MyVisionTest News Archive
Feb 16, 2012
High AMD risk genotypes respond better to Lucentis therapy
A new study finds that among patients with wet AMD those with higher risk genotypes response better to Lucentis (ranibizumab) therapy than patients with lower risk genotypes.
Epidemiological and association studies have shown that both genetic and environmental factors play a major role in the development of AMD. Association studies have implicated variants in a number of genes, with the largest effects observed with alleles of the complement factor H (CFH), HTRA1 and Apolipoprotein E genes. Association with AMD has also been reported for polymorphisms in the VEGF gene.
This study compared genotypes for CFH, HTRA1 and VEGF, and other potential variables, with visual acuity response after 6 months of intravitreal ranibizumab therapy for neovascular AMD.
Methods & Results
Best corrected visual acuity letter score was recorded at baseline and each subsequent visit. Age, sex, smoking history, lesion type and the number of injections were also recorded. Genotypes were obtained for rs11200638 in HTRA1, rs1061170 in CFH and rs1413711 in VEGF. Data were analysed with treatment response at month 6 as both a binary (>5 letter improvement vs =5 letter gain) and a linear trait.
This initial study cohort consisted of 104 Caucasian neovascular AMD patients treated with intravitreal ranibizumab. Trends towards a more favourable outcome were seen with the higher AMD risk genotypes in CFH and VEGF in both the linear and binary models and in HTRA1 in the linear model alone. For CFH, mean letter score change after 6 months was +1.6, +5.9 and +7.2 letters for the TT, TC and CC genotypes and a >5 letter gain was seen in 34.6%, 56.6% and 56%, respectively. For VEGF, mean letter score change after 6 months was +1.3, +5.8 and +7.4 letters for the TT, TC and CC genotypes and a >5 letter gain was seen in 40%, 55.8% and 51.9%, respectively. For HTRA1, mean letter score change was +2.2, +7.5 and +2.9 letters for the GG, GA and AA genotypes. (TABLE)
Discussion & Conclusions
In the ANCHOR and MARINA studies, the response to treatment seemed to be consistent despite baseline variation in lesion size, visual acuity and lesion characteristics. Although current evidence still suggests that regular monthly treatment is associated with the optimum visual acuity response, a number of other studies have suggested that a proportion of patients may not need such regular dosage after the initial loading phase to maintain the early gain in visual acuity. In the PIER study, 40% of patients maintained their initial gain with quarterly treatment after the initial loading phase although 60% lost their initial gain. We hypothesised that the variable acuity responses seen in these trials may be related to genotype. The results of our pilot study suggest that the visual acuity change after 6 months of ranibizumab therapy may indeed be influenced by polymorphisms in three genes that are known to increase the risk of developing neovascular AMD.
Prior studies have investigated a possible association between the CFH genotype and response to verteporfin photodynamic therapy (PDT) and both intravitreal bevacizumab and ranibizumab therapies. For PDT, the results are conflicting. Goverdhan reported greater loss of visual acuity after PDT in patients with the CC and CT CFH genotypes and Feng reported a trend towards an association between a negative PDT response and the CC genotype. However, Brantley identified a worse outcome with the TT CFH genotype and Seitsonen found a lower proportion of PDT responders in the TT genotype group. With intravitreal bevacizumab, Brantley and Nischler reported a trend towards reduced visual acuity and a lower percentage of subjects with improved acuity for the CC genotype. Lee identified that patients with the CC genotype required one more ranibizumab injection over the first 9 months, but the CFH genotype was not significantly associated with post-treatment visual acuity at either 6 or 9 months, after adjusting for pretreatment acuity. In our study, we did not find an association between CFH genotype and the number of injections in the first 6 months, but we did find a trend towards a better visual acuity response with the higher risk TC or CC genotypes.
Although the VEGF gene does not appear to be a major genetic contributor to the development of neovascular AMD, the +674 C/T polymorphism has been most strongly associated with neovascular AMD in a Caucasian population. To our knowledge, no other group has investigated the influence of this polymorphism on the response to ranibizumab therapy for AMD. However, Immonen has recently identified a potential link between other intronic and promoter site VEGF polymorphisms and the anatomic response to PDT.
