Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT)
Open accessAbstract
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.
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Claims the paper makes
19 of 27 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured
- Premiseown data
More than 92% of CATT participants had stable or improved VA relative to baseline.
“The majority of CATT participants (>92%) had stable or improved VA relative to baseline.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [1] 2011, Ranibizumab and bevacizumab for neovascular age-related macular degeneration, N Engl J Med source
The Results (Mean Change in Visual Acuity; page unavailable) report improved mean visual acuity in all four CATT groups. The Discussion defines maintained acuity as losing fewer than 15 letters, which can include a decline from baseline. Neither passage establishes that more than 92% of individual participants had unchanged or improved acuity. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Premisecitation
CATT showed that bevacizumab was equivalent to ranibizumab in improving VA in neovascular AMD when given monthly or PRN.
“The Comparison of AMD Treatments Trials (CATT) showed that bevacizumab was equivalent to ranibizumab in improving visual acuity (VA) of patients with neovascular AMD when treatment was administered either monthly or pro re nata (PRN).1”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] 2011, Ranibizumab and bevacizumab for neovascular age-related macular degeneration, N Engl J Med source
- Premisenone given
There was a wide range in treatment response despite the overall clinical effect.
“However, despite this remarkable clinical effect, there was a wide range in treatment response.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] 2011, Ranibizumab and bevacizumab for neovascular age-related macular degeneration, N Engl J Med source
- Findingown data
No high-risk alleles predicted the number of injections in the PRN treatment groups.
“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.”
- Also stated in: § Number of Injections in the PRN Treatment Groups · plain
“Among the participants in the two PRN groups, no statistically significant difference was found in the number of injections among the different genotypes for any of the four SNPs, or for the total number of risk alleles from the four SNPs (Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Number of Injections in the PRN Treatment Groups · plain
- Findingown data
No high-risk alleles predicted anatomical outcomes (fluid on OCT or FA, retinal thickness, change in total foveal thickness, or change in lesion size) at one year.
“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.”
- Also stated in: § Anatomical Outcomes by Genotype · plain
“For each of the five anatomic outcomes evaluated at one year, there was no significant association with any of the genotypes or with the number of alleles from the four SNPs (Table 3).”
Quote in the paperSubstantial claim - Also stated in: § Anatomical Outcomes by Genotype · plain
- Findingown data
Longitudinal models using additional time points (12, 24, 36 weeks) found no association between genotype and mean change in VA from baseline (smallest p=0.30).
“Furthermore, when additional time-points (12, 24 and 36 weeks) were evaluated using longitudinal models, there was no association between genotype and mean change in VA from baseline (smallest p value = 0.30).”
Quote in the paperSubstantial claim - Findingown data
No high-risk alleles predicted visual outcomes (final VA, change in VA, or ≥15 letter increase) at one year.
“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.”
- Also stated in: § Visual Outcomes by Genotype · plain
“For each of the three visual measures evaluated at one year, there was no association with any of the genotypes or with the number of risk alleles from the four SNPs (Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Visual Outcomes by Genotype · plain
- Findingown data
In the CATT genetics substudy, no statistically significant differences in response to anti-VEGF therapy were found by genotype for any of the clinical measures studied at one year.
“No statistically significant differences in response by genotype were identified for any of the clinical measures studied.”
- Also stated in: § Discussion · plain
“In our study, we found no statistically significant pharmacogenetic association between these SNPs and visual acuity outcomes, anatomical outcomes or the number of injections required.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Longitudinal models using additional time points (12 and 24 weeks) found no association between genotype and mean change in total foveal thickness from baseline (smallest p=0.27).
“Furthermore, when additional time-points (12 and 24 weeks) were evaluated using longitudinal models, there was no association between genotype and mean change in total foveal thickness from baseline (smallest p value = 0.27).”
Quote in the paperNot a substantial claim - Study design and conductown data
Genotypic frequencies for each SNP were balanced across treatment groups, drug, and dosing regimen.
“The genotypic frequencies for each SNP analyzed were balanced across treatment groups, drug and dosing regimen (data not shown).”
Quote in the paperSubstantial claim - Study design and conductown data
Allele identification for the SNP assays was verified by direct DNA sequencing of 10 samples per assay, yielding 100% concordance.
“The allele identification of the SNP assays was verified by direct DNA sequence analysis from 10 samples for each assay yielding 100% concordance.”
Quote in the paperNot a substantial claim - Interpretationown data
Alteration of ARMS2 or HTRA1 via these SNPs does not strongly influence anti-VEGF therapy.
