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Clinical Sciences | ONLINE FIRST

Relationship Among CFH and ARMS2 Genotypes, Macular Pigment Optical Density, and Neuroretinal Function in Persons Without Age-Related Macular Degeneration

Beatrix Feigl, MD, PhD; C. Phillip Morris, PhD; Brian Brown, PhD; Andrew J. Zele, PhD
Arch Ophthalmol. 2012;130(11):1402-1409. doi:10.1001/archophthalmol.2012.1940.
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Objectives  To determine whether there is a difference in neuroretinal function and in macular pigment optical density between persons with high- and low-risk gene variants for age-related macular degeneration (AMD) and no ophthalmoscopic signs of AMD, and to compare the results on neuroretinal function to patients with manifest early AMD.

Methods  Neuroretinal function was assessed with the multifocal electroretinogram for 32 participants (22 healthy persons with no AMD and 10 patients with early AMD). The 22 healthy participants with no AMD had either high- or low-risk genotypes for CFH (rs380390) and/or ARMS2 (rs10490924). Trough-to-peak response densities and peak-implicit times were analyzed in 5 concentric rings. Macular pigment optical density was assessed by use of customized heterochromatic flicker photometry.

Results  Trough-to-peak response densities for concentric rings 1 to 3 were, on average, significantly greater in participants with high-risk genotypes than in participants with low-risk genotypes and in persons with early AMD after correction for age and smoking (P < .05). The group peak-implicit times for ring 1 were, on average, delayed in the patients with early AMD compared with the participants with high- or low-risk genotypes, although these differences were not significant. There was no significant correlation between genotypes and macular pigment optical density.

Conclusions  Increased neuroretinal activity in persons who carry high-risk AMD genotypes may be due to genetically determined subclinical inflammatory and/or histological changes in the retina. Neuroretinal function in healthy persons genetically susceptible to AMD may be a useful additional early biomarker (in combination with genetics) of AMD before there is a clinical manifestation.

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Figure 1. Slow-flash multifocal electroretinogram (mfERG) arrays: hexagonal mfERG stimulus array of 5 concentric rings (A) and mfERG trace arrays showing the results of a representative sample of healthy participants with a high-risk genotype (B) or a low-risk genotype (C) and patients with early age-related macular degeneration (AMD) (D) who demonstrated supernormal, normal, and centrally delayed responses, respectively.

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Figure 2. Mean response densities for rings 1 to 5 of the 3 groups of individuals. These densities demonstrate significantly larger N1-P1 response densities for the healthy participants with high-risk genotypes compared with the healthy participants with low-risk genotypes and the patients with early age-related macular degeneration (AMD) (A). No significant difference was found in P1-implicit times for rings 1 to 5 among the 3 groups, but those were, on average, delayed for ring 1 in the early AMD group (B). Error bars indicate SD. * P ≤ .05.

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Figure 3. Multifocal electroretinogram N1-P1 response densities shown for an individual person of each of the 3 groups. The model suggests that, in stage 1 (subclinical), persons with high-risk genotypes show supernormal responses in rings 1 to 3. As the disease becomes manifest (stage 2), responses decrease to “normal (low-risk)” values, which are more pronounced in the paracentral and pericentral areas (rings 2 and 3) where there are the greatest changes in retinal topography (photoreceptor/bipolar cell loss) in age-related macular degeneration (AMD). In stage 3 of early AMD, neuroretinal responses have decreased further and below normal values, which is reflected in progressive fundus changes (drusen size >125 μm).

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