MyVisionTest News Archive
Feb 15, 2012
AMD treatment response to Lucentis influenced by genetics
Age-related macular degeneration (AMD) has a complex etiology arising from genetic and environmental influences. This past decade have seen several genes associated with the disease. Variants in five genes have been confirmed to play a major role. It is hoped that such research will define the genetic biomarker spectrum to allow treatment individualization and optimize visual outcomes.
The objective of this study was to evaluate whether genes influence treatment response to ranibizumab for neovascular AMD.
PHARMACOGENETICS OVERVIEW
The theory of complex traits is based upon the idea that multiple variations in the genetic code (most frequently single-nucleotide polymorphisms [SNPs], insertions or deletions [“indels”], and copy number variants) act in concert to determine a particular phenotype.
Evidence suggests that these variants result in functionally important alterations in, among other things, the activity, expression levels, stability, and splicing of the RNA and proteins they encode. The action of these variants is, however, not independent of external and environmental influences.
This forms the basis of pharmacogenetics, which attempts to define the genetic variants that influence variable response to medication. The ultimate goal of pharmacogenetic studies is to identify those who respond best and avoid adverse reactions.
There are several significant social consequences of successful pharmacogenetics research. There will be a major change in the way individuals view their health and the taking of medicines. The hope would be that the large numbers of adverse drug reactions would be reduced. There is a possibility that when whole genome sequencing becomes a routine and inexpensive undertaking, a pharmacogenetic profile might be constructed in early life in readiness for future therapeutic need.
GENETICS OF AMD
That genetics has a significant etiological role in AMD is now beyond question. Studies to identify causal variants initially concentrated on genome-wide linkage and association analyses. A meta-analysis of these and other results showed reassuring replication of similar chromosomal loci, several of which remain under investigation.
The first specific replicated genetic variant to be associated with advanced AMD was the SNP rs1061170 (T1277C; Y402H) in the complement factor H (CFH) gene. Additional SNPs and haplotypes in CFH and neighboring genes have also been associated with drusen formation and advanced AMD. CFH is a regulator of complement, dysfunction of which has been linked to retinal pathology. Recently, SNPs in other complement components have been associated with advanced AMD: complement factors 2 (C2), B (CFB), 3 (C3), and I (CFI).
A major AMD-susceptibility locus has also been identified on chromosome 10q26, a region where linkage disequilibrium has made it difficult to distinguish the causal genetic variant: the SNP, rs10490924 (A69S), is within the gene, ARM-susceptibility 2 (ARMS2). This putative gene has unknown function, and its protein product has been identified in several subcellular compartments or the cytoplasm. The SNP, rs11200638, is located in the promoter of the gene HTRA1, a serine protease found in the retina (among other tissues), and the SNP may alter gene expression. In complete linkage disequilibrium with this SNP is an indel in ARMS2 that may affect translation of the ARMS2 protein.
PHARMACOGENETICS IN AMD
Genetic variants contribute substantially to the etiology of AMD. As a result, there has been interest in examining whether these common SNPs and other candidate genes may play a pharmacogenetic role. Three treatments are currently utilized for the treatment of AMD: Age-Related Eye Disease Study (AREDS) supplementation, anti-VEGF therapy, and photodynamic therapy (PDT). Studies thus far have largely been limited to retrospective analyses.
AREDS Supplements
The AREDS study (a large prospective multicenter randomized trial) found a beneficial effect of zinc and antioxidants (beta carotene, vitamin C, and vitamin E) in slowing progression of disease as compared with placebo alone. Using this progression data and combining it with genetic analyses of samples from the cohort, it has been possible to suggest that those individuals taking the supplements who had the low-risk genotype in CFH experienced less disease progression. One potential conclusion is that any genetic predisposition to AMD reduces the effectiveness of the supplements that remain commonly used for dry AMD in the United States.
Photodynamic Therapy
PDT has largely been replaced by anti-VEGF therapy, though it still has a role for certain patients with AMD, potentially in combination with other agents and in those where other treatments may be contraindicated.
Experience has shown variability in treatment success, leading some observers to begin to hypothesize that effectiveness might be altered by an individual’s ability to activate coagulation factors in response to PDT. A number of single gene disorders result in coagulapathies and their prevalence was evaluated in two studies. Patients determined to be PDT responders and nonresponders were genotyped for a number of coagulation factor mutations. The results suggested that those carrying the G185T mutation of factor XIII-A, which results in a hyperfibrinolytic state, were more likely not to respond to PDT, whereas those with factor V 1691A and prothrombin 20210A, both prothrombotic state, did better.