“The precise mechanisms by which these genetic variants affect AMD susceptibility are still not fully understood and our data indicate that alteration of either ARMS2 or HTRA1 via these SNPs does not strongly influence anti-VEGF therapy.”
Quote in the paperSubstantial claim - Interpretationreasoning
The lack of association is supported by the study's high power and rigorously assessed outcome variables.
“This lack of association is supported by the high power provided by our large sample size and rigorously assessed outcome variables.”
Quote in the paperSubstantial claim - Interpretationown data
The major risk alleles that influence AMD development do not strongly affect clinical response to therapy.
“This study provides convincing evidence that the major risk alleles that influence the development of AMD do not strongly affect clinical response to therapy.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 15
- May combine two claims. 18
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOther studies report no association between the CFH risk genotype and treatment response.
“However, other studies report no association with the risk genotype.9,10”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [9] Orlin, 2012, Association between high-risk disease loci and response to anti-vascular endothelial growth factor treatment for wet age-related macular degeneration, Retina source
- cites [10] McKibbin, 2012, CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration, Br J Ophthalmol source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGenetic variation at this locus confers differential risk for CNV versus geographic atrophy.
“Genetic variation at this locus has been shown to confer a differential risk for CNV versus geographic atrophy.21”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] Sobrin, 2011, ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration, Am J Ophthalmol source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe A69S polymorphism has been proposed to alter ARMS2 function and increase photoreceptor susceptibility to oxidative damage and aging.
“it has been proposed that the A69S polymorphism alters ARMS2 function and increases susceptibility of photoreceptor cells to oxidative damage and aging.22”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [22] Kanda, 2007, A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration, Proc Natl Acad Sci U S A source
Classified as probably not a substantial claim.
PremisecitationReports indicate that patients homozygous for the CFH Y402H risk allele had worse visual outcomes or required more injections than patients with other genotypes.
“Reports investigating either bevacizumab or ranibizumab indicate that patients homozygous for the risk allele at the CFH Y402H polymorphism experienced worse visual outcomes or required more injections than patients with other genotypes.4–8”
Quote in the paperSubstantial claim3 of 5 sources checked- cites [4] Brantley, 2007, Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab, Ophthalmology sourceExperimental — accuracy not yet measured
- cites [5] Lee, 2009, Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab, Br J Ophthalmol sourceExperimental — accuracy not yet measured
- cites [6] Teper, 2010, Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration, Mol Vis [serial online]
- cites [7] Nischler, 2011, Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age-related macular degeneration [report online], Acta Ophthalmol sourceExperimental — accuracy not yet measured
- cites [8] Francis, 2011, The influence of genetics on response to treatment with ranibizumab (Lucentis) for age-related macular degeneration: the Lucentis Genotype Study (an American Ophthalmological Society thesis), Trans Am Ophthalmol Soc
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreased inflammation in patients with complement-related AMD-risk alleles has been hypothesized to favor recurrence of neovascularization via increased VEGF.
“The increased inflammation found in patients harboring complement-related AMD-risk alleles has been hypothesized to favor recurrence of neovascularization due to increased levels of VEGF.5”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Lee, 2009, Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab, Br J Ophthalmol source
The Conclusions hypothesize that CFH Y402H risk variants may be associated with higher background inflammation and more rapid recurrence of neovascularization. The paper does not establish that these patients had increased inflammation or attribute recurrence to increased VEGF levels; its mention of VEGF concerns anti-VEGF treatment. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationAt one year, monthly bevacizumab and ranibizumab groups gained 8.0 and 8.5 letters, respectively, while PRN groups gained 5.9 and 6.8 letters.
“At one year, participants treated monthly with bevacizumab or ranibizumab gained 8.0 and 8.5 letters, respectively, and those treated as needed gained 5.9 and 6.8 letters, respectively.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [1] 2011, Ranibizumab and bevacizumab for neovascular age-related macular degeneration, N Engl J Med source
Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
PremisecitationOverexpression of HTRA1 has been hypothesized to alter Bruch's membrane integrity and favor CNV development.
“It has been hypothesized that overexpression of HTRA1 may alter the integrity of Bruch’s membrane and favor the development of CNV.2”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] Ding, 2009, Molecular pathology of age-related macular degeneration, Prog Retin Eye Res source
Classified as probably not a substantial claim.
PremisecitationNumerous SNPs in multiple genes have been associated with the prevalence of early and/or late AMD.
“Pioneering developments in AMD genetics research have identified numerous single nucleotide polymorphisms (SNPs) in multiple genes associated with the prevalence of the early and/or late stages of AMD.2,3”
Quote in the paperSubstantial claim2 of 2 sources checkedMay combine two claims.
