Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration

Abstract

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration.

Coagulation Factor XIIIA (F13A1): Novel Perspectives in Treatment and Pharmacogenetics

“…They were treated with photodynamic therapy with verteporfin (PDT-V) for severe macular degenerations complicated by choroidal neovascularization (CNV). The study aimed to define a pharmacogenetics correlation between this SNP and CNV responsiveness to either single PDT-V procedure [121][122][123] or to long-term PDT-V standardized asneeded protocol [124]. The therapeutic photo-thrombotic action, on which is based PDT-V [125][126][127][128],…”

“…both persistence and extensiveness of CNV hemodynamic occlusion represent pivotal aspects for the assessment of therapeutic efficacy and, the early recanalization of the neovascular network, can be a key factor in determining poor responsiveness to photodynamic protocol [127,128]. The unsatisfactory post-PDT-V result observed in the carriers of the "hyperfibrinolytic" L34-allele should be rationally related to a weak photo-thrombotic action within the CNV [121][122][123][124], similarly to what has been described also in patients taking aspirin during PDT-V protocol [133]. The locally PDT-V activated thrombosis [125] is responsible for the formation of a very different fibrin clot structures according to local fibrinogen levels and FXIII genotype [112], with more loosely packed fibers and larger pores in patients with the polymorphic L34-allele.…”

Epigenomic signatures in age-related macular degeneration: Focus on their role as disease modifiers and therapeutic targets

“…Indeed, several pharmacogenetic studies have been conducted to dissect the inner factors underlying the differential response, unveiling the significant contribution of a plethora of genetic variants to the efficacy of treatments. [41][42][43][44][45][46][47] However, pharmacoepigenetic approaches have not been reported up to date. Indeed, these studies will be useful to deeper understand the variability of response to AMD drugs.…”

Impact of methylenetetrahydrofolate reductase C677T polymorphism on the efficacy of photodynamic therapy in patients with neovascular age-related macular degeneration

“…In fact, within patients treated with PDT-V for AMD-related CNV, other factors appear to be implicated in those differences of therapeutic responsiveness, which are clearly noticeable reviewing the final outcomes of both randomized controlled trials 22–26 and real-life clinical studies 54–56 . Focusing on a pharmacogenetic predictive approach, our previous investigations have pointed out the role of thrombophilic and anti-thrombophilic single nucleotide polymorphisms (SNPs) in modifying the result of PDT-V in Caucasian patients with neovascular macular degenerations 57–60 . In fact, several coagulation-balance SNPs are able to influence the response to PDT-V as a consequence of the multifaceted photo-thrombotic mechanism triggered by this therapeutic strategy within the neovascular complex 61–65 .…”