Polymorphisms in the promoter region of the HTRA1 (high-temperature requirement factor A-1) gene have been shown to increase susceptibility to AMD, especially the neovascular form, in Caucasian and other populations. Possession of the high-risk A allele is associated with increased levels of the HTRA1 protein in drusen, retinal pigment epithelium and choroidal neovascular membranes of eyes with AMD. In our series, a trend towards better visual acuity outcome after 6 months of intravitreal ranibizumab therapy was seen for the increasing AMD risk HTRA1 genotypes, using the linear model alone. Although the total number of injections was similar for all three HTRA1 genotypes, there was a large gain in visual acuity in the individuals who were heterozygous for the high AMD risk A allele and a more modest gain in homozygotes. The apparent advantage of heterozygotes over homozygotes for either HTRA1 genotype is unexpected.
In this pilot study, we have identified preliminary evidence of associations between visual acuity outcome after 6 months of intravitreal ranibizumab and polymorphisms in the CFH, VEGF and HTRA1 genes. For each gene, a trend towards a better outcome was seen with the polymorphisms considered to increase the risk of developing neovascular or advanced AMD. Although the mechanism by which these polymorphisms contribute to AMD susceptibility is not known, these findings may imply that neovascular AMD is not one disease but rather several different diseases with a common end point. There may be a common form of AMD that results from the action of one or more high-risk alleles at HTRA1, CFH and VEGF. This form of AMD may be characterised by high levels of intraocular VEGF and may respond favourably to ranibizumab therapy. Another form of AMD, secondary to other susceptibility genes, may not be characterised by high intraocular VEGF and may respond differently to treatment.
In this study, we have identified trends suggesting a more favourable visual acuity outcome after 6 months of intravitreal ranibizumab therapy with the higher AMD risk CFH, VEGF and HTRA1 genotypes. These findings may imply that the mechanisms underlying the more common form(s) of AMD, due largely to the action of risk alleles at the loci tested in this study, are those best targeted by anti-VEGF therapy. Neovascular AMD in individuals without these high-risk alleles may in part be due to mechanisms that respond less favourably to anti-VEGF therapy.
Read more...
Br J Ophthalmol. 2012 Feb;96(2):208-12
Tags: wet AMD, Lucentis, genetics, pharmacogenetics
A new study finds that among patients with wet AMD those with higher risk genotypes response better to Lucentis (ranibizumab) therapy than patients with lower risk genotypes.Epidemiological and association studies have shown that both genetic and environmental factors play a major role in the development of AMD. Association studies have implicated variants in a number of genes, with the largest effects observed with alleles of the complement factor H (CFH), HTRA1 and Apolipoprotein E genes. Association with AMD has also been reported for polymorphisms in the VEGF gene.
Methods & Results
Best corrected visual acuity letter score was recorded at baseline and each subsequent visit. Age, sex, smoking history, lesion type and the number of injections were also recorded. Genotypes were obtained for rs11200638 in HTRA1, rs1061170 in CFH and rs1413711 in VEGF. Data were analysed with treatment response at month 6 as both a binary (>5 letter improvement vs =5 letter gain) and a linear trait.
This initial study cohort consisted of 104 Caucasian neovascular AMD patients treated with intravitreal ranibizumab. Trends towards a more favourable outcome were seen with the higher AMD risk genotypes in CFH and VEGF in both the linear and binary models and in HTRA1 in the linear model alone. For CFH, mean letter score change after 6 months was +1.6, +5.9 and +7.2 letters for the TT, TC and CC genotypes and a >5 letter gain was seen in 34.6%, 56.6% and 56%, respectively. For VEGF, mean letter score change after 6 months was +1.3, +5.8 and +7.4 letters for the TT, TC and CC genotypes and a >5 letter gain was seen in 40%, 55.8% and 51.9%, respectively. For HTRA1, mean letter score change was +2.2, +7.5 and +2.9 letters for the GG, GA and AA genotypes. (TABLE)
Discussion & Conclusions
In the ANCHOR and MARINA studies, the response to treatment seemed to be consistent despite baseline variation in lesion size, visual acuity and lesion characteristics. Although current evidence still suggests that regular monthly treatment is associated with the optimum visual acuity response, a number of other studies have suggested that a proportion of patients may not need such regular dosage after the initial loading phase to maintain the early gain in visual acuity. In the PIER study, 40% of patients maintained their initial gain with quarterly treatment after the initial loading phase although 60% lost their initial gain. We hypothesised that the variable acuity responses seen in these trials may be related to genotype. The results of our pilot study suggest that the visual acuity change after 6 months of ranibizumab therapy may indeed be influenced by polymorphisms in three genes that are known to increase the risk of developing neovascular AMD.
Prior studies have investigated a possible association between the CFH genotype and response to verteporfin photodynamic therapy (PDT) and both intravitreal bevacizumab and ranibizumab therapies. For PDT, the results are conflicting. Goverdhan reported greater loss of visual acuity after PDT in patients with the CC and CT CFH genotypes and Feng reported a trend towards an association between a negative PDT response and the CC genotype. However, Brantley identified a worse outcome with the TT CFH genotype and Seitsonen found a lower proportion of PDT responders in the TT genotype group. With intravitreal bevacizumab, Brantley and Nischler reported a trend towards reduced visual acuity and a lower percentage of subjects with improved acuity for the CC genotype. Lee identified that patients with the CC genotype required one more ranibizumab injection over the first 9 months, but the CFH genotype was not significantly associated with post-treatment visual acuity at either 6 or 9 months, after adjusting for pretreatment acuity. In our study, we did not find an association between CFH genotype and the number of injections in the first 6 months, but we did find a trend towards a better visual acuity response with the higher risk TC or CC genotypes.Although the VEGF gene does not appear to be a major genetic contributor to the development of neovascular AMD, the +674 C/T polymorphism has been most strongly associated with neovascular AMD in a Caucasian population. To our knowledge, no other group has investigated the influence of this polymorphism on the response to ranibizumab therapy for AMD. However, Immonen has recently identified a potential link between other intronic and promoter site VEGF polymorphisms and the anatomic response to PDT.
Polymorphisms in the promoter region of the HTRA1 (high-temperature requirement factor A-1) gene have been shown to increase susceptibility to AMD, especially the neovascular form, in Caucasian and other populations. Possession of the high-risk A allele is associated with increased levels of the HTRA1 protein in drusen, retinal pigment epithelium and choroidal neovascular membranes of eyes with AMD. In our series, a trend towards better visual acuity outcome after 6 months of intravitreal ranibizumab therapy was seen for the increasing AMD risk HTRA1 genotypes, using the linear model alone. Although the total number of injections was similar for all three HTRA1 genotypes, there was a large gain in visual acuity in the individuals who were heterozygous for the high AMD risk A allele and a more modest gain in homozygotes. The apparent advantage of heterozygotes over homozygotes for either HTRA1 genotype is unexpected.
In this pilot study, we have identified preliminary evidence of associations between visual acuity outcome after 6 months of intravitreal ranibizumab and polymorphisms in the CFH, VEGF and HTRA1 genes. For each gene, a trend towards a better outcome was seen with the polymorphisms considered to increase the risk of developing neovascular or advanced AMD. Although the mechanism by which these polymorphisms contribute to AMD susceptibility is not known, these findings may imply that neovascular AMD is not one disease but rather several different diseases with a common end point. There may be a common form of AMD that results from the action of one or more high-risk alleles at HTRA1, CFH and VEGF. This form of AMD may be characterised by high levels of intraocular VEGF and may respond favourably to ranibizumab therapy. Another form of AMD, secondary to other susceptibility genes, may not be characterised by high intraocular VEGF and may respond differently to treatment.
In this study, we have identified trends suggesting a more favourable visual acuity outcome after 6 months of intravitreal ranibizumab therapy with the higher AMD risk CFH, VEGF and HTRA1 genotypes. These findings may imply that the mechanisms underlying the more common form(s) of AMD, due largely to the action of risk alleles at the loci tested in this study, are those best targeted by anti-VEGF therapy. Neovascular AMD in individuals without these high-risk alleles may in part be due to mechanisms that respond less favourably to anti-VEGF therapy.
Read more...
Br J Ophthalmol. 2012 Feb;96(2):208-12