PremisecitationThe four SNPs studied have consistently shown the strongest associations with AMD development and progression and have been postulated to influence treatment response.
“Although other susceptibility genes have been reported, these four SNPs have consistently been shown to have the strongest associations with the development and progression of AMD and have been postulated to influence response to therapy.2,3,12”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [2] Ding, 2009, Molecular pathology of age-related macular degeneration, Prog Retin Eye Res source
Sections 3.2 and 3.4 report strong associations of particular CFH, ARMS2, and HtrA1 variants with AMD risk, and section 7 reports that a risk-conferring CFH variant was associated with reduced response to antioxidant and zinc therapy. The paper does not establish that the citing study’s four SNPs, as a group, consistently have the strongest associations with both AMD development and progression or that all four may influence treatment response. No page numbers were provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [3] Deangelis, 2011, Genetics of age-related macular degeneration: current concepts, future directions, Semin Ophthalmol source
The Introduction (page unavailable) identifies the CFH and ARMS2/HTRA1 regions as having large effects on AMD risk, particularly neovascular AMD risk. It does not establish that the four SNPs in the citing study are consistently the strongest for both development and progression. The Conclusions (page unavailable) say that no consistent correlation between genotype and treatment response had been established; they do not support the claim that these four SNPs had been postulated to influence treatment response. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [12] Schwartz, 2011, Pharmacogenetics and age-related macular degeneration, J Ophthalmol [serial online] source
In §2 (Studied Genotypes; page unavailable), the paper describes CFH as strongly linked to AMD and the ARMS2/HTRA1 locus as consistently associated with it. Sections 3–5 examine whether genetic variants influence treatment response. The paper does not identify four SNPs as consistently having the strongest associations with both AMD development and progression; §3 reports no significant association with progression for ARMS2 A69S in the AREDS analysis. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationResults for ARMS2 A69S and HTRA1 promoter polymorphisms are conflicting, and no definitive conclusions can be drawn.
“Results from studies evaluating the ARMS2 A69S and HTRA1 promoter polymorphisms are also conflicting with regard to treatment response and no definitive conclusions can be drawn.9–11”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [9] Orlin, 2012, Association between high-risk disease loci and response to anti-vascular endothelial growth factor treatment for wet age-related macular degeneration, Retina source
The Discussion (page unavailable) reports no significant association between the tested ARMS2/HTRA1 variants and anti-VEGF response and calls for a larger study, supporting the lack of a definitive conclusion. But the paper does not establish conflicting results from studies of both named polymorphisms: it says there were no previously published reports assessing HTRA1’s influence on treatment response. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [10] McKibbin, 2012, CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration, Br J Ophthalmol source
- cites [11] Kloeckener-Gruissem, 2011, Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD, Invest Ophthalmol Vis Sci source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe ARMS2 gene product has been localized to the mitochondrial outer membrane.
“The ARMS2 gene product has been localized to the mitochondrial outer membrane”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [22] Kanda, 2007, A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration, Proc Natl Acad Sci U S A source
May combine two claims.
Findingown dataThe strongest injection association was for HTRA1 (p=0.25), with the highest mean number of injections (8.0) in AA homozygotes and equal mean injections (7.3) in AG heterozygotes and GG homozygotes.
“The strongest association was for HTRA1 (p=0.25) where the highest mean number of injections (8.0) was among those homozygous for the risk allele (AA) and an equal mean number of injections (7.3) was required among those heterozygous for the risk allele (AG) or homozygous for the non-risk allele (GG).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe strongest visual association was for mean VA with C3 (p=0.03), with better VA among those homozygous for the risk allele (GG).
“The strongest association was for mean visual acuity with C3 (p=0.03); however, the association was for better visual acuity among those homozygous for the risk allele (GG).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe lack of association between genotype and response was similar whether patients received ranibizumab or bevacizumab and whether dosing was monthly or PRN.
“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.”
- Also stated in: § Results · plain
“The effect of risk alleles on each measure did not differ by treatment group, drug or regimen.”
Quote in the paperSubstantial claim- Also stated in: § Results · plain
May combine two claims.
Findingown dataA stepwise analysis found no significant epistatic interaction among the four variants, and response did not vary with the number of risk alleles present.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe strongest anatomical association was for mean change in total retinal thickness with CFH (p=0.03), with less improvement in CC homozygotes and largest improvement in CT heterozygotes.
“The strongest association was for mean change in total retinal thickness with CFH (p=0.03) where the association was for less improvement (decrease 142 microns) among those homozygous for the risk allele (CC) and largest improvement (decrease 188 microns) among those with heterozygous for risk allele (CT).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe study had high power (93-98%) to detect a 2.5-letter VA difference, moderate power (75-85%) for a 2-letter difference, and >85% power for a 0.06 difference in categorical proportions.
