Researchers at the Massachusetts Eye and Ear Infirmary (MEEI) and the Channing Laboratory, Harvard Medical School, report for the first time how two behavioral lifestyle factors together alter the genetic susceptibility to age-related macular degeneration (AMD), associated with the common coding variant in the complement factor H (CFH) gene, Y402H. After controlling for genotype, the modifiable lifestyle factors of smoking and body mass index (BMI) were related to increased risk of AMD. The susceptibility to advanced AMD conferred by this common genetic polymorphism was modified by
BMI, meaning there was a statistically significant interaction between BMI and the Y402H genotype. Although there was no statistical interaction between
smoking and the CFH genotype, both smoking and genotype were independently associated with increased
risk of AMD.
Current cigarette smoking was associated with a fivefold increased risk and high BMI (30 or higher) was associated with a twofold higher risk of AMD. The homozygous risk genotype (CC) plus smoking conferred a tenfold higher risk of AMD, compared with non-smokers with the non-risk (TT) genotype, while the risk genotype plus higher BMI increased risk of AMD almost sixfold. Gene plus environment risk scores provided an area under the receiver operating characteristic (ROC) curve of 0.70-0.75. The attributable risks for the combination of genes and environment were 69 percent to 73 percent. These findings are published online now in the journal Human Heredity.
Subjects in this study were Caucasians who had either advanced AMD (574 people) or no evidence of AMD (280 individuals), based on ocular examination and ocular photographs. DNA samples were obtained from the genetic repository of the Age-Related Eye Disease Study, a National Institutes of Health (NIH) clinical trial for which Johanna M. Seddon, M.D., director of the Epidemiology Unit at MEEI and an associate professor of ophthalmology at Harvard Medical School, was clinic director at MEEI. DNA samples were genotyped at the Broad Institute Center for Genotyping and Analysis, Boston, Mass. and statistical analyses were done in the Epidemiology Unit at MEEI.
"These findings convey an important message. Although we cannot change our genotype, we can alter or modify our risk of getting AMD by controlling our weight and not smoking," said Dr. Seddon. "There is no question that genetic factors play an important role in this disease. However, individuals with the risk genotype may be more motivated to adhere to healthy lifestyles such as not smoking, maintaining a normal weight, getting exercise, eating an antioxidant rich diet, as well as fish, and getting exercise."
AMD is the leading cause of irreversible visual impairment and blindness among persons aged 60 and older. With the elderly population steadily growing, the burden related to this loss of visual function will increase. Limited treatment options exist for the late stages of the disease and prevention remains a promising approach for addressing this public health concern.
Lead author Dr. Seddon and her colleagues have studied the genetics of AMD since 1989, and previously reported that the heritability of AMD is high (46 percent to 71 percent) in a cohort of WWII twins and that both genetic and environmental factors are involved (Arch Ophthalmol 2005), and that there is a familial aggregation (Am J Ophthalmol, 1997), as well as linkage of AMD to several chromosomes (Am J Hum Genetics 2003). A decade ago they reported the increased risk of AMD with cigarette smoking (JAMA 1996). They also reported the increased risk associated with higher body mass index or obesity (Arch Ophthalmol 2003). This article in Human Heredity is the first to combine both of these behavioral factors with genetic risk. Dr. Seddon and her colleagues have also found other cardiovascular risk factors to be related to AMD, including an increased risk with elevated C-reactive protein (JAMA 2004) and a reduced risk associated with fish and omega-3 fatty acid intake (Arch Ophthalmol 2001, 2003, 2006).
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