Glaucoma is sometimes called the "silent thief of sight" because it
slowly damages the eyes and can cause irreparable harm before there is
any vision loss. But this disease is stealthy in more ways than one.
Glaucoma has been known at least since antiquity, and yet, researchers
today still do not know what causes it in most cases. There are
treatments to delay vision loss, but no cure, making it a leading cause
of blindness all over the world.
Glaucoma is a group of diseases that damage the optic nerve, a cable
at the back of each eye that connects it to the brain. It affects more
than 2.7 million people in the United States and more than 60 million
worldwide. There are many forms of the disease, but primary open-angle
glaucoma is the most common form and the most mysterious.
Since January is Glaucoma Awareness Month, it's a good time to ask: Are researchers making progress in solving this mystery?
"Primary open-angle glaucoma remains a black box, but researchers are
pursuing many avenues to investigate the underlying causes. As we
develop a better understanding of the disease process, we hope this will
lead to new, more effective treatments and possibly even preventive
therapies for it," said Hemin Chin, Ph.D., director of the Glaucoma and
Optic Neuropathies program at the National Eye Institute (NEI), part of
the National Institutes of Health.
High-pressure research
If you've ever had an air-puff test, also known as tonometry, then
you may have heard that glaucoma is linked to an increase in eye
pressure, or intraocular pressure. The unique anatomy of the eye, when
combined with other factors, can cause a rise in eye pressure that can
in turn cause some types of glaucoma.

The
eye is filled with fluid that drains through a gap between the cornea
and iris. A build-up of fluid and eye pressure can damage the optic
nerve.
The front of the eye, between the cornea (the eye's front window) and
the iris (the colored part of the eye), is filled with a clear fluid.
This fluid leaves the eye and enters the blood by passing through a gap
at the angle where the cornea and iris meet. The gap is filled with a
sponge-like tissue called the trabecular meshwork, which helps regulate
fluid passage. Sometimes, eye infections, injuries, or certain
medications can narrow the gap and compress this spongy tissue,
producing a rapid buildup of fluid and eye pressure. This is called
angle-closure glaucoma.
In the United States, open-angle glaucoma is more common than
angle-closure glaucoma, affecting about three times as many people. It
has a more gradual course and there are no clear signs of blockage
within the eye's drainage system. Yet, researchers estimate that 50 to
80 percent of people with open-angle glaucoma have eye pressure that is
higher than average. Others have normal pressure or even low pressure.
On the flip side, many people have high eye pressure but never develop
glaucoma.

Dr. Robert Weinreb. Credit: UCSD
"Elevated intraocular pressure is a leading risk factor for primary
open-angle glaucoma," said Robert N. Weinreb, M.D., chair and
distinguished professor of ophthalmology, and director of the Hamilton
Glaucoma Center at the University of California, San Diego (UCSD). "The
higher the intraocular pressure, the more likely the person is to
develop glaucoma and the more likely it is to progress."
Because of these data, medications that lower eye pressure are a
mainstay of glaucoma treatment. In some cases, a doctor may recommend
surgery to increase fluid drainage from the eye. Drugs, surgery, or both
approaches together are often successful at slowing the course of
open-angle glaucoma. The NEI-funded Ocular Hypertension Treatment Study
also found that pressure-lowering eye drops can delay the onset of
glaucoma in people with high eye pressure. But even with medication or
surgery, open-angle glaucoma usually continues to attack the optic nerve
and cause gradual vision loss.
Other clues to glaucoma
There are other risk factors for open-angle glaucoma besides high eye
pressure, and they may provide some clues about what causes it. For
example, age is a clear risk factor. Open-angle glaucoma is rare among
Americans under age 50, but affects nearly eight percent of Americans
over 80.
Other risks come into play long before we grow old and even before
we're born, including our ancestry. Open-angle glaucoma is about five
times more common among African Americans and Mexican Americans compared
to whites, and it has an earlier, more rapid course in African
Americans. Family history also has a strong influence. A person's risk
of developing open-angle glaucoma is about 10 times higher if a parent
or sibling has it, and the risk is higher still if an identical twin has
it.
These data from family and twin studies have prompted researchers to
dig more deeply into the genetics of open-angle glaucoma. It turns out
that sometimes open-angle glaucoma is passed from parent to child due to
defects within a single gene. Eight such genes have been identified so
far, and they tend to cause glaucoma with an early onset, before age 50.
Thanks to these discoveries, there are now genetic tests that can help
people with early-onset glaucoma determine the risk that their children
will inherit the disease.
Unfortunately, it's rare that primary open-angle glaucoma can be
traced to a single cause. In the vast majority of cases, experts
theorize that the risk of the disease is influenced by many small
genetic differences that vary from person to person. Alone, a single
gene probably has a small impact on glaucoma risk.