“Data from the CATT study provided high power (93% to 98%) to detect a mean difference of 2.5 letters in VA and moderate power (75% to 85%) to detect a difference of 2 letters in VA associated with one risk allele change, under the observed standard deviation of 16 to 18 letters in VA and type I error of 0.01.”
- Also stated in: § Data Analysis · plain
“For categorical outcomes, the CATT study data provided high power (>85%) to detect a difference of 0.06 or more in the proportion associated with the addition of one risk allele.”
Quote in the paperSubstantial claim- Also stated in: § Data Analysis · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe possibility cannot be excluded that other SNPs less predictive of AMD risk may be associated with treatment response.
“We cannot exclude the possibility that other SNPs that are less predictive of AMD risk may be associated with response to therapy.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAlthough specific alleles for CFH, ARMS2, HTRA1, and C3 may predict AMD development, they did not predict response to anti-VEGF therapy.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenVisual acuities were determined by masked examiners using electronic EDTRS testing, OCT measurements by a masked independent OCT Reading Center, and photographic/FA outcomes by masked assessment at an independent Fundus Photographic Reading Center.
“Specifically, all visual acuities were determined by masked examiners using electronic EDTRS testing, all OCT measurements were determined in a masked fashion by an independent OCT Reading Center and all photographic and fluorescein angiographic outcomes were determined by masked assessment at an independent Fundus Photographic Reading Center.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningCATT is a large, prospectively defined cohort from multiple clinical sites with follow-up treatment and outcomes carried out under well-defined protocols.
“CATT is a large, prospectively defined cohort of patients with neovascular AMD drawn from multiple clinical sites with all follow-up treatment and outcomes carried out under well-defined protocols.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataPatients were randomly assigned to one of four treatment groups: ranibizumab monthly, bevacizumab monthly, ranibizumab PRN, or bevacizumab PRN.
“Patients were randomly assigned to one of the four treatment groups: (1) ranibizumab monthly; (2) bevacizumab monthly; (3) ranibizumab PRN; and (4) bevacizumab PRN.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductreasoningTo account for multiple comparisons across SNPs and outcomes, p≤0.01 was considered statistically significant.
“To account for multiple comparisons from multiple SNPs and multiple outcomes, we considered p≤0.01 as statistically significant.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningAll examiners, readers, and laboratory personnel were masked to treatment assignment and clinical data.
“All examiners and readers were masked to treatment assignment.”
- Also stated in: § Genotype Determination · plain
“All laboratory personnel were masked to treatment assignment and patient clinical data.”
Quote in the paperSubstantial claim- Also stated in: § Genotype Determination · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationARMS2 and HTRA1 lie in the AMD susceptibility locus on chromosome 10q26 and are expressed in the retina.
“ARMS2 and HTRA1 both lie in the AMD susceptibility locus identified on chromosome 10q26 and are expressed in the retina.20”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Tong, 2010, LOC387715/HTRA1 gene polymorphisms and susceptibility to age-related macular degeneration: a HuGE review and meta-analysis, Mol Vis [serial online]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInflammation has been postulated to reduce response to anti-VEGF treatment.
“In addition, inflammation has been postulated to reduce response to anti-VEGF treatment.19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Bressler, 2009, Introduction: understanding the role of angiogenesis and antiangiogenic agents in age-related macular degeneration, Ophthalmology source
May combine two claims.
Interpretationown dataThe complement pathway, or at least these SNPs in it, does not strongly influence response to anti-VEGF therapy.
“However, there is little biological evidence to support this idea and our data provides convincing evidence that the complement pathway, or at least these SNPs in the complement pathway, do not strongly influence response to therapy.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataGenetic substudy participants were generally comparable to nonparticipants except that they were two years younger, had better baseline VA, and had higher rates of hypertension and occult lesion.
“The genetic study participants were generally comparable to those who were still alive but chose not to participate (n = 315) except that the genetic study participants were two years younger (p<0.001), had better baseline VA (p=0.005), higher percentage with hypertension (p=0.045), and higher percentage with occult lesion (p=0.04) (Table 1).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe HTRA1 SNP is located in the promoter region and is predicted to increase gene expression.
“The SNP evaluated in HTRA1 is located in the promoter region and is predicted to increase expression levels of the gene.23”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Dewan, 2006, HTRA1 promoter polymorphism in wet age-related macular degeneration, Science source
The authors state this as an assumption.
Genetic variants play a role in the heterogeneity of clinical response to anti-VEGF therapy.
