Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT)

Abstract

Purpose To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis) or bevacizumab (Avastin) for neovascular AMD. Design Clinical trial. Participants 834 (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers. Methods Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays. Main Outcomes Measures Genotypic frequencies were compared to clinical measures of response to therapy at one year including mean visual acuity (VA), mean change in VA, ≥15 letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, p≤0.01 was considered statistically significant. Results No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomical response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size) or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; i.e., response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata (PRN) dosing. Conclusions Although specific alleles for CFH, ARMS2, HTRA1 and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor (VEGF) therapy.

Defining response to anti-VEGF therapies in neovascular AMD

“…36 Thus far, the larger studies have not found pharmacogenetic associations with responsiveness to treatment. 37,38 There is, however, emerging evidence that responses to anti-VEGF therapy in n-AMD may be influenced by the genetic profile of the individual. 13,15,18 It is possible that other factors such as lifestyle may also affect the responsiveness to treatment and patients should be encouraged to quit smoking even if there is no evidence of reduced effectiveness of anti-VEGF agents in smokers 39,40 given the link between smoking and AMD and the risk to the fellow eye.…”

Effect of ARMS2 gene polymorphism on intravitreal ranibizumab treatment for neovascular age-related macular degeneration

“…There have been reports that CFH Y402H, ARMS2 rs10490924, HTRA1 rs11206038, and VEGFA polymorphisms are associated with responsiveness to ranibizumab treatment (Lee et al, 2009;Smailhodzic et al, 2012;Boltz et al, 2012;Chang et al, 2013). However, in the CATT and IVAN trials, which were multicentric randomized trials, the authors reported that there were no statistically significant associations between the genetic variants and anti-VEGF responsiveness (Hagstrom et al, 2013(Hagstrom et al, , 2014Lotery et al, 2013). Therefore, the association of genetic factors with anti-VEGF treatment responsiveness in neovascular AMD remains unclear (Park et al, 2014).…”

“…The mechanism underlying this heterogeneity in clinical response is unknown. The genetic factors and variations may be effective on the course of the disease (Hagstrom et al, 2013).…”

“…Many AMD related single nucleotide polymorphisms (SNPs) in different genes have been reported (Ding et al, 2009;Deangelis et al, 2011;Zhang et al 2015). Although the risks associated with these SNPs have been reported, the influence of these genetic variants on the response to therapy is still unclear (Lotery et al, 2013;Hagstrom et al, 2013Hagstrom et al, , 2014. Through pharmacogenetic studies, the confirmed genetic biomarkers may allow for individualized treatment with optimized results.…”

Vascular Endothelial Growth Factor: An Overview Across Multiple Disease Conditions

“…The categorization of the identified SNPs into the two above groups, AMD-related and pharmacologically related SNPs, revealed that the more widely studied AMD-related SNPs have yet to provide a substantiated clinical predictive value (Hagstrom et al, 2013). Anti-VEGF-related SNPs have not yet accumulated the same amount of evidence as AMD-related SNPs either to commend or reject them as potentially useful biomarkers.…”