The phenotypic analysis of patients with age-related macular degeneration indicates that peripheral reticular pigmentary change is the only phenotypic feature that correlates significantly with the CFH Y402H variant.
Durham, NC-An extensive phenotypic analysis of the complement factor H (CFH) variant Y402H in age-related macular degeneration (AMD) indicates that peripheral reticular pigmentary change is the only phenotypic feature of the 34 features investigated that correlates significantly with the CFH variant Y402H, according to R. Keith Shuler Jr., MD.
Because of the recent association between the CFH Y402H variant and AMD, Dr. Shuler, Eric A. Postel, MD, and associates examined the phenotypes of AMD patients, both carriers and non-carriers of the CFH variant. The study was a case series conducted at Duke and Vanderbilt universities. The data set contained 956 unrelated cases with grade 3 or worse AMD. The main outcome measure was the presence or absence of 34 phenotypic features. Dr. Shuler is vitreoretinal fellow and clinical associate in the Eye Center and the Center for Human Genetics and Dr. Postel is associate professor of ophthalmology, Duke University, Durham, NC.
Each patient underwent a complete ophthalmic examination that included a slit-lamp examination, biomicroscopy, and indirect ophthalmoscopy of the periphery of the retina. Each participant underwent a minimum of three standard fields of 35-mm color photographs and stereo photographs of the disc and the macula, according to Dr. Shuler.
The AMD phenotypes of 796 carriers who possessed the CFH Y402H variant were analyzed for association with any of the phenotypic characteristics and then were compared with the phenotypes of 160 non-carriers, who lacked the Y402H variant. With 34 comparisons, a p value less than 0.001 indicated statistical significance.
"In our sample, the number of carriers was nearly five times the number of non-carriers," Dr. Shuler said. "The groups were similar in mean age, gender, mean EDTRS visual acuity, and the distribution of stage 3, 4, and 5 AMD cases."
The difference in AMD grade between eyes in a single individual very nearly reached statistical significance, he said.
"We attributed this to the asymmetric natural history of AMD between eyes in a single patient and to the fact that patients often present at the time of vision loss in one eye," Dr. Shuler added.
The most noteworthy finding of this study was that, of the 34 phenotypic features analyzed, only the peripheral reticular pigmentary change correlated significantly with the CFH variant (p = 0.0006), Dr. Shuler reported.
"As the number of risk alleles increased, the proportion of AMD cases with peripheral reticular pigmentary change also increased in a dose-response fashion," he said.
Peripheral reticular pigmentary change is characterized by a reticular pattern of hyperpigmented changes. Anecdotally, this is often prominent in the nasal retina, according to Dr. Shuler.
"Considering these data, we can conclude that the CFH Y402H variant is associated with peripheral reticular pigmentary change, which suggests that AMD changes are not limited to the macula," Dr. Shuler said. "The current AMD grading methods assess only the macula. Consideration should be given to including peripheral retinal changes. Phenotypes that suggest a high-risk genotype may prove valuable for diagnostic, prognostic, therapeutic, and research purposes."
Peripheral findings important
The currently used classification schemes ignore extramacular AMD variations.
"However, peripheral findings are clearly important," Dr. Shuler said.
Dr. Postel and his colleagues reported another example of the importance of peripheral retinal findings: peripheral drusen were found to be the only statistically significant phenotypic difference between singleton and multiplex probands with grade 3 or worse AMD.
"One susceptibility gene does not account for all the signs of AMD. Instead, interactions between multiple genes as well as dietary and environmental factors in the setting of the aging process all contribute to the phenotype," Dr. Postel said. "This may explain why, despite the significant correlation between the CFH Y402H variant and peripheral reticular pigmentary change, nearly half of the patients with two risk alleles did not demonstrate peripheral reticular pigmentary change.
"Our study represents only a point in time for each patient and it is unknown when peripheral reticular pigmentary changes initially present," he continued. "It is possible that more patients in this study eventually may develop this finding.
"Because the macula may be more prone to environmental effects due to anatomic, metabolic, optical, and vascular factors, peripheral changes may represent a more global retinal dysfunction with a genetic etiology compared with central findings alone. Improved characterization of the phenotype/genotype relationship in AMD may provide insights into the molecular mechanisms of the different subtypes of AMD and make the investigation of non-genetic components more straightforward," he concluded.