Age-related macular degeneration phenotypes associated with mutually exclusive homozygous risk variants in CFH and HTRA1 genes

Purpose: To determine age-related macular degeneration (AMD) phenotypes associated with mutually exclusive homozygotic risk variants in rs1061170 (CFH) and rs11200638 (HTRA1). Methods: Nested case-control study of 2,982 eyes (2,129 control, 809 drusen ≥125 m, 44 advanced AMD) homozygous for CFH [TT (-/-) or CC (+/+) ] and HTRA1 [GG (-/-) or AA (+/+) ] were analyzed using logistic regression and generalized estimating equations specifically regards to homozygous risk variants in one but homozygous no-risk in the other gene. Results: In early AMD, [CFH +/+ HTRA1 -/- ] and [CFH -/- HTRA1 + / + ] were associated with central drusen (odds ratio [95% confidence interval] 4.13 [2.97-5.73] and 3.65 [1.88-7.09], respectively). However, only [CFH +/+ HTRA1 -/- ] was associated with central drusen occupying ≥50% area (13.9 [2.97-64.7]). In advanced AMD, [CFH +/+ HTRA1 -/- ] was associated with geographic atrophy (4.04 [1.57-10.4]), whereas [CFH -/- HTRA1 + / + ] was associated with neovascular AMD (36.5 [8.3-160.9]). In doubly homozygous risk groups [CFH +/+ HTRA1 + / + ], odds ratios were multiplicative. Conclusion: Central but not peripheral drusen location was strongly associated with both [CFH +/+ HTRA1 -/- ] and [CFH -/- HTRA1 + / + ]. Only [CFH +/+ HTRA1 -/- ] was significantly associated with increased central drusen area.