Article Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration (original) (raw)
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Scientific Reports, 2019
The most severe visual impairments due to age-related macular degeneration (AMD) are frequently caused by the occurrence of choroidal neovascularization (CNV). Although photodynamic therapy with verteporfin (PDT-V) is currently a second-line treatment for neovascular AMD, it can be conveniently combined with drugs acting against vascular endothelial growth factor (anti-VEGF) to reduce the healthcare burden associated with the growing necessity of anti-VEGF intravitreal re-injection. Because the common 677 C > T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR-C677T; rs1801133) has been described as predictor of satisfactory short-term responsiveness of AMD-related CNV to PDT-V, we retrospectively examined the outcomes of 371 Caucasian patients treated with standardized, pro-re-nata, photodynamic regimen for 24 months. Responder (R) and non-responder (NR) patients were distinguished on the basis of the total number of scheduled PDT-V (TN-PDT-V) and change of best-corrected visual acuity (∆-BCVA). The risk for both TN-PDT-V and ∆-BCVA to pass from R to NR group was strongly correlated with CT and TT genotypes of MTHFR-C677T variant resulting, respectively, in odd ratios of 0.19 [95% CI, 0.12-0.32] and 0.09 [95% CI, 0.04-0.21] (P < 0.001), and odd ratios of 0.24 [95% CI, 0.15-0.39] and 0.03 [95% CI, 0.01-0.11] (P < 0.001). These pharmacogenetic findings indicate a rational basis to optimize the future clinical application of PDT-V during the combined treatments of AMD-related CNV, highlighting the role of thrombophilia to be aware of the efficacy profile of photodynamic therapy. Age-related macular degeneration (AMD) [MIM 603075] is the most common cause of central blindness or low vision in the elderly population of the industrialized countries, i.e. in the areas defined by the World Health Organization as AMR-A (Amr, Region of the Americas), Eur-A (Eur, European Region), and WPR-A (WPR, Western Pacific Region) 1-3. Caucasian populations are largely more affected by AMD than other ethnic groups 4-7. There are two different clinical forms of sight-threatening AMD: (i) atrophic AMD (or dry AMD), characterized by atrophic changes of photoreceptors, retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris; and (ii) neovascular AMD (or wet/exudative AMD), complicated by choroidal neovascularization (CNV)
Current Drug Targets, 2011
In Western Countries, the occurrence of choroidal neovascularization (CNV) secondary to different forms of macular degeneration represents a common cause of blindness. Particularly, age-related macular degeneration (AMD) and pathologic myopia (PM) are the most frequent diseases related to CNV development. At present, the combined employment of drugs acting against vascular endothelial growth factor (anti-VEGF) and photodynamic therapy with verteporfin (PDT-V) is a promising therapeutic strategy for neovascular macular degenerations. However, this approach inevitably leads to an increase in health-resource utilization. In several clusters of patients treated for CNV, correlations among common gene polymorphisms implicated in coagulation-or complement-cascade and different levels of, respectively, post-PDT-V or post-anti-VEGF benefit have been reported. Factor XIII-A G185T substitution (rs5985), a frequent anti-thrombophilic genetic variant of Caucasian ethnic groups, unequivocally influences a worsening of the CNV responsiveness to PDT-V in patients affected by either AMD-or PM-related CNV. These coherent pharmacogenetic findings point out the opportunities to: i. optimize the eligibility criteria of PDT-V and, ii. customize the interventional strategy against CNV, for finally minimizing the socioeconomic burden of neovascular macular degenerations.
Clinical ophthalmology (Auckland, N.Z.), 2014
This study aimed to demonstrate the phenotypic and genotypic factors associated with photodynamic therapy (PDT) for age-related macular degeneration (AMD). The study included 149 patients with exudative AMD treated by PDT. Eight phenotypic factors and ten genotypic factors for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the complement factor H (CFH) gene, rs 11200638-SNP in the high temperature requirement A-1 (HTRA1) gene, two SNPs (rs699947, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and four SNPs (rs12948385, rs12150053, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were evaluated. A significant association with best-corrected visual acuity change was demonstrated in the greatest linear dimension, presence or absence of pigment epithelial detachment, and HTRA1-rs11200638 genotype statistically (P=3.67×10(-4), 1.95×10(-2), 1.24×10(-3), respectively). Best-corrected visual acuity in patients wit...
2009
Age-related macular degeneration (AMD) represents the leading cause of central blindness in developed countries. The majority of severe vision loss occurs in the neovascular form of AMD, generally characterized by the presence of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) and drugs acting against vascular endothelial growth factor are the most commonly employed treatments for AMD-related subfoveal CNV. The combined use of both these strategies is the most promising therapeutic approach towards this harmful disease. The therapeutic action of PDT-V depends to a photochemical perturbation of thrombo-coagulative processes within CNV. Predictive correlations between peculiar coagulation-balance gene polymorphisms and different levels of post-PDT-V benefit have been recently documented in Caucasian patients with neovascular AMD. Particularly, heterozygous A-allele carriers of factor V Leiden 1691 or prothrombin 20210 gene are characterized by a greater possibility to exhibit clinical benefit after PDT-V. Both mutations induce thrombophilia increasing the thrombin generation in plasma and, thus, they can consistently intensify the photothrombotic phase of the therapeutic CNV occlusion. In prospect, considering the different individual susceptibility to PDT-V, a preoperative assessment of the genotypic thrombophilic background could optimize the eligibility criteria of this intriguing treatment. This review summarizes some of the recent published patents on treatment of neovascular AMD, with a particular attention to PDT-V application in combined therapeutic modalities.
Investigative Ophthalmology & Visual Science, 2008
To determine whether different coagulation-balance genetic polymorphisms explain the variable clinical outcomes of photodynamic therapy with verteporfin (PDT-V) in Caucasian patients with occult subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). METHODS. The clinical records of consecutive patients with AMD-related occult CNV, treated with PDT-V for evidence of disease progression, were retrospectively examined. Eightyfour eligible subjects were subdivided into responders and nonresponders based on CNV responsiveness to the first PDT-V over a 3-month period. Six gene polymorphisms (i.e., factor V G1691A, prothrombin G20210A, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, methionine synthase A2756G, and methionine synthase reductase A66G) were genotyped in each patient. Logistic regression analyses were performed to explore the predictive role of phenotypic and genotypic variables for PDT-V effectiveness. RESULTS. Regression models documented that PDT-V nonresponders were more frequently patients with the hyperfibrinolytic G185T mutation of factor XIII-A (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11-0.73; P Ͻ 0.01). Univariate logistic regression was indicative of an overrepresentation of PDT-V responders among the combined carriers of thrombophilic factor V 1691A and prothrombin 20210A alleles (OR ϭ 3.8; 95% CI: 0.94 -15.6; P ϭ 0.07). All the other predictors considered did not significantly influence the short-term CNV responsiveness to PDT-V. CONCLUSIONS. These data provide evidence of the presence of a pharmacogenetic relationship between peculiar coagulationbalance genetic backgrounds and different levels of PDT-V effectiveness in patients with AMD with occult CNV. (Invest Ophthalmol Vis Sci. 2008;49:3100 -3106)