.

"You simply close your eye and rub the eyelid like you might casually rub your eye," said Enikov, a professor of aerospace and mechanical engineering. "The instrument detects the stiffness and, therefore, infers the intraocular pressure." Enikov also heads the Advanced Micro and Nanosystems Laboratory.

While the probe is simple to use, the technology behind it is complex, involving a system of micro-force sensors, specially designed microchips, and math-based procedures programmed into its memory.

Enikov began working on the probe four years ago in collaboration with Dr. Gholan Peyman, a Phoenix ophthalmologist. "We went through several years of refinement and modifications to arrive at the current design," Enikov noted.

The National Science Foundation has funded the work, and Enikov and Peyman now are seeking investors to help fund final development and commercialization of the product.

In addition to screening for Glaucoma, an eye disease that can lead to blindness if left untreated, the device corrects some problems with the current procedure, and can be used to measure drainage of intraocular fluid.

"Eye pressure varies over a 24-hour cycle," Enikov said. "So it could be low at the doctor's office and three hours later it might be high. With only a single test, the doctor might miss the problem. Having the ability to take more frequent tests can lead to earlier detection in some cases."

Once the diagnosis is made, several treatments are available. The question then is: How effective are they? Patients could use the probe at home to trace how much the pressure decreases after using eye drop medications, for instance.

"One of the reasons pressure builds up in the eye is because fluid doesn't drain properly," Enikov noted. "Currently, there are no methods available to test drainage."

Current tests require applying pressure directly to the cornea, but only very light pressure is safe to use, and it doesn't cause the fluid to drain.

"Our technique allows us to apply slightly greater pressure, but it's still not uncomfortable," he said. "It's equivalent to rubbing your eye for a brief period to find out if the pressure changes. If it does, we know by how much and if there is a proper outflow of intraocular fluid."

Sometimes, a surgical shunt is used to help fluid drain from the eye. "The problem with Glaucoma shunts is they can plug up over time," Enikov noted. "Or if they're not properly installed, they may drain too quickly. So you would want to know how well the shunt is working and if it is properly installed. Our device could help answer those questions."

In another scenario, certain patients cannot be tested for Glaucoma using currently available procedures. "If a patient had cataract surgery or some other surgery through the cornea, the cornea sometimes thickens," Enikov said. "The cornea's structure is different, but our test remains accurate because it's not applied to the cornea."

Instead, it presses the entire eyeball, much as you might press a balloon to determine its stiffness.

"The innovation with our device is that it's noninvasive, simpler to use and applies to a variety of situations that are either difficult to address or impossible to test using the current procedures," Enikov said. "That's why we're so excited about this probe. It has great potential to improve medical care, and significant commercial possibilities, as well."

http://www.sciencedaily.com/releases/2011/01/110104101331.htm

The above story is reprinted from materials provided by University of Arizona College of Engineering. The original article was written by Ed Stiles.

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Glaucoma, the silent thief...

When it comes to whether or not you will develop exfoliation syndrome (ES) -- an eye condition that is a leading cause of secondary open-angle glaucoma and increased risk of cataract as well as cataract surgery complications -- age, gender and where you live does matter.

"Although many studies from around the world have reported on the burden of the disease, some aspects of the basic descriptive epidemiologic features, which may help shed light on the cause, are inconsistent," said Louis Pasquale, M.D., study co-author and director of Massachusetts eye and Ear's glaucoma Center of Excellence. "In this study we found that women are more vulnerable to this disease then men, that ES is not a disease of Norwegian descent, and that where you live does matter when it comes to developing the disease."

Researchers from the Mass. eye and Ear, Harvard Medical School, Boston, Mass., Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, Mass., Department of Ophthalmology and Visual Sciences, and University of Michigan, Ann Arbor, Mich., set out to find out how demographic and geographic risk factors are associated with ES. Their study, the "Demographic and Geographic Features of Exfoliation glaucoma in two United States-Based Prospective Cohorts" is published in the January 2012 issue of Ophthalmology.

Researchers used data from 78,955 women in the Nurses' Health Study (NHS) and 41,191 men in the Health Professionals Follow-up Study (HPFS) residing throughout the continental United States who were prospectively followed for 20 years or more and who provided lifetime residence information to examine the descriptive epidemiologic features of ES or exfoliation glaucoma suspect (EGS).

This study confirmed established associations with age and family history and exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS), as well as provided new data on associations with gender, eye color and ancestry. "Importantly, those with a lifetime residential history of living in the middle tier and south tier of the United States was associated with 47% and 75% reduced risks, respectively, compared with living in the northern tier, and across the life span, residence at age 15 was the most strongly associated with risk, followed by current residence," the authors wrote.

The study showed an increased risk in females, but it was unclear as if gender-specific differences in the eye, such as axial length differences or environmental factors related to lifestyle, account for why women are more at risk for this disease.

Other findings include:

• A positive family history of glaucoma was associated with a more than doubling of risk.


• Neither Scandinavian decent nor Southern European ancestry was associated with risk when compared with the larger reference group of mainly other white persons in the study, which indicates that there may be strong environmental factors that may increase risk among populations in Scandinavian countries. Overall the study lacked adequate power to determine whether incidence rates differed by minority groups.


• Iris ( eye) color did not seem to be a risk factor.

"This large prospective cohort study demonstrates that there is a positive association between latitude and ES risk that is robust and not related to demographic features or other systemic covariates," Dr. Pasquale explained. "Another manuscript we published recently suggests that lower ambient temperature interacts with increased solar exposure to increase the risk of ES. This new work demonstrates a relation between increasing latitude and a condition with a strong predisposition to glaucoma. More work is needed to determine how environmental factors conspire to contribute to ES."

According to the National eye Institute, ES is the major known cause of open-angle glaucoma, and is one of the leading causes of blindness. With the rapid aging of the U.S. population, the number of individuals affected by the disease will increase to more than three million by 2020.

ScienceDaily (Jan. 1, 2012) —

http://www.sciencedaily.com/releases/2012/01/120101143342.htm

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