Model predicts advanced AMD development

June 15, 2008

A new model can predict the percentage of people who will develop advanced age-related macular degeneration (AMD) at various ages. The model, which is based on well-established risk factors for the disease such as age, smoking, and genetics, considers high-risk, intermediate-risk, and low-risk genotypes. Genotypes are more predictive of the risk of developing advanced AMD than is age.

Boston

-A new model based on well-established risk factors for age-related macular degeneration (AMD) can predict the percentage of people who will develop advanced AMD at various ages. The model considers high-risk, intermediate-risk, and low-risk genotypes. Investigators found that the genotypes of only two AMD genes are more predictive of the risk of developing advanced AMD than age.

 "There have been numerous epidemiologic and genetic studies of AMD that have pointed out the risk factors for AMD-three of which are generally accepted by all groups, namely, age, smoking, and genetics. The last is recently the most newsworthy," said Thaddeus Dryja, MD. He is clinical professor of ophthalmology, Harvard Medical School, Boston, and head of translational medicine in ophthalmology at Novartis.

Seven genes thus far have been associated with AMD. Dr. Dryja demonstrated that the risk ratios of the genotypes vary from about 1.6 for the ERCC6 gene to about 11 for the HTRA1 LOC complex, with 1 being the arbitrary reference genotype. In a clinical setting, however, can this information be translated into the actual risk factor for AMD among individual patients? Dr. Dryja asked rhetorically.

To answer this question, he, Sergej Aksenov, PhD, and colleagues at the Novartis Institutes for BioMedical Research in Cambridge, MA, translated data in the literature into the precise risks for AMD based on an individual's age, smoking status, and two of the primary AMD genes, namely, the complement factor H gene and HTRA1 LOC 387715 gene.

During this process, Dr. Dryja and colleagues surveyed 15 studies of Caucasian patients for whom there were genotypic data on the two loci. The investigators also looked up the prevalence of AMD by age and sex, the prevalence of smoking by age and sex, the relative risk of AMD in individuals who smoke compared with those who do not smoke, and the demographics of the population.

"There were assumptions that we had to make, but I believe that those assumptions were reasonable. The main assumptions were that an individual's genotype at the AMD loci does not influence whether the individual will smoke and that there is no difference in longevity depending on genotype at AMD genes," he said.

Proportion estimated

Based on this work, the researchers were able to estimate for any given age group the actual proportion of people who have advanced AMD, meaning AMD cases with geographic atrophy, choroidal neovascularization, or both. The model demonstrated that for those aged more than 80 years, about 10% will develop advanced AMD regardless of knowledge of any risk factors for the disease. By adding the genotype information, Dr. Dryja and colleagues found that a large range of risks of the development of advanced AMD exists.

“If an individual is among the one in four individuals, smokers and nonsmokers, who have the low-risk genotype, the chance of developing advanced AMD by age 80 or older is less than 5% regardless of sex,” he said. “If an individual is among the one in about 200 individuals who have an unfavorable genotype, the chance of developing advanced AMD by age 80 or older is over 50%.”

Clinically useful

This model is practical for use in a clinical setting, he added. For example, in a patient who is aged 70 or 75 years and has not yet developed advanced AMD but who has the unfavorable genotype, a clinician can counsel the patient that by age 80 or older, an approximate chance of 50% exists for developing the disease.In another example of the usefulness of the model, Dr. Dryja demonstrated the risk of developing advanced AMD among smokers.

“For smokers with the unfavorable genotype, more than 80% of individuals will develop advanced AMD after age 80. On the other hand, in smokers with the favorable genotype, there is a small risk of developing advanced AMD,” he said.

“This is the area where genetic testing might be of value. Smokers who have the unfavorable genotype may be more motivated to stop smoking.”

The investigators found a great deal more variation in risk among smokers compared with risk by sex, Dr. Dryja added.

Genotype more predictive of risk

A noteworthy observation was that genotype was more predictive of the risk of developing advanced AMD than was age, he said.“Perhaps we should refer to the disease as gene-related macular degeneration rather than AMD,” Dr. Dryja said.

“It is possible with the use of this type of model to predict the risk of an individual for developing advanced AMD based on smoking status, sex, and age. The two genotypes that we evaluated are more predictive of advanced AMD than age in predicting the risk,” he said. “Perhaps future AMD therapies might target only those with high-risk genotypes, which might result in a name change of this disease.”OT