“Given the impact of genetic factors on disease manifestation and progression, a logical assumption would be that genetic variants play a role.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Two large, multicenter randomized clinical trials could not replicate the reported pharmacogenetic associations with anti-VEGF treatment.
“However, two large, multicenter randomized clinical trials could not replicate these findings [36,37].”
From Genetics and Age-Related Macular Degeneration: A Practical Review for Clinicians. (2024) · cites this paper as [36]
Larger studies have not found pharmacogenetic associations with responsiveness to treatment.
“Thus far, the larger studies have not found pharmacogenetic associations with responsiveness to treatment.37,38”
From Defining response to anti-VEGF therapies in neovascular AMD (2015) · cites this paper as [37]
Experimental — accuracy not yet measuredSpecific alleles for CFH (rs1061170), ARMS2 (rs10490924), and HTRA1 (rs11200638) did not predict response to anti-VEGF therapy in the CATT randomized controlled trial.
“However, specific alleles for CFH (rs1061170), ARMS2 (rs10490924), and HTRA1 (rs11200638) did not predict response to anti-VEGF therapy in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) randomized controlled trial.24”
From <i>ANO2</i> Genetic Variants and Anti-VEGF Treatment Response in Neovascular AMD: A Pharmacogenetic Substudy of VIEW 1 and VIEW 2 (2024) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
C3 amino-acid change is described in reverse
MinorThe designation R80G indicates a change from arginine (R) to glycine (G) at codon 80, but the description states the reverse change.
“Complement component 3 (C3) R80G (rs2230199)”
“resulting in the amino acid glycine to arginine at codon 80.”
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“The Comparison of AMD Treatments Trials (CATT) showed that bevacizumab was equivalent to ranibizumab in improving visual acuity (VA) of patients with neovascular AMD when treatment was administered either monthly or pro re nata (PRN).(1) At 1 year, participants treated monthly with bevacizumab or ranibizumab gained r”
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“The increased inflammation found in patients harboring complement-related AMD-risk alleles has been hypothesized to favor recurrence of neovascularization resulting from increased levels of VEGF.”
Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD
Kloeckener-Gruissem, B., Barthelmes, D., Labs, S., Schindler, C., Kurz-Levin, M., Michels, S., Fleischhauer, J., Berger, W., Sutter, F., & Menghini, M. (2011) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.10-6080 · Cited by 120 · see citing works
McKibbin, M., Ali, M., Bansal, S., Baxter, P. D., West, K., Williams, G., Cassidy, F., & Inglehearn, C. F. (2012) · British Journal of Ophthalmology · doi:10.1136/bjo.2010.193680 · Cited by 100 · see citing works
Genetics of age-related macular degeneration: current concepts, future directions
DeAngelis, M. M., Silveira, A. C., Carr, E. A., & Kim, I. K. (2011) · Seminars in Ophthalmology · doi:10.3109/08820538.2011.577129 · Cited by 94 · cited 2× · see citing works
“Pioneering developments in AMD genetics research ave identified numerous single nucleotide polymorphisms SNPs) in multiple genes associated with the prevalence of he early or late stages of AMD, or both.(2,3) Although the isk associated with these SNPs is well characterized, the”
Self-citationAssessing Susceptibility to Age-related Macular Degeneration with Proteomic and Genomic Biomarkers
Gu, J., Pauer, G. J. T., Yue, X., Narendra, U., Sturgill, G. M., Bena, J., Gu, X., Peachey, N. S., Salomon, R. G., Hagstrom, S. A., et al. (2009) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800453-mcp200 · Cited by 89 · see citing works
Self-citationNischler, C., Oberkofler, H., Ortner, C., Paikl, D., Riha, W., Lang, N., Patsch, W., & Egger, S. F. (2011) · Acta Ophthalmologica · doi:10.1111/j.1755-3768.2010.02080.x · Cited by 81 · see citing works
Yu, T., Liao, J., Zhang, Y., Zhou, J., Zhang, H., & Mao, M. (2010) · PubMed Central · Cited by 79 · see citing works
Sobrin, L., Reynolds, R., Yu, Y., Fagerness, J., Leveziel, N., Bernstein, P. S., Souied, E. H., Daly, M. J., & Seddon, J. M. (2011) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2010.08.015 · Cited by 78 · see citing works
(2010) · PubMed Central · Cited by 71 · see citing works
Orlin, A., Hadley, D., Chang, W., Ho, A. C., Brown, G., Kaiser, R. S., Regillo, C. D., Godshalk, A. N., Lier, A., Kaderli, B., et al. (2012) · Retina · doi:10.1097/iae.0b013e31822a2c7c · Cited by 60 · cited 1× · see citing works
“However, other studies report no association with the risk genotype.(9,10) Results from studies evaluating the ARMS2 A69S and HTRA1 promoter polymorphisms also conflict with regard to treatment response, and no definitive conclusions can be drawn.”
