Prognostic phenotypic and genotypic factors associated with photodynamic therapy response in patients with age-related 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)
Ophthalmology, 2009
To investigate the association between complement factor H (CFH) and C-reactive protein (CRP) genotypes and response to photodynamic therapy (PDT) treatment for neovascular age-related macular degeneration (AMD). Retrospective cohort study. The study cohort consisted of 273 neovascular AMD patients treated with PDT. Genotypes were determined for the common T--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;C single nucleotide polymorphism (SNP) in exon 9 of the CFH gene (rs1061170; Y402H), as well as 9 selected tagging SNPs across the CRP gene (rs2808635, rs1417938, rs1800947, rs1130864, rs1205, rs3093077, rs876538, rs876537, and rs1572970). Visual acuity outcome after PDT was retrospectively calculated and patients were classified as PDT-positive responders or PDT-negative responders. Logistic regression analysis was used to evaluate the association between individual SNPs and PDT treatment response while adjusting for relevant covariates. Response to PDT treatment defined by visual acuity; genotypes of CFH Y402H and CRP polymorphism. Of the 273 patients, 75 had a positive response after PDT treatment. The frequency of CC genotype of the CFH Y402H polymorphism in the PDT-positive response group was lower than in the negative PDT response group (26.4% vs 31.6%) but this difference failed to reach statistical significance. Two CRP SNPs (rs2808635 and rs876538) were significantly associated with PDT treatment response. Positive treatment response was seen in individuals homozygous for the minor allele of the rs2808635 (GG; odds ratio [OR], 3.92; 95% confidence interval [CI], 1.40-10.97; P = 0.048) and rs876538 (AA; OR, 6.49; 95% CI, 1.65-25.47; P = 0.048) variants after adjusting for relevant covariates. The remaining 7 CRP genetic variants did not reveal any significant association with treatment response. Our data did not show significant association between the CFH Y402H polymorphism and PDT treatment response for neovascular AMD; however, CRP genetic variants were associated with a positive response to PDT treatment for neovascular AMD.
Eye, 2008
Aim To determine whether there is an association between complement factor H (CFH) or LOC387715 genotypes and response to treatment with photodynamic therapy (PDT) for exudative age-related macular degeneration (AMD). Methods Sixty-nine patients being treated for neovascular AMD with PDT were genotyped for the CFH Y402H and LOC387715 A69S polymorphisms by allele-specific digestion of PCR products. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography. Results Adjusting for age, pre-PDT visual acuity (VA), and lesion type, mean VA after PDT was significantly worse for the CFH TT genotype than for the TC or CC genotypes (P ¼ 0.05). Post-PDT VA was significantly worse for the CFH TT genotype in the subgroup of patients with predominantly classic choroidal neovascular lesions (P ¼ 0.04), but not for the patients with occult lesions (P ¼ 0.22). For the LOC387715 A69S variant, there was no significant difference among the genotypes in response to PDT therapy. Conclusions The CFH Y402H variant was associated with a response to PDT treatment in this study. Patients with the CFH TT genotype fared significantly worse with PDT than did those with the CFH TC and CC genotypes, suggesting a potential relationship between CFH genotype and response to PDT.
Investigation of genetic base in the treatment of age-related macular degeneration
International Ophthalmology, 2020
Purpose To determine whether gene polymorphisms which are associated with age-related macular degeneration (AMD) influence treatments' response and specifically the antioxidant supplementation in dry AMD patients, as well as the anti-vascular endothelial growth factor (anti-VEGF) therapy in neovascular AMD patients. Methods A total of 170 patients with dry AMD and 52 neovascular AMD patients were genotyped for the following single nucleotide polymorphisms (SNPs): rs1061170/Y402H in CFH gene, rs10490924/A69S in ARMS2 gene, rs9332739/E318D and rs547154/IVS10 in C2 gene, and rs4151667/L9H and rs2072633/IVS17 in CFB gene. Treatment response was evaluated by comparing visual acuity and optical coherence tomography between baseline and at the end of the treatment. Results She CFH/Y402H variant was associated with the response to antioxidants in dry AMD patients. Carriers of one or two CFH risk alleles displayed a lower chance of responding compared to those with no risk allele. No association of antioxidants' response and ARMS2/A69S genotype was identified. The analysis of the C2 and CFB genetic variants (protective SNPs) revealed that antioxidant supplementation was much more effective in protective SNP carriers. In neovascular AMD patients, the analysis indicated that Y402H homozygous patients were less likely to respond to anti-VEGF therapy compared to heterozygous. Regarding the ARMS2/A69S genotype, carriers of the risk variant experienced significantly worse treatment outcome compared to wild-type patients. Conclusion In AMD patients, the efficacy of the antioxidant supplementation and the anti-VEGF therapy appears to differ by genotype. The detection of genetic variants, associated with treatment responsiveness, could lead to improved visual outcomes through genotype-directed therapy.
Journal of ocular biology, diseases, and informatics, 2010
We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study coho...
Molecular vision, 2008
Single nucleotide polymorphisms (SNPs) in the tightly linked LOC387715/ARMS2 and HTRA1 genes have been associated with age-related macular degeneration (AMD). We tested whether these SNPs are associated with AMD in Israeli populations, if they underlie variable phenotype and response to therapy in neovascular AMD (NVAMD), and if HTRA1 expression in vivo is associated with its promoter variant. Genotyping for the rs10490924 SNP in LOC387715/ARMS2 and the rs11200638 SNP in HTRA1 was performed on 255 NVAMD patients and 119 unaffected controls from Ashkenazi and Sephardic Jewish, and from Arab origins which are the main ethnic groups composing the Israeli population. Genotyping was correlated with phenotype and response to therapy among 143 patients who underwent photodynamic therapy (PDT). HTRA1 mRNA levels in white blood cells (WBCs), measured by quantitative PCR, were correlated with genotype in 27 participants. Both SNPs were in almost complete linkage disequilibrium (D'=0.96-1)...
Neovascular age-related macular degeneration: too many theories, too little knowledge?
Acta Ophthalmologica, 2008
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.
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.