Genotype Analysis for Single Nucleotide Polymorphisms Profile of Eyes with Vascularized Pigment Epithelial Detachment due to AMD

Abstract

Purpose: To compare the single nucleotide polymorphisms (SNPs) profile for eyes with a vascularized pigment epithelial detachment (vPED) due to age-related macular degeneration (AMD) with 1) Control 1: eyes without AMD (AREDS Severity Scale zero), and 2) Control 2: eyes with drusen (AREDS Severity Scale 2), as well as 3) to compare the SNPs profile of high responders with low responders.

Methods: Blood samples obtained from 39 eyes (39 patients) with vPED treated with either 0.5 or 2.0 mg ranibizumab were sent to the Institute of Genomic Medicine, Shiley Eye Center, UCSD for SNPs-specific genotype analysis. The analyses included: 1) Comparison of variant allele frequencies (VAF) of 23 SNPs with known association with AMD in 39 vPED eyes with the VAF in 184 Control 1 eyes, 2) Comparison VAF of 23 SNPs associated with AMD in same 39 eyeswith the VAF in 85 Control 2 eyes, and 3) Comparison of SNPs of high responders (≥ 50% decrease of PED height or ≥ 10 letter gainers) (HR-50%) with low responders, and comparison of SNPS of high responders (≥ 75% decrease of PED height or ≥ 10 letter gainers) (HR-75%) with low responders. P ≤ 0.05 was considered significant.

Results: 1) 1st analysis: Following SNPs were significantly associated with vPED eyes vs. eyes without AMD: VEGF rs943080 (P=0.05), CFH rs1061170 (p=0.02), CFH rs2274700 (p=0.001), APOE rs4420638 (p=0.005), HTRA1 rs10490924 (0.005), CFH rs10737680 (p=0.002), and CFH rs10801555 (p=0.02). 2) 2nd analysis: Following SNPs were significantly associated with vPED eyes vs. eyes with drusen and dry AMD: COL15A1/TGFBR1 rs334353 (T/G) (p=0.002), APOE rs4420638 (A/G) (p=0.003), and CFI rs4698775 (G/T) (p=0.008). 3) Comparisons for high vs. low responders showed significant association of FRK rs3812111 (T/A) with both HR-50 and HR-75 groups (p=0.03).

Conclusions: This study shows that 7 SNPs with prior known association with AMD were more frequently associated with vPED eyes when compared to non-AMD eyes, whereas 3 SNPs were more frequently associated with vPED eyes when compared to eyes with drusen. APOE rs4420638 was single SNP more frequently linked to vPED eyes for both comparisons. One SNP [FRK rs3812111 (T/A)] was also consistently associated with high responders. To our knowledge, this is the first report on SNPs-specific profile of vPED eyes associated with AMD.

Keywords: 412 age-related macular degeneration • 701 retinal pigment epithelium • 539 genetics