(2011) · Europe PMC (PubMed Central) · Cited by 55 · see citing works
Grunwald, J. E., Daniel, E., Ying, G., Pistilli, M., Maguire, M. G., Alexander, J., Martin, R., Parker, C., Sepielli, K., Blodi, B. A., et al. (2012) · Ophthalmology · doi:10.1016/j.ophtha.2012.02.013 · Cited by 53 · see citing works
Self-citationA Nanoliter Fluidic Platform for Large-Scale Single Nucleotide Polymorphism Genotyping
Roberts, D., Morrison, T. B., Liu-Cordero, S. N., et al. (2009) · BioTechniques · doi:10.2144/000112887 · Cited by 22 · see citing works
Pharmacogenetics and Age-Related Macular Degeneration
Schwartz, S. G., & Brantley, M. A. (2011) · Journal of Ophthalmology · doi:10.1155/2011/252549 · Cited by 15 · see citing works
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Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials
Grunwald, J. E., Daniel, E., Huang, J., Ying, G.-S., Maguire, M. G., Toth, C. A., Jaffe, G. J., Fine, S. L., Blodi, B., Klein, M. L., et al. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2013.08.015 · Cited by 590 · see citing works
Self-citationImmunology of age-related macular degeneration
Ambati, J., Atkinson, J. P., & Gelfand, B. D. (2013) · Nature reviews. Immunology · doi:10.1038/nri3459 · Cited by 591 · see citing works
Anti-vascular endothelial growth factor for neovascular age-related macular degeneration
Solomon, S. D., Lindsley, K., Vedula, S. S., Krzystolik, M. G., & Hawkins, B. S. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005139.pub3 · Cited by 520 · see citing works
A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration
Schmidt-Erfurth, U., & Waldstein, S. M. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2015.07.007 · Cited by 390 · see citing works
“However, other reports failed to replicate these findings (Hagstrom et al., 2013, 2014; Park et al., 2014).”
ResultMettu, P. S., Allingham, M. J., & Cousins, S. W. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100906 · Cited by 370 · see citing works
Defining response to anti-VEGF therapies in neovascular AMD
Amoaku, W. M., Chakravarthy, U., Gale, R., Gavin, M., Ghanchi, F., Gibson, J., Harding, S., Johnston, R. L., Kelly, S., Lotery, A., et al. (2015) · Eye · doi:10.1038/eye.2015.48 · Cited by 355 · see citing works
Risk factors and biomarkers of age-related macular degeneration
Lambert, N. G., Elshelmani, H., Singh, M. K., Mansergh, F. C., Wride, M. A., Padilla, M., Keegan, D., Hogg, R. E., & Ambati, B. K. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2016.04.003 · Cited by 352 · see citing works
“In the recent Comparison of AMD Treatments Trial (CATT), there was no statistically significant difference between different allelic genotypes in patients with CFH SNP rs1061170 (Hagstrom et al., 2013) – a CFH SNP strongly associated with AMD development (Klein et al., 2013).”
InfluentialAnti-vascular endothelial growth factor for neovascular age-related macular degeneration
Solomon, S. D., Lindsley, K. B., Vedula, S. S., Krzystolik, M. G., & Hawkins, B. S. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005139.pub4 · Cited by 275 · see citing works
Grunwald, J. E., Pistilli, M., Daniel, E., Ying, G.-S., Pan, W., Jaffe, G. J., Toth, C. A., Hagstrom, S. A., Maguire, M. G., & Martin, D. F. (2017) · Ophthalmology · doi:10.1016/j.ophtha.2016.09.012 · Cited by 214 · see citing works
Self-citationGrowth of Geographic Atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials
Grunwald, J. E., Pistilli, M., Ying, G., Maguire, M. G., Daniel, E., & Martin, D. F. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2014.11.007 · Cited by 204 · see citing works
Self-citationNature and nurture- genes and environment- predict onset and progression of macular degeneration
Sobrin, L., & Seddon, J. M. (2014) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2013.12.004 · Cited by 178 · see citing works
“substudy did not find that AMD risk alleles predicted response to anti-VEGF therapy (Hagstrom et al., 2013).”
