Jonathan Haines, Ph.D.
Smoking and genetics raise vision disorder risk
The combination of cigarette smoking and a gene variant on chromosome 10 raises the risk for age-related macular degeneration (AMD) significantly more than either factor alone, according to a study released online recently in The American Journal of Human Genetics.
The report from a team of investigators at Vanderbilt University Medical Center and Duke University Medical Center is one of the first to demonstrate an interaction between a gene and the environment in a common disease, said Jonathan Haines, Ph.D., director of the Center for Human Genetics Research at Vanderbilt.
It also adds to a growing number of findings related to AMD, suggesting that preventive measures for individuals at high risk for the vision disorder may be on the horizon, Haines said.
“I think we're getting to the stage where we can use this information to predict who is likely to develop AMD well before they actually develop it,” he said. “Then we can conduct trials of preventive treatments — something that's never been possible before.”
AMD is a progressive eye condition that affects as many as 10 million people in the United States and is the leading cause of vision loss and legal blindness in people over age 60.
Severe AMD robs affected individuals of the sharp central vision necessary for everyday activities like reading, driving, watching television, safely navigating stairs, and identifying faces. The toll of the disease is expected to mount as the U.S. population ages, Haines said.
Haines and his colleagues were one of three teams which reported last year that a variant of the gene for Complement Factor H (CFH) increases an individual's risk for AMD and accounts for up to 43 percent of the disorder.
The new study confirms that a previously suspected variation in a gene called LOC387715 on chromosome 10 also increases the risk for AMD, and it demonstrates that individuals who have this variant and smoke have an even greater risk of developing the vision disorder. The investigators estimate that CFH, LOC387715 and cigarette smoking together account for 61 percent of AMD cases.
The study population included 1,395 individuals in two groups: a family-based group and a case-control dataset. The investigators used modern genomic technologies and statistical analyses to determine the gene linkage and association with cigarette smoking.
Unlike CFH, which is known to participate in regulating inflammation, LOC387715 is an unknown gene. It was predicted to be a gene based on computer analysis of genome sequences, but it lacks “motifs” that might suggest a biological role. Its interaction with smoking is intriguing, Haines said.
“Nobody really knows what smoking does,” he said. “It's a risk factor for a lot of different diseases. We can hypothesize that cigarette smoke is a direct insult on the cells of the lung, which leads to lung cancer, but how it contributes to eye diseases or Alzheimer's disease is really a mystery.
“These results give us a chance to begin to see what genes smoking is interacting with, which might be important for other diseases in addition to macular degeneration.”
An obvious next task, he said, is for investigators to examine the function of LOC387715 at the molecular level, particularly in light of the role it may play in smoking-associated pathways leading to AMD.
The speed of discovery in the area of AMD genetics is “amazing,” Haines said, and makes it possible to test ideas for preventing or at least slowing the development of AMD.
“There are all kinds of hypotheses for treatments — sometimes as simple as dietary changes — that might prevent vision loss if they were given before the degeneration started,” he said. “Now we potentially have a way of screening for patients at high risk of developing AMD and doing early intervention trials.”
It should also be possible to reduce the impact of the LOC387715 gene variant on the aging population by public health efforts such as smoking prevention and smoking cessation programs, he added.
Vanderbilt co-authors include Anita Agarwal, M.D., of the Vanderbilt Eye Institute, Kylee Spencer, and Nathalie Schnetz-Boutaud, Ph.D. The research was supported by the National Eye Institute, the National Institute on Aging, and a General Clinical Research Center Award to Vanderbilt University.