The mainstream perception that “bookish” kids need to wear glasses may have some grounding in the science of refractive error development. Although refractive errors are believed to be governed largely by genetics (60% to 90%), whereby certain alleles impact one’s predisposition to ametropia when exposed to environmental variables, less than 10% of refractive error is attributed to known genetic variations in the genes responsible for regulating it.1 A new study found that variants of one such gene—called APLP2—set the preconditions for susceptibility to myopia. Extensive near work in childhood then allows myopia to manifest clinically.

Researchers at the Columbia University Medical Center measured refractive error in a cohort of pediatric close readers (relative to controls) over eight years. The prospective study looked at the impact of APLP2 on myopia induction and progression in the presence of environmental factors favorable to the condition. The study, published in PLOS Genetics, suggests that low-frequency variants in downstream segments of APLP2 are responsible for the refractive error susceptibility phenotype. Time spent reading, in combination with these variants was associated with differential degrees of myopia when the cohort was evaluated longitudinally.

Refraction Regulation: Genes and the Environment
We already know that genetic factors govern emmetropization—the process by which the eye regulates power (e.g. focal length) relative to axial length—and that these genes are expressed differentially in response to external cues (e.g, visual cues).2 In other words, the growth of the eye is under homeostatic control. The synchronicity of axial and focal lengths is crucial to maintaining a sharp image on the retina. In cases where they diverge, the scleral tissue of the posterior pole, thickness of the choroid and the vasculature between the retina and sclera grow at unequal rates. As a fundamental developmental property of the eye is the achievement of emmetropia postnatally—the organ develops visual acuity after birth—differential growth is thus crucial to proper function.2

Differential growth rates are mediated by the differential expression of many genes, which in turn are controlled by chemical signals that are also regulated by differential gene expression. If any of the genes responsible for the mediation of homeostatic growth in the eye are altered, corresponding physical changes (e.g., refractive error) may occur.2 The study aimed to make headway in understanding the key players in eye growth homeostasis, of which the specific genomic basis for it is still largely unknown.

The Protocol
Pediatric data from the Avon longitudinal study cohort, consisting of 13,988 pediatric subjects from the United Kingdom, were analyzed for low-frequency variations near and within the APLP2 gene. These variants were then tested for evidence of association with myopia by comparing carriers of the variants within or near APLP2 to longitudinal refractive errors in those subjects over 15.5 years. Refractive error was evaluated by autorefraction every three years between the ages of approximately seven and 15. The variant most strongly associated with development of refractive error was associated with a -0.6D shift. The low frequency of each allele made it hard to causally associate a single allele with refractive error. Rather, because there are a large number of different types of variants within and near the gene, it stands to reason that variation in APLP2 is associated with an increase in refractive error in humans. The authors point out that “further work will be required to pinpoint the causal variants at the APLP2 locus that determine susceptibility to myopia”—the sum of the risk associations of all the variants provide evidence for the role of APLP2 variation in myopia but it is unclear which particular variant is ultimately responsible.

Time spent reading was determined using a questionnaire issued to parents of the study subjects at the age of approximately eight years. Statistical analyses were used to predict the association of close work with development of myopia in children who carried the “riskiest” form of the gene. Readers having read daily between one and three hours were placed in a “high” reading amount category, while those who self-indicated less than one hour of daily reading were categorized in the “low“ reading amount group. Those who identified as having read for longer durations were predicted to show significantly greater myopia relative to those in the “low” reading group, up to -0.6D at 15 years of age. Although gene variants alone were associated with some degree of refractive error, reading time in combination with the gene variants showed a significantly greater association with the development of myopia than the risk associated with the variant alone, 3.44 times more likely vs. 1.98x and 1.61x when carrying the high-risk form or high reading amounts alone, respectively.

Clinical Impact
Andrei Tkatchenko, PhD, assistant professor of ophthalmic sciences at Columbia University’s College of Physicians and Surgeons and lead author of the study, said in a press release that engaging in behaviors in an environment that is favorable to reducing myopia during the critical ages is a practical measure for ensuring refractive health but that, in the future, gene therapy could eliminate myopia.

Jeffrey J. Walline, OD PhD, an associate dean for research at the Ohio state University, agrees. “While genetics play a large role in determining who will become myopic, myopia probably involves several genes. Additionally, since genetic therapies are years away from implementation, this research does not change what I recommend to prevent or slow the progression of myopia,” he says.

“I recommend that parents encourage outdoor activities to decrease the likelihood of myopia onset,” he says, adding that the best evidence for slowing the progression of myopia comes empirically, from soft bifocal or corneal reshaping contact lens wear.

Bill Potter, OD, chief of optometry and contact lens services at Millennium Eye Care in West Freehold, N.J., says that atropine therapy, ortho-k and distance-center multifocal soft lenses may also be of value, and that while they are not perfect, the science surrounding them is developing. He recommends limiting reading sessions and spending time outdoors for every pediatric patient. “A half hour of reading, with breaks in between, is doable,” he says.

Retinal blur and peripheral hyperopic defocus are the prevailing hypotheses for the progression of myopia, according to the study. But little was offered in the way of an explanation as to why staying outdoors might be helpful in preventing myopia. “Unfortunately, we don't know why outdoor time decreases the likelihood of myopia onset,” says Dr. Walline. “Theories include increased light that leads to a biochemical cascade in the retina, resulting in less eye growth, increased vitamin D and more uniform visual demands,” he says. “However, it does not appear to be a trade-off with near work.” 

The discovery of new genes that contribute to ocular diseases and conditions seen routinely in the office is always great news. Further, new research that supports a genes-plus-environment disease manifestation paradigm is always welcome.

But, given the complexity of the underlying etiologies of many of these conditions and our current lack of their complete understanding, adhering to the empiric therapies that have been proven to be effective for their prevention and management remain the prevailing therapeutic indications.

1. Tkatchenko AV, Tkatchenko TV, Guggenheim JA, et al. APLP2 regulates refractive error and myopia development in mice and humans. PLoS genet 2015 Aug;(11)8 [Epub].
2. Wallman J, Winawer J. Homeostasis of eye growth and the question of myopia. Neuron 2012 April 12;(74)1:207.