Dr. Janey Wiggs.
Credit: Massachusetts Eye and Ear Infirmary.
"It's like tossing little pebbles into a pool," said Janey Wiggs,
M.D., Ph.D., associate director of the Ocular Genomics Institute at the
Massachusetts Eye and Ear Infirmary, part of Harvard Medical School in
Boston. "They only have a big impact when a bunch of them are thrown in
together."
The search for glaucoma genes
Dr. Wiggs and other researchers are conducting ambitious studies to
compare the full genetic makeup—or genome—of people who have open-angle
glaucoma to people who are free from the disease. They hope to sort out
all of the suspected genetic differences that put people at risk.
This research began more than 20 years ago. Two of Dr. Wiggs'
colleagues at Harvard—Susan Hankinson, Sc.D., and Louis Pasquale,
M.D.—had begun monitoring for open-angle glaucoma cases and collecting
genetic samples from participants in two large public health studies.
Dr. Wiggs began another genetic study of open-angle glaucoma in 1996,
based on patients seen through the glaucoma service at Massachusetts Eye
and Ear. But progress in these studies was painstakingly slow.
The pace accelerated dramatically with the completion of the NIH-led
Human Genome Project in 2003, and the advent of technology to rapidly
and cheaply decode each person's unique genome. Soon, Dr. Wiggs and her
Harvard colleagues merged their efforts, and began working with
researchers at other sites. In 2012, with funding and additional
guidance from NEI, Dr. Wiggs began leading the NEI Glaucoma Human
Genetics Collaboration (NEIGHBOR). This consortium includes 12
institutions across the U.S., and has collected genetic samples from
about 4,500 patients and about 20,000 (control) individuals without the
disease. Recently, it has been expanded to include a number of other
ongoing studies, and to build a database of genetic and clinical
information on glaucoma cases and controls, called the NEIGHBOR
Heritable Overall Operational Database (NEIGHBORHOOD). There are also
major genetic studies of glaucoma based in the United Kingdom,
Australia, Singapore, and Iceland.
So far, these efforts have uncovered five regions of the genome that
are strongly associated with primary open-angle glaucoma, Dr. Wiggs
said. Within each region, investigators have found specific genes that,
together, form a line-up of suspects believed to contribute to the
disease. "Every gene has its own story, but most of them divide neatly
into two groups," she said. "There are some that impact eye pressure and
others that impact the optic nerve."
Remember the trabecular meshwork, the spongy tissue that regulates
fluid flow out of the eye? At least two of the genes linked to higher
eye pressure and higher glaucoma risk appear to affect the function of
this tissue, Dr. Wiggs said.
Genes affecting the cornea may also have an effect on glaucoma risk,
she said. Many past studies have found that people with thin corneas are
more likely to develop open-angle glaucoma. The NEIGHBOR consortium has
found genetic factors that are associated with both a decrease in
corneal thickness and an increase in the risk of open-angle glaucoma.
Linking genes with other risk factors
Another effort that is yielding data on glaucoma risk is the African
Descent and Glaucoma
Evaluation Study (ADAGES). This NEI-funded study was launched in 2002,
in order to seek explanations for the high prevalence and rapid course
of primary open-angle glaucoma in African Americans. Dr. Weinreb is
leading it in collaboration with his UCSD colleague Linda Zangwill,
Ph.D., and with Jeffrey Liebmann, M.D., at New York University Langone
Medical Center, and Christopher Girkin, M.D., at the University of
Alabama at Birmingham.
Soon after the study began, the researchers found that, compared to
whites, African Americans have thinner corneas and subtle abnormalities
in the visual field that aren't detected with standard diagnostic tests.
(The visual field is the area of space a person can see at a given
instant without moving the eyes.) These abnormalities may be an early
sign of disease. Recently, the study has expanded to include a search
for genetic factors that put African Americans at risk for open-angle
glaucoma.
"By identifying genetic and non-genetic factors associated with
glaucoma in this high-risk population, we hope to develop better means
to diagnose it and detect progression, and improved drug targets that
could benefit all patients," Dr. Weinreb said.
There is likely much more to glaucoma risk than a person's genes.
Lifestyle, environment, and other factors are also believed to play a
role, experts say. Various studies have examined the potential role of
smoking, alcohol, caffeine, fat intake, and exercise in open-angle
glaucoma, but so far, none of these has shown a strong relationship with
the disease. In women, earlier age at menopause has been linked to a
higher risk of the disease. In collaboration with Dr. Pasquale at
Harvard, Dr. Wiggs has found that in women, but not men, open-angle
glaucoma is associated with small variations in genes that regulate the
reproductive hormone estrogen. These findings have led to speculation
that estrogen replacement therapy may help protect older women from
glaucoma, but research on this topic is inconclusive.
"As a community, there's still a lot we don't know about glaucoma,"
Dr. Wiggs said. "However, we've been able to achieve some success by
pooling resources and ideas. I think we will see more rapid progress in
the next few years."
Protecting yourself against glaucoma
Even though the risks of glaucoma aren't fully understood,
remembering these tips can help you protect yourself and your family
against it:
- People at higher risk include African Americans age 40 and older,
everyone over age 60, especially Mexican Americans, and those with a
family history of the disease.
- Because glaucoma often has no symptoms in its early stages, people
at higher risk should have a comprehensive dilated eye exam every one to
two years.
- With early detection and treatment, it is possible to slow progression of the disease and preserve vision.
NEI has more information about how to reduce your risk of vision loss from glaucoma, including this
fact sheet and
video. The NEIGHBORHOOD study is funded by NEI grant
EY022305 and ADAGES is funded by NEI grant
EY023704.