Association between Polymorphisms in CFH, ARMS2, CFI, and C3 Genes and Response to Anti-VEGF Treatment in Neovascular Age-Related Macular Degeneration

Abstract

Neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss in the elderly. The gold standard of nAMD treatment is intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors. Genetic factors may influence the response to anti-VEGF therapy and result in a high degree of response variability. The aim of the study was to evaluate the association of the polymorphisms in genes related to the complement system (rs2285714-CFI, rs10490924-ARMS2, rs2230199-C3, rs800292-CFH, and rs6677604-CFH) with nAMD its clinical features and optical coherent tomography (OCT) biomarkers of treatment response to anti-VEGF therapy. Genotyping by allele-specific PCR was performed in 193 AMD patients and 147 age-matched controls. A prospective study of the dynamics of changes in OCT biomarkers during aflibercept treatment included 110 treatment-naive patients. Allele T rs10490924 was associated with the increased risk of nAMD. For both rs800292 and rs6677604, carriage of the A allele was protective and decreased the nAMD risk. Associations of rs2230199 with central retinal thickness (CRT) and intraretinal cysts were revealed. The height of pigment epithelium detachment and the height of neuroretinal detachment were significantly higher in carriers of the minor allele of rs2285714, both at baseline and during treatment. The reduction of CRT was associated with higher CRT at baseline and the presence of the T allele of rs2285714. By the end of one-year follow-up the patients homozygous for the minor allele rs2285714 had significantly higher odds of the presence of anastomoses and loops and active neovascular membrane. Furthermore, minor allele carriers had decreased levels of complement factor I level in aqueous humor but not in the plasma, which may be due to the influence of rs2285714 on tissue-specific splicing. Our results suggest that the severity of AMD macular lesions is associated with rs2285714 and rs2230199 polymorphisms, which could be explained by their high regulatory potential. Patients with the minor allele of rs2285714 respond worse to antiangiogenic therapy.

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

“…The CFH gene may influence treatment outcomes in patients with AMD [ 139 ], proving to be much less effective in Y402H AMD patients treated with anti-VEGF and suggesting that the mutation may be a useful predictor of treatment response; additionally, rs1065489 and rs800292 influence treatment outcomes after anti-VEGF [ 140 ]. Similarly to CFH, CFI rs2285714 is shown to respond worse to antiangiogenic treatment [ 141 ]. ARMS2 A69S is a prognostic factor for an anti-VEGF response in wet AMD in the East Asian population, but not in the Caucasian or Middle Eastern group [ 48 ].…”

Emerging therapeutic strategies for unmet need in neovascular age-related macular degeneration

“…There is emerging evidence that a patient’s underlying genetic predisposition may affect response to existing anti-VEGF therapies. Lower risk genotypes of the VEGFA, CFH, ARMS2 and HTRA1 genes may be associated with better visual outcomes and potentially fewer injections [ 98 – 101 ]. Some of these genotypes were associated with poor response to one, but better response to a different anti-VEGF agent [ 102 ].…”

Pharmacogenetic Association between Allelic Variants of the Autophagy-Related Genes and Anti-Vascular Endothelial Growth Factor Treatment Response in Neovascular Age-Related Macular Degeneration

“…Variability in therapeutic response may be due to hereditary factors such as genetic polymorphism. Indeed, the studies indicate that in patients with nAMD, the response to anti-VEGF therapy depends on the genotype of genes in the complement system [6,[8][9][10][11][12] and VEGF-related pathway [6,[13][14][15]. Recently, Paterno et al [16] found that single nucleotide polymorphisms (SNPs) of autophagy genes have been associated with nAMD and the outcomes of anti-VEGF treatment in a cohort of Finnish patients.…”