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Dimple Modi, Carlos Alexandre A. Garcia Filho, Zohar Yehoshua, Kang Zhang, Li Zhang, Giovanni Gregori, William Feuer, Philip J. Rosenfeld; Influence Of Genetics On Baseline Characteristics And Disease Progression In Dry AMD. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3322.
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To evaluate the role of genetics on baseline characteristics and disease progression in eyes with dry age-related macular degeneration (AMD).
Two cohorts of dry AMD patients were enrolled in the COMPLement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-Related Macular Degeneration (COMPLETE) Study. Cohort-1 was comprised of eyes with drusen in the absence of GA, and the drusen had a volume of at least 0.03 mm3 within a 3 mm diameter circle centered on the fovea based on SDOCT imaging. Cohort-2 was comprised of eyes with GA measuring from 1.25 mm2 to 18mm2 based on SDOCT fundus imaging. Ophthalmologic exams, ETDRS visual acuity testing, and SDOCT were performed at baseline and at follow-up months 3, 6, 9, and 12. SDOCT system was used to generate an OCT fundus image (OFI) and drusen volume maps. SDOCT images were obtained using the 200x200 scan pattern with the Cirrus instrument. The OFI was manually outlined by two independent graders, and a consensus image was used for quantitation. Genetic testing for 7 single-nucleotide polymorphisms (SNP) was performed in all patients, and the prevalence of the following [alleles] was assessed: C5-rs17611 [G], CFH-rs1061170 [C], C3-rs2230199 [G], CFH-rs2274700 [C], HTRA1-rs10490924 [T], CFB-rs641153-R32Q [G] C2-rs9332739-E318D [G]. Statistical analysis was performed using the Armitage test of trend in proportions, analysis of variance, and Pearson’s correlation.
A total of 60 patients were enrolled in the study, 30 in each cohort. The drusen cohort had a higher prevalence of at-risk HTRA1-rs10490924 alleles than the GA cohort (p=0.034). In total, the drusen cohort averaged 5.8 (SD=0.5) SNPs with at risk alleles per patient compared to 5.3 (SD=1.4) for the GA cohort (p=0.095). At baseline, neither the areas of GA (p=0.37, r=0.17) or the drusen volume (p=0.87, r=-0.03) measured by SDOCT were associated with the number of at-risk alleles. Whether a particular locus was homozygous or heterozygous (all p >0.05) was not associated with the area of GA or the volume of drusen. Examination of the correlations between genotypes and disease progression are currently underway.
The drusen cohort had a higher prevalence of at-risk alleles than the GA cohort, suggesting that a drusen phenotype represents a more genetically homogeneous population compared with GA phenotype, which may represent a mixture of diseases with a similar end-stage phenotype. This is noteworthy when designing future AMD studies to investigate treatments that target specific at-risk genotypes.
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