Anti-VEGF Agents
This treatment has been shown to have significant efficacy and has been the subject of interest as to whether genetics may play a role in outcomes. In a study of 86 patients treated with bevacizumab (Avastin), those with the risk CC genotype in CFH had worse visual outcomes than those with other genotypes. This appears to be replicated by a larger study of patients receiving ranibizumab. Although these are associations rather than causal findings, these studies introduce the idea that common AMD-susceptibility genes may play a role in determining treatment outcome.
METHODS & RESULTS
The study was a two-site prospective open-label observational study of patients newly diagnosed with exudative (neovascular) AMD receiving intravitreal ranibizumab therapy. Treatment-naïve patients were enrolled at presentation and received monthly "as needed" therapy. Clinical data was collected monthly and DNA extracted. Genotyping was performed using the Illumina (San Diego, California) 660-Quad single-nucleotide polymorphism (SNP) chip. Regression analyses were performed to identify SNPs associated with treatment-response end points.
Sixty-five patients were enrolled. No serious adverse events were recorded. The primary outcome measure was change in ETDRS visual acuity at 12 months. A SNP in the CFH gene was found to be associated with less improvement in visual acuity while receiving ranibizumab therapy. The C3 gene, among others, was associated with reduced thickening and improved retinal architecture. VEGFA, FLT1, and CFH were associated with requiring fewer ranibizumab injections over the 12-month study.
DISCUSSION & CONCLUSIONS
To date, two pharmacogenetic studies of anti-VEGF therapy for neovascular AMD have been published. Both were retrospective. The first reported the results of 86 patients treated with bevacizumab (Avastin), the humanized monoclonal antibody from which ranibizumab (Lucentis) was developed. The second included 156 patients who received bevacizumab.110 It was the intent of this study to overcome many of these problems with prospective enrollment and clearly stated inclusion/exclusion criteria that limit phenotypic heterogeneity while achieving a reasonable enrollment rate.
When outcomes are examined independent of genotype, the eyes enrolled performed similarly to other studies. On average, individuals gained almost 6 ETDRS letters, and the OCT central macular thickness reduced by about 110 µm. On average, six or seven ranibizumab injections were required over the year, which indicates that treating physicians/investigators adhered to clinical practice norms. Overall, these are typical results for eyes with neovascular AMD.
In line with the two previous retrospective studies, the CFH gene was implicated in determining poorer visual outcomes together with a SNP in the CTGF gene. It is not known why the CFH gene, which has been identified in numerous studies as one of the two major susceptibility variants for AMD development, might influence treatment response. It is tempting to speculate that this is because genotypes in CFH dictate the severity or persistence of the CNV.
In analyses on the change in central macular thickness (at both 6 and 12 months), a good surrogate for improved anatomy of the central macular region and in turn crudely correlated with better vision, the minor allele of a SNP in complement factor 3 (C3) appears associated with reduced thickening and improved architecture. This same SNP has been previously implicated as an AMD susceptibility variant.
The candidate gene analysis strongly implicates FLT1 (VEGFA receptor) in the treatment response, identifying several SNPs associated with persistent leakage on fluorescein angiography at both 6 and 12 months. No other genes are identified on genome-wide analysis.
One of the most pertinent pharmacogenetic findings would be the identification of genetic variants that might be used to predict which eyes might receive less frequent injections. In this regard, this study reveals three biologically plausible candidates warranting further investigation: VEGFA, its receptor FLT1, and CFH.
The findings from this study have several uses. Once validated, screening for these specific genetic variants can be performed quickly and easily in the clinical environment to identify patients’ response characteristics. In those with favorable genetic predisposition, in the case of ranibizumab, fewer injections need to be scheduled and perhaps the intervals between treatments and visits can be lengthened. In the case of those with worse genotypes, more frequent interventions can be considered, including potentially involving the use of other modalities. Additionally, this form of research can identify new avenues for drug development by implicating novel genes and the proteins they encode in disease pathogenesis and susceptibility.
In summary, this study is a prospective pharmacogenetic study of genetically determined treatment response to intravitreal ranibizumab for neovascular AMD. Although small in nature, the aim was principally to demonstrate the methodology needed to conduct such studies. Encouragingly, the results identify a number of putative genetic variants, which will be further examined by replication and functional studies to elucidate the complete pharmacogenetic architecture of therapy for AMD.
Read more...
