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Michael A. Grassi, MD; James C. Folk, MD; Todd E. Scheetz, PhD; Christine M. Taylor, BS; Val C. Sheffield, MD, PhD; Edwin M. Stone, MD, PhD

Arch Ophthalmol. 2007;125(1):93-97.

Objective  To determine the histidine frequency in patients with the cuticular drusen phenotype of age-related macular degeneration (AMD).

Methods  Fifty individuals were identified who met the criteria for the cuticular drusen phenotype using a standard threshold photograph. We genotyped DNA samples using a polymerase chain reaction–based restriction digest assay. Seven hundred individuals with typical AMD and 252 controls were also genotyped. Fisher exact test was used to analyze the significance of allele frequency differences.

Results  The histidine variant was present in 70% (frequency ± SE, 0.70 ± 0.05) of the cuticular cohort, 55% (frequency ± SE, 0.55 ± 0.01) of the more typical AMD cases, and 34% (frequency ± SE, 0.34 ± 0.02) of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = .003; odds ratio, 2.0; 95% confidence interval, 1.21-3.07; vs AMD cases P<.001; odds ratio 4.54; 95% confidence interval, 2.79-7.50; vs controls). Genotype distribution between the 3 groups was similarly significant (P<.001).

Conclusion  The cuticular drusen phenotype is highly associated with the Tyr402His variant of the complement factor H (CFH) gene. The significantly higher histidine allele frequency in this group compared with the typical AMD cohort suggests that the complement cascade may play a greater role in the pathogenesis of the cuticular drusen subtype than in AMD as a whole.

Clinical Relevance  The c.1204T>C, p.Tyr402His allelic variant in the CFH gene is associated with a 3-fold increased risk for AMD. A high frequency of the histidine allele has also been noted in patients with membranoproliferative glomerulonephritis type II.

Author Affiliations: Departments of Ophthalmology and Visual Sciences (Drs Grassi, Folk, Scheetz, Sheffield, and Stone and Ms Taylor) and Pediatrics (Dr Sheffield), Carver College of Medicine, University of Iowa, Iowa City; Heed Ophthalmic Foundation, Cleveland, Ohio (Dr Grassi); Center for Bio-informatics and Computational Biology, Iowa City (Drs Scheetz, Sheffield, and Stone); Howard Hughes Medical Institute, Chevy Chase, Md (Drs Sheffield and Stone); and Carver Family Center for Macular Degeneration, Iowa City (Drs Folk, Scheetz, Sheffield, and Stone).

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