Complement factor H 402H variant and reticular macular disease

Abstract

Objective: To determine the association of high-risk alleles in the complement factor H (CFH; Y402H, rs1061170) and age-related maculopathy susceptibility (ARMS2; A69S, rs10490924) genes with reticular macular disease (RMD), a major clinical subphenotype of age-related macular degeneration (AMD).

Methods: Using retinal images from the Columbia Macular Genetics Study, we identified 67 subject individuals with RMD. A comparison group of 64 subjects with AMD without RMD was matched by ethnicity, age, sex, and AMD clinical stage.

Results: In the RMD group, 53 of 67 subjects (79.1%) were female, the mean age was 83 years, and 47 of 67 (70.1%) had late AMD, with closely matched values in the non-RMD group. The frequencies of the CFH 402H allele were 39.6% in the RMD group (53 of 134 individuals) and 58.6% in the non-RMD group (75 of 128 individuals) (χ(2) = 8.8; P = .003; odds ratio, 0.46 [95% confidence interval, 0.28-0.76]). The corresponding frequencies of the risk allele for ARMS2 were 44.0% (40 of 128 individuals) and 31.3% (40 of 128 individuals), respectively (χ(2) = 4.0; P = .045; odds ratio, 1.73 [95% confidence interval, 1.04-2.90]). Homozygosity for 402H was particularly associated with the absence of RMD, occurring in 8 of 67 subjects (11.9%) with RMD vs 24 of 64 subjects (37.5%) without RMD (P < .001). Retinal macular disease also was associated with hypertension among male patients.

Conclusions: The AMD-associated CFH 402H risk variant is significantly associated with the absence of RMD but enhanced risk for RMD is conferred by the ARMS2 69S AMD risk allele. These results are consistent with the hypothesis that 402H may confer a survival benefit against certain infections, some of which may cause RMD.

Clinical relevance: Reticular macular disease may be genetically distinct from the rest of AMD.

Figure

Macula of a 79-year-old woman from the Columbia Macular Genetics Study with early-stage age-related macular degeneration (ie, large soft drusen) accompanied by reticular macular disease (RMD). A, Near infrared image reveals the characteristic hyporeflectant reticular pattern of RMD in the peripheral macula. The central soft drusen are hyperreflectant. White arrows point to the location of the registered spectral domain optical coherence tomography (SD-OCT) sections. B, The autofluorescence image reveals the characteristic hypoautofluorescent reticular pattern of RMD in the peripheral macula. Some of the central soft drusen are hyperautofluorescent. The quality of the image is slightly decreased by cataract. C, The red-free image demonstrates the characteristic reticular pattern of reticular pseudodrusen (RPD). D and E, The SD-OCT scans reveal the apparent deposits of RPD in the subretinal space (blue arrows) and ordinary large soft drusen below the retinal pigment epithelium (white arrows).