MyVisionTest News Archive
Feb 17, 2012
Genetic factors determine outcome of PDT for AMD
A new study finds 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 response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population.
Studies have identified several major chromosomal regions, including 1q31 and 10q26 that are associated with the incidence of are-related macular degeneration (AMD). Recently, the complement factor H (CFH) gene on chromosome 1q31 has been demonstrated as the major AMD susceptibility gene. Genetic variants at another chromosomal locus, 10q26 also confers strong disease risk, including age-related maculopathy susceptibility (ARMS2) and high-temperature requirement factor A1 (HTRA1) genes.
Other efforts are underway to identify genetic and/or pharmacologic biomarkers that may predict response to therapy, thereby contributing important information to clinical decision making and care. Known and novel phenotypic biomarkers, those that associate with or predict variation in an individual’s state of health or predict the consequences of altered genes on protein expression, are strategic candidates for evaluation. Recently, a genetic variant of CFH Y402H was reported to be associated with responses to photodynamic therapy (PDT) and to anti–vascular endothelial growth factor (VEGF) therapy.
The phenotypic and genotypic characteristics of Asian and Japanese AMD is unique from those of Caucasian AMD. For example, the incidence of polypoidal choroidal vasculopathy in the Asian populations with neovascular AMD has been reported to be as high as 20% to 55%, whereas the incidence is <10% in Caucasians.
Methods & Results:
In this prospective, case-control study 110 patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan.
The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay.
Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (FIGURE). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype. Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype. Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/-rs2274700.
Discussion & Conclusions
This study found a significant association of the HTRA1 and CFH genotype variants with therapeutic response to PDT in AMD. Improvement in BCVA was significantly greater in patients with the HTRA1-rs11200638 wild-type allele homozygous genotype as compared with patients with the risk allele with heterozygous or homozygous genotypes. The incidence of CNV recurrence during the 12 month period after PDT was associated with the HTRA1-rs11200638 genotype. Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of CNV recurrence as compared with patients with the GG genotype.
These results support the hypothesis that known genetic polymorphisms may be utilized as genetic biomarkers to predict responses to PDT in AMD. The results demonstrate significant predictive power with regard to visual outcomes and interval to CNV recurrence after PDT. However, no genetic associations were found to correlate with PDT complications, such as subretinal hemorrhage.
There is variable efficacy of PDT in the reported literature, including the TAP, VIP, and JAT reports. This variability in treatment response underscores the importance of identifying and strategically applying appropriate predictive biomarkers in making treatment decisions.
Although study design, treatment methodology, study population ethnicity, and methods of statistical analysis were different, the researchers compared vision improvement in the TAP, VIP, JAT, MARINA, and ANCHOR studies and the current study. Vision improvement 1 year after PDT treatment in patients with the GG genotype of HTRA1 lay between those in MARINA and ANCHOR study results and is obviously better than those in TAP and JAT studies. This comparison clearly demonstrates the importance of HTRA1 genotyping as a genetic biomarker in predicting the PDT treatment outcome and in driving treatment decision making.
Recently, Parmeggiani et al and others have published evidence of a pharmacogenetic relationship between coagulation-balance gene polymorphisms and PDT effectiveness in patients with both classic and occult CNVs.
In summary, the present work supports a hypothesis that known genetic polymorphisms may be utilized as genetic biomarkers to predict responses to PDT in AMD. The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power.
Read more...
Ophthalmology. 2011 Jan;118(1):93-100
Tags: photodynamic therapy, pharmacogenetics, racial differences, wet AMD, Japan
A new study finds 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 response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population.Studies have identified several major chromosomal regions, including 1q31 and 10q26 that are associated with the incidence of are-related macular degeneration (AMD). Recently, the complement factor H (CFH) gene on chromosome 1q31 has been demonstrated as the major AMD susceptibility gene. Genetic variants at another chromosomal locus, 10q26 also confers strong disease risk, including age-related maculopathy susceptibility (ARMS2) and high-temperature requirement factor A1 (HTRA1) genes.
The phenotypic and genotypic characteristics of Asian and Japanese AMD is unique from those of Caucasian AMD. For example, the incidence of polypoidal choroidal vasculopathy in the Asian populations with neovascular AMD has been reported to be as high as 20% to 55%, whereas the incidence is <10% in Caucasians.
Methods & Results:
In this prospective, case-control study 110 patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan.
The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay.
Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (FIGURE). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype. Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype. Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/-rs2274700.
Discussion & Conclusions
This study found a significant association of the HTRA1 and CFH genotype variants with therapeutic response to PDT in AMD. Improvement in BCVA was significantly greater in patients with the HTRA1-rs11200638 wild-type allele homozygous genotype as compared with patients with the risk allele with heterozygous or homozygous genotypes. The incidence of CNV recurrence during the 12 month period after PDT was associated with the HTRA1-rs11200638 genotype. Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of CNV recurrence as compared with patients with the GG genotype. These results support the hypothesis that known genetic polymorphisms may be utilized as genetic biomarkers to predict responses to PDT in AMD. The results demonstrate significant predictive power with regard to visual outcomes and interval to CNV recurrence after PDT. However, no genetic associations were found to correlate with PDT complications, such as subretinal hemorrhage.
There is variable efficacy of PDT in the reported literature, including the TAP, VIP, and JAT reports. This variability in treatment response underscores the importance of identifying and strategically applying appropriate predictive biomarkers in making treatment decisions.
Although study design, treatment methodology, study population ethnicity, and methods of statistical analysis were different, the researchers compared vision improvement in the TAP, VIP, JAT, MARINA, and ANCHOR studies and the current study. Vision improvement 1 year after PDT treatment in patients with the GG genotype of HTRA1 lay between those in MARINA and ANCHOR study results and is obviously better than those in TAP and JAT studies. This comparison clearly demonstrates the importance of HTRA1 genotyping as a genetic biomarker in predicting the PDT treatment outcome and in driving treatment decision making.
Recently, Parmeggiani et al and others have published evidence of a pharmacogenetic relationship between coagulation-balance gene polymorphisms and PDT effectiveness in patients with both classic and occult CNVs.
In summary, the present work supports a hypothesis that known genetic polymorphisms may be utilized as genetic biomarkers to predict responses to PDT in AMD. The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power.
Read more...
Ophthalmology. 2011 Jan;118(1):93-100
