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38 EW FEATURE February 2011 Pseudoexfoliation July 2012 The "latitude effect" and pseudoexfoliation glaucoma by Faith A. Hayden EyeWorld Staff Writer AT A GLANCE • 99% of people with pseudoexfolia- tion glaucoma have the LOXL1 gene, but 80% of people without the disease have the gene as well • The development of pseudoexfolia- tion glaucoma can be due to environmental factors such as sun exposure and ambient temperature F ew discoveries are as thrilling to physicians as the link between specific genes, and environmental interactions, and the devel- opment of disease. These findings have "real clinical implications," said Louis R. Pasquale, M.D., direc- tor, Glaucoma Service, Massachu- setts Eye and Ear Infirmary, Boston. "Even though you have a gene that predisposes you to a disease that you don't want to get, if you do x, y, and z, you reduce your chances of get- ting that disease." Such is the hope for pseudoex- foliation glaucoma, a blinding disease characterized by the accumu- lation of protein-like fibers within the anterior segment. Although the cause of this type of glaucoma is of- ficially unknown, research over the last few years has illuminated some potential sources. A research group out of Norway discovered the LOXL1 gene variant was associated with exfoliation syn- drome after scanning the genome of 1,000 patients with the disease and comparing it to about 14,000 con- trols. The results were astonishing. An unthinkable 99% of people with pseudoexfoliation glaucoma had the LOXL1 gene. "But the big kicker here is roughly 80% of controls also has this gene variant," Dr. Pasquale ex- plained. "This ratio of 99% to 80% held up in populations around the world when other people went to look for this gene and whether it was associated with exfoliation." Interestingly, the prevalence of the disease varies widely around the world. For example, in China, preva- lence of exfoliation syndrome is 0.5%, yet 80% of that population also has LOXL1. "This says to me one of two things," Dr. Pasquale said. "There are Research shows gene-environmental interaction link to development of disease Source: Maciej Frolow/Brand X Pictures/Getty Images other genes involved, or there must be environmental risk factors for the disease. That's how we began the search for environmental risk factors for this condition." The latitude effect When looking at the disease burden of pseudoexfoliation glaucoma worldwide, Dr. Pasquale and col- leagues noted that countries closer to the equator had a lower preva- lence of the condition. "The farther away you went from the equator, heading toward the North Pole, the prevalence of the disease increased," he said. This is what Dr. Pasquale calls the "latitude effect." A study published in Archives of Ophthalmology (2011 Aug;129(8): 1053-60) by Dr. Pasquale et al. fur- ther examined this latitude effect in the U.S. The study assessed exfolia- tion syndrome by geographic lati- tude tier in the lower 48 states and assigned state-level climatic data such as temperature, elevation, and sun exposure according to patients' residential location. "We looked at whether or not living in the Northern tier was asso- ciated with an increased risk of exfo- liation syndrome or glaucoma after adjusting for age, race, gender, and other potential confounders," he said. "We found on multiple occa- sions now that this latitude effect did hold up." But what's driving this? Could it be vitamin D or perhaps elevation? Maybe, but Dr. Pasquale has some other theories: solar exposure and colder ambient temperatures. "We believe it's sun bouncing off reflective surfaces into the eye that's the major problem," he said. "The sun that's bouncing off of re- flective surfaces into the eye can pass through the cornea and be ab- sorbed by the iris. That's where there are blood vessels that are aligned with elastin. So we think that hav- ing this gene somewhat diminishes the ability for elastin to line the blood vessels over time, plus the ul- traviolet (UV) damage contributes to the formation of the exfoliation ma- terial." The temperature factor is even more compelling. The temperature inside the human body is typically a steady 98.6 degrees Fahrenheit. But there's reason to believe the eye does not hold that heat. "The eye is more exposed to the elements than we can appreciate," Dr. Pasquale explained. "There aren't a lot of blood vessels inside the front of the eye. When it's 32 degrees F outside, the temperature in the front of your eye is probably not 98.6 de- grees. It's not 32 degrees, obviously, but it's somewhere below 98.6 de- grees. The point is this exfoliation material is a heterogeneous group of large molecules that given a colder temperature will want to precipitate out a solution." Dr. Pasquale is currently build- ing an even stronger case to support his hypothesis. The research has yet to be published, but using a vali- dated solar exposure questionnaire, Dr. Pasquale and colleagues found that people who previously were lifeguards during their young adult life had a three-fold risk of exfolia- tion syndrome. Ski instructors had an eight-fold increased risk. "This makes perfect sense with light bouncing off reflective sur- faces," he said. "Light is going to bounce more strongly off of snow than water. Both are reflective but the snow is going to be a stronger re- flector." Prevention or disease modification? If this research proves true, it would be a huge victory in the fight against glaucoma. Physicians will be able to advise the next generation of patients how to protect themselves against the disease. "The most obvious recommen- dation would be sunglasses," he said. "Sunglasses not only protect your eyes from the sun, but they increase