Pharmacogenetics of Complement Factor H Y402H Polymorphism and Treatment of Neovascular AMD with Anti-VEGF Agents: A Meta-Analysis

Abstract

The purpose of this study is to investigate whether the Y402H polymorphism (rs1061170, a T-to-C transition at amino acid position 402) in the complement factor H (CFH) gene have a pharmacogenetics effect on the anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). We performed a meta-analysis using databases including PubMed and EMBASE to find relevant studies. 13 published association studies were selected for this meta-analysis, including 2704 patients. For the CFH Y402H polymorphism, anti-VEGF treatment was much less effective in AMD patients with the CFH CC genotype (CC versus TT: odds ratio (OR) = 55, 95% confidence interval (CI), 0.31 to 0.95, P = 0.03; CC versus CT: OR = 0.60, 95% CI, 0.40 to 0.91, P = 0.02; and CC versus CT + TT: OR = 0.59, 95% CI, 0.38 to 0.90, P = 0.02, respectively). In subgroup analysis, CFH Y402H polymorphism was more likely to be a predictor of response for Caucasians (CC versus CT+TT: OR = 0.63, 95% CI, 0.42 to 0.95, P = 0.03). In conclusion, pharmacogenetics of CFH Y402H polymorphism may play a role in response to anti-VEGF treatment for neovascular AMD, especially for Caucasians.

Complement System and Age-Related Macular Degeneration: Implications of Gene-Environment Interaction for Preventive and Personalized Medicine

“…Pooled analysis indicated that CFH risk genotypes were weakly but significantly associated with less effective response to any form of treatment, including anti-VEGF agents, photodynamic therapy, and antioxidants/zinc supplementation [ 32 ]. This finding was further confirmed by more specific meta-analyses of studies, investigating the relationship between CFH rs1061170 polymorphism and response to anti-VEGF treatment [ 97 , 173 ].…”

VEGF regulates local inhibitory complement proteins in the eye and kidney

“…These effects were more pronounced in cells expressing CFH 402H, possibly because they already have reduced complement regulatory capacity and anti-VEGF treatment could decrease this further. This could explain why the CFH 402H polymorphism has been reported to correlate with a reduced response to anti-VEGF therapy (19, 45, 46), although in this complex disease, it is likely that several other factors also contribute to the variable response to anti-VEGF therapy (47). Furthermore, while controversial, there are patient studies suggesting that VEGF antagonists may enhance progression of GA (8, 9, 48, 49), which could be related to direct complement-mediated damage of the RPE cells.…”

“…Therefore, complete VEGF inhibition may be detrimental, but given the variability in reported effects, modifying factors could influence patient response and risk of developing side effects. A recent meta-analysis combining 13 studies reported reduced response to anti-VEGF therapy in patients homozygous for the complement factor H (CFH) polymorphism Y402H (19). The reason why these patients respond less well is unclear, but could suggest a relationship between VEGF and complement.…”

Analysis of the association between CFH Y402H polymorphism and response to intravitreal ranibizumab in patients with neovascular age-related macular degeneration (nAMD)

“…With the increasing use of anti-VEGF agents in treating nAMD, a growing number of studies has been investigating the association between the patient response to treatment and specific gene variants [22,23]. Among the genes linked to the development of nAMD, CFH Y402H polymorphism has been studied most extensively, although with contradictory findings in different populations [24].…”