Trans Am Ophthalmol Soc. 2011 Dec;109:115-56
Tags: genetics, wet AMD, pharmacogenetics, Lucentis
Age-related macular degeneration (AMD) has a complex etiology arising from genetic and environmental influences. This past decade have seen several genes associated with the disease. Variants in five genes have been confirmed to play a major role. It is hoped that such research will define the genetic biomarker spectrum to allow treatment individualization and optimize visual outcomes. The objective of this study was to evaluate whether genes influence treatment response to ranibizumab for neovascular AMD.
The theory of complex traits is based upon the idea that multiple variations in the genetic code (most frequently single-nucleotide polymorphisms [SNPs], insertions or deletions [“indels”], and copy number variants) act in concert to determine a particular phenotype.
Evidence suggests that these variants result in functionally important alterations in, among other things, the activity, expression levels, stability, and splicing of the RNA and proteins they encode. The action of these variants is, however, not independent of external and environmental influences.
This forms the basis of pharmacogenetics, which attempts to define the genetic variants that influence variable response to medication. The ultimate goal of pharmacogenetic studies is to identify those who respond best and avoid adverse reactions.
There are several significant social consequences of successful pharmacogenetics research. There will be a major change in the way individuals view their health and the taking of medicines. The hope would be that the large numbers of adverse drug reactions would be reduced. There is a possibility that when whole genome sequencing becomes a routine and inexpensive undertaking, a pharmacogenetic profile might be constructed in early life in readiness for future therapeutic need.
GENETICS OF AMD
That genetics has a significant etiological role in AMD is now beyond question. Studies to identify causal variants initially concentrated on genome-wide linkage and association analyses. A meta-analysis of these and other results showed reassuring replication of similar chromosomal loci, several of which remain under investigation.
The first specific replicated genetic variant to be associated with advanced AMD was the SNP rs1061170 (T1277C; Y402H) in the complement factor H (CFH) gene. Additional SNPs and haplotypes in CFH and neighboring genes have also been associated with drusen formation and advanced AMD. CFH is a regulator of complement, dysfunction of which has been linked to retinal pathology. Recently, SNPs in other complement components have been associated with advanced AMD: complement factors 2 (C2), B (CFB), 3 (C3), and I (CFI).
A major AMD-susceptibility locus has also been identified on chromosome 10q26, a region where linkage disequilibrium has made it difficult to distinguish the causal genetic variant: the SNP, rs10490924 (A69S), is within the gene, ARM-susceptibility 2 (ARMS2). This putative gene has unknown function, and its protein product has been identified in several subcellular compartments or the cytoplasm. The SNP, rs11200638, is located in the promoter of the gene HTRA1, a serine protease found in the retina (among other tissues), and the SNP may alter gene expression. In complete linkage disequilibrium with this SNP is an indel in ARMS2 that may affect translation of the ARMS2 protein.
PHARMACOGENETICS IN AMD
Genetic variants contribute substantially to the etiology of AMD. As a result, there has been interest in examining whether these common SNPs and other candidate genes may play a pharmacogenetic role. Three treatments are currently utilized for the treatment of AMD: Age-Related Eye Disease Study (AREDS) supplementation, anti-VEGF therapy, and photodynamic therapy (PDT). Studies thus far have largely been limited to retrospective analyses.
AREDS Supplements
The AREDS study (a large prospective multicenter randomized trial) found a beneficial effect of zinc and antioxidants (beta carotene, vitamin C, and vitamin E) in slowing progression of disease as compared with placebo alone. Using this progression data and combining it with genetic analyses of samples from the cohort, it has been possible to suggest that those individuals taking the supplements who had the low-risk genotype in CFH experienced less disease progression. One potential conclusion is that any genetic predisposition to AMD reduces the effectiveness of the supplements that remain commonly used for dry AMD in the United States.
Photodynamic Therapy
PDT has largely been replaced by anti-VEGF therapy, though it still has a role for certain patients with AMD, potentially in combination with other agents and in those where other treatments may be contraindicated.
Experience has shown variability in treatment success, leading some observers to begin to hypothesize that effectiveness might be altered by an individual’s ability to activate coagulation factors in response to PDT. A number of single gene disorders result in coagulapathies and their prevalence was evaluated in two studies. Patients determined to be PDT responders and nonresponders were genotyped for a number of coagulation factor mutations. The results suggested that those carrying the G185T mutation of factor XIII-A, which results in a hyperfibrinolytic state, were more likely not to respond to PDT, whereas those with factor V 1691A and prothrombin 20210A, both prothrombotic state, did better.
Anti-VEGF Agents
This treatment has been shown to have significant efficacy and has been the subject of interest as to whether genetics may play a role in outcomes. In a study of 86 patients treated with bevacizumab (Avastin), those with the risk CC genotype in CFH had worse visual outcomes than those with other genotypes. This appears to be replicated by a larger study of patients receiving ranibizumab. Although these are associations rather than causal findings, these studies introduce the idea that common AMD-susceptibility genes may play a role in determining treatment outcome.
METHODS & RESULTS
The study was a two-site prospective open-label observational study of patients newly diagnosed with exudative (neovascular) AMD receiving intravitreal ranibizumab therapy. Treatment-naïve patients were enrolled at presentation and received monthly "as needed" therapy. Clinical data was collected monthly and DNA extracted. Genotyping was performed using the Illumina (San Diego, California) 660-Quad single-nucleotide polymorphism (SNP) chip. Regression analyses were performed to identify SNPs associated with treatment-response end points.
Sixty-five patients were enrolled. No serious adverse events were recorded. The primary outcome measure was change in ETDRS visual acuity at 12 months. A SNP in the CFH gene was found to be associated with less improvement in visual acuity while receiving ranibizumab therapy. The C3 gene, among others, was associated with reduced thickening and improved retinal architecture. VEGFA, FLT1, and CFH were associated with requiring fewer ranibizumab injections over the 12-month study.
DISCUSSION & CONCLUSIONS
To date, two pharmacogenetic studies of anti-VEGF therapy for neovascular AMD have been published. Both were retrospective. The first reported the results of 86 patients treated with bevacizumab (Avastin), the humanized monoclonal antibody from which ranibizumab (Lucentis) was developed. The second included 156 patients who received bevacizumab.110 It was the intent of this study to overcome many of these problems with prospective enrollment and clearly stated inclusion/exclusion criteria that limit phenotypic heterogeneity while achieving a reasonable enrollment rate.
When outcomes are examined independent of genotype, the eyes enrolled performed similarly to other studies. On average, individuals gained almost 6 ETDRS letters, and the OCT central macular thickness reduced by about 110 µm. On average, six or seven ranibizumab injections were required over the year, which indicates that treating physicians/investigators adhered to clinical practice norms. Overall, these are typical results for eyes with neovascular AMD.
In line with the two previous retrospective studies, the CFH gene was implicated in determining poorer visual outcomes together with a SNP in the CTGF gene. It is not known why the CFH gene, which has been identified in numerous studies as one of the two major susceptibility variants for AMD development, might influence treatment response. It is tempting to speculate that this is because genotypes in CFH dictate the severity or persistence of the CNV.
In analyses on the change in central macular thickness (at both 6 and 12 months), a good surrogate for improved anatomy of the central macular region and in turn crudely correlated with better vision, the minor allele of a SNP in complement factor 3 (C3) appears associated with reduced thickening and improved architecture. This same SNP has been previously implicated as an AMD susceptibility variant.
The candidate gene analysis strongly implicates FLT1 (VEGFA receptor) in the treatment response, identifying several SNPs associated with persistent leakage on fluorescein angiography at both 6 and 12 months. No other genes are identified on genome-wide analysis.
One of the most pertinent pharmacogenetic findings would be the identification of genetic variants that might be used to predict which eyes might receive less frequent injections. In this regard, this study reveals three biologically plausible candidates warranting further investigation: VEGFA, its receptor FLT1, and CFH.
The findings from this study have several uses. Once validated, screening for these specific genetic variants can be performed quickly and easily in the clinical environment to identify patients’ response characteristics. In those with favorable genetic predisposition, in the case of ranibizumab, fewer injections need to be scheduled and perhaps the intervals between treatments and visits can be lengthened. In the case of those with worse genotypes, more frequent interventions can be considered, including potentially involving the use of other modalities. Additionally, this form of research can identify new avenues for drug development by implicating novel genes and the proteins they encode in disease pathogenesis and susceptibility.
In summary, this study is a prospective pharmacogenetic study of genetically determined treatment response to intravitreal ranibizumab for neovascular AMD. Although small in nature, the aim was principally to demonstrate the methodology needed to conduct such studies. Encouragingly, the results identify a number of putative genetic variants, which will be further examined by replication and functional studies to elucidate the complete pharmacogenetic architecture of therapy for AMD.
Read more...
Trans Am Ophthalmol Soc. 2011 Dec;109:115-56