Age-Related Macular Degeneration: Pathophysiology, Management, and Future Perspectives
Flores, R., Carneiro, Â. M., Vieira, M., Tenreiro, S., & Seabra, M. C. (2021) · Ophthalmologica · doi:10.1159/000517520 · Cited by 175 · see citing works
Age-Related Macular Degeneration
Apte, R. S. (2021) · New England Journal of Medicine · doi:10.1056/nejmcp2102061 · Cited by 174 · see citing works
Targeting the complement system for the management of retinal inflammatory and degenerative diseases
Xu, H., & Chen, M. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.03.001 · Cited by 162 · see citing works
“However, the data about whether polymorphisms in complement genes and other AMD risk factor genes can be used to predict the response to VEGFA ‑ targeted therapies are con fl icting (Hagstrom et al., 2013, Smailhodzic et al., 2012).”
BackgroundPredictors of anti-VEGF treatment response in neovascular age-related macular degeneration
Finger, R. P., Wickremasinghe, S. S., Baird, P. N., & Guymer, R. H. (2014) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2013.03.009 · Cited by 144 · see citing works
Kuroda, Y., Yamashiro, K., Miyake, M., Yoshikawa, M., Nakanishi, H., Oishi, A., Tamura, H., Ooto, S., Tsujikawa, A., & Yoshimura, N. (2015) · Ophthalmology · doi:10.1016/j.ophtha.2015.06.053 · Cited by 118 · see citing works
Lechner, J., Chen, M., Hogg, R. E., Tóth, L., Silvestri, G., Chakravarthy, U., & Xu, H. (2016) · Immunity & Ageing · doi:10.1186/s12979-016-0060-5 · Cited by 113 · see citing works
Ying, G., Maguire, M. G., Daniel, E., Ferris, F. L., Jaffe, G. J., Grunwald, J. E., Toth, C. A., Huang, J., & Martin, D. F. (2015) · Ophthalmology · doi:10.1016/j.ophtha.2015.08.015 · Cited by 105 · see citing works
Self-citationMaguire, M. G., Daniel, E., Shah, A. R., Grunwald, J. E., Hagstrom, S. A., Avery, R. L., Huang, J., Martin, R. W., Roth, D. B., Castellarin, A. A., et al. (2013) · Ophthalmology · doi:10.1016/j.ophtha.2013.03.017 · Cited by 93 · see citing works
Self-citationChew, E. Y., Klein, M. L., Clemons, T. E., Agrón, E., Ratnapriya, R., Edwards, A. O., Fritsche, L. G., Swaroop, A., & Abecasis, G. R. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2014.05.008 · Cited by 94 · see citing works
Self-citationEmerging therapeutic strategies for unmet need in neovascular age-related macular degeneration
Khachigian, L. M., Liew, G., Teo, K. Y. C., Wong, T. Y., & Mitchell, P. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-03937-7 · Cited by 96 · see citing works
Towards the application of precision medicine in Age-Related Macular Degeneration
Cascella, R., Strafella, C., Caputo, V., Errichiello, V., Zampatti, S., Milano, F., Potenza, S., Mauriello, S., Novelli, G., Ricci, F., et al. (2018) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.11.004 · Cited by 76 · see citing works
Csaky, K. G., Dugel, P. U., Pierce, A. J., Fries, M. A., Kelly, D. S., Danis, R. P., Wurzelmann, J. I., Xu, C., Hossain, M. S., & Trivedi, T. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2014.09.036 · Cited by 75 · see citing works
Martin, D. F. (2018) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2017.12.019 · Cited by 76 · see citing works
Self-citationGenetics and genetic testing for age-related macular degeneration
Warwick, A., & Lotery, A. (2018) · Eye · doi:10.1038/eye.2017.245 · Cited by 67 · see citing works
Lotery, A. J., Gibson, J., Cree, A. J., Downes, S. M., Harding, S. P., Rogers, C. A., Reeves, B. C., Ennis, S., & Chakravarthy, U. (2013) · Ophthalmology · doi:10.1016/j.ophtha.2013.07.046 · Cited by 64 · see citing works
VEGFA and VEGFR2 Gene Polymorphisms and Response to Anti–Vascular Endothelial Growth Factor Therapy
Hagstrom, S. A., Ying, G., Pauer, G. J. T., Sturgill-Short, G. M., Huang, J., Maguire, M. G., & Martin, D. F. (2014) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2014.109 · Cited by 63 · see citing works
Self-citationBaseline Predictors for Five-Year Visual Acuity Outcomes in the Comparison of AMD Treatment Trials
