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Vision researchers at Columbia University Medical Center have discovered a gene that causes myopia, but only in people who spend a lot of time in childhood reading or doing other “nearwork.”

Using a database of approximately 14,000 people, the researchers found that those with a certain variant of the gene – called APLP2 – were five times more likely to develop myopia in their teens if they had read an hour or more each day in their childhood. Those who carried the APLP2 risk variant but spent less time reading had no additional risk of developing myopia.

“We have known for decades that myopia is caused by genes and their interactions with environmental factors like reading and nearwork, but we have not had hard proof. This is the first known evidence of gene-environment interaction in myopia,” says the study’s lead investigator, Andrei Tkatchenko, MD, PhD, of CUMC. The research was published August 27 in PLOS Genetics.

Reducing APLP2 activity in eyes could prevent myopia

Although it’s not yet known how genetic variation at the APLP2 gene causes myopia, Dr. Tkatchenko and his colleagues think the risk variant may increase the amount of APLP2 protein produced in the eye, which in turn may cause the eye to undergo excessive elongation.

They found that mice exposed to a visual environment that mimics reading were less likely to develop myopia when little APLP2 protein was present in the eye.

“By reducing the level of APLP2 in the eye, you can reduce susceptibility to environmentally induced myopia. This gives us an opportunity to develop a therapy to prevent myopia in everyone, regardless of the APLP2 variant they carry,” Dr. Tkatchenko says.

The image shows a mouse retina.

An antibody-stained cross section of a mouse retina. Credit: Andrei Tkachenko/Columbia University Medical Cente.

Developing such a therapy, however, could take years, as researchers don’t yet know how APLP2 levels could be reduced in people. And the therapy would be most effective in young children, before the eye has started to elongate and become myopic.

“Once the eye has elongated, you cannot shrink it, so we would need to identify kids with genetic risk factors as they enter school,” Dr. Tkatchenko says. That’s not yet possible because there are probably hundreds of genes that can cause myopia, and so far, only 25 candidates have been identified. The high-risk variant of APLP2 is relatively uncommon, occurring in about 1 percent of the population.

Outdoor time during childhood can reduce risk of developing myopia

Though a drug or gene therapy to prevent myopia may be years away, Dr. Tkatchenko says spending time outdoors is the best way to reduce kids’ risk of developing myopia.

“We pretty much know all the environmental risk factors: time spent reading increases the risk, while time spent outdoors reduces it,” Dr. Tkatchenko says.

Myopia rates have shot up in recent years due to changes in these environmental factors. In the U.S., 44 percent of adults are now nearsighted, up from 25 percent 30 years ago. And in some parts of Asia, 80 percent of young adults are now myopic.

“The critical period for myopia development is during elementary and middle school, so when kids are in school, make sure they also spend at least two hours outdoors each day,” Dr.Tkatchenko says.

Preventing myopia not only reduces the need for vision correction, but also prevents potentially blinding eye conditions later in life.

“People say, ‘What’s so terrible about myopia? You just have to get glasses,’” Dr. Tkatchenko says, “But myopia increases the risk of developing cataracts, glaucoma, and retinal detachment later in life. All of these can lead to blindness.

“Even in people with mild myopia there is a significant risk, but it’s especially high in people who need five or more diopters of vision correction (about 20/400 vision). That’s why it’s important to study myopia.”

About this genetics research

The authors are: Andrei V. Tkatchenko, Tatiana V. Tkatchenko, Jeremy A. Guggenheim (Cardiff University), Virginie J. M. Verhoeven (Erasmus Medical Center), Pirro G. Hysi (King’s College London School of Medicine), Robert Wojciechowski (Johns Hopkins Bloomberg School of Public Health and NIH), Pawan Kumar Singh (Wayne State University), Ashok Kumar (Wayne State University), Gopal Thinakaran (University of Chicago), Consortium for Refractive Error and Myopia, and Cathy Williams (University of Bristol).

Funding: The work was supported by the National Eye Institute of NIH (grants R21EY018902 and R01EY023839), research grants from the Midwest Eye-Banks, and the generous donations from the Acquavella Family Foundation and Joseph Connors.

The CUMC investigators report no conflicts of interest.

Source: Columbia University Medical Center
Image Credit: The image is credited to Andrei Tkachenko/Columbia University Medical Cente
Video Source: The video is available at the Columbia University Medical Center YouTube page
Original Research: Full open access research for “APLP2 regulates refractive error and myopia development in mice and humans” by Andrei V. Tkatchenko, Tatiana V. Tkatchenko, Jeremy A. Guggenheim, Virginie J. M. Verhoeven, Pirro G. Hysi, Robert Wojciechowski, Pawan Kumar Singh, Ashok Kumar, Gopal Thinakaran, Consortium for Refractive Error and Myopia (CREAM), and Cathy Williams in PLOS Genetics. Published online August 27 2015 doi:10.1371/journal.pgen.1005432


Abstract

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10−4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10−3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10−3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10−4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10−4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10−4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10−4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10−4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.

“APLP2 regulates refractive error and myopia development in mice and humans” by Andrei V. Tkatchenko, Tatiana V. Tkatchenko, Jeremy A. Guggenheim, Virginie J. M. Verhoeven, Pirro G. Hysi, Robert Wojciechowski, Pawan Kumar Singh, Ashok Kumar, Gopal Thinakaran, Consortium for Refractive Error and Myopia (CREAM), and Cathy Williams in PLOS Genetics. Published online August 27 2015 doi:10.1371/journal.pgen.1005432

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