Ying, G., Maguire, M. G., Pan, W., Grunwald, J. E., Daniel, E., Jaffe, G. J., Toth, C. A., Hagstrom, S. A., & Martín, D. (2017) · Ophthalmology Retina · doi:10.1016/j.oret.2017.10.003 · Cited by 59 · see citing works
Self-citationThe Role of the Complement System in Age-Related Macular Degeneration
Weber, B. H. F., Issa, P. C., Pauly, D., Herrmann, P., Graßmann, F., & Holz, F. G. (2014) · Deutsches Ärzteblatt international · doi:10.3238/arztebl.2014.0133 · Cited by 54 · see citing works
Yang, H., Ratnapriya, R., Cogliati, T., Kim, J.-W., & Swaroop, A. (2015) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2015.01.005 · Cited by 51 · see citing works
Advances in the genomics of common eye diseases
Bailey, J. N. C., Sobrin, L., Pericak‐Vance, M. A., Haines, J. L., Hammond, C. J., & Wiggs, J. L. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt396 · Cited by 49 · see citing works
Ho, A. C., Albini, T. A., Brown, D. M., Boyer, D. S., Regillo, C. D., & Heier, J. S. (2017) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2016.5314 · Cited by 48 · see citing works
Kuroda, Y., Yamashiro, K., Tsujikawa, A., Ooto, S., Tamura, H., Oishi, A., Nakanishi, H., Miyake, M., Yoshikawa, M., & Yoshimura, N. (2015) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2015.09.032 · Cited by 44 · see citing works
Lorés‐Motta, L., Riaz, M., Grunin, M. A., Corominas, J., van Asten, F., Pauper, M., Leenders, M., Richardson, A. J., Muether, P. S., Cree, A. J., et al. (2018) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2018.2019 · Cited by 43 · see citing works
Shah, A. R., Williams, S. L., Baumal, C. R., ROSNER, B. A., Duker, J. S., & Seddon, J. M. (2015) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2015.11.033 · Cited by 42 · see citing works
Nguyen, Q. D., Agarwal, A. K., Rhoades, W. R., Hanout, M., Soliman, M. K., Sarwar, S., Sadiq, M. A., Sepah, Y. J., & Diana, V. (2015) · Clinical ophthalmology · doi:10.2147/opth.s74959 · Cited by 41 · see citing works
Bonilha, V. L., Bell, B. A., Hu, J. G., Milliner, C., Pauer, G. J. T., Hagstrom, S. A., Radu, R. A., & Hollyfield, J. G. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.8.15 · Cited by 39 · see citing works
Self-citationPHARMACOGENOMICS OF RESPONSE TO ANTI-VEGF THERAPY IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION
Dedania, V. S., Grob, S., Zhang, K., & Bakri, S. J. (2015) · Retina · doi:10.1097/iae.0000000000000466 · Cited by 38 · see citing works
“In addition to this study, two studies also reported no association between genotype and the number of injections.(12,26) There was also no difference in the percentage of predominantly classic CNV lesions among the ARMS2 genotypes although patients heterozygous for the risk-allele were found to have the largest mean…”
BackgroundResultInfluentialHIGH-DOSE HIGH-FREQUENCY AFLIBERCEPT FOR RECALCITRANT NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
You, Q. S., Gaber, R. A., Meshi, A., Ramkumar, H. L., Alam, M. M. R., Müftüoğlu, İ. K., & Freeman, W. R. (2017) · Retina · doi:10.1097/iae.0000000000001726 · Cited by 38 · see citing works
Hong, N., Shen, Y., Yu, C., Wang, S., & Tong, J. (2016) · Acta Ophthalmologica · doi:10.1111/aos.13049 · Cited by 38 · see citing works
“…Smailhodzic et al. 2012; Tian et al. 2012; Yamashiro et al. 2012; Abedi et al. 2013; Chang et al. 2013; Dikmetas et al. 2013; Habibi et al. 2013; Hagstrom et al. 2013; Hautamaki et al. 2013, 2014; Kitchens et al. 2013; Lotery et al. 2013; Yuan et al. 2013; van Asten et al. 2014; Matsumiya et…”
BackgroundHagstrom, S. A., Ying, G.-S., Maguire, M. G., Martin, D. F., Gibson, J., Lotery, A., & Chakravarthy, U. (2015) · Ophthalmology · doi:10.1016/j.ophtha.2015.04.024 · Cited by 37 · see citing works
“DNA was extracted and purified from leukocytes as previously described.(4) Two SNPs in VEGFR2 (rs4576072 and rs6828477) were evaluated in each patient.”
InfluentialSelf-citationFauser, S., & Lambrou, G. N. (2014) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2014.11.002 · Cited by 36 · see citing works
Complement pathway biomarkers and age-related macular degeneration
Gemenetzi, M. K., & Lotery, A. J. (2015) · Eye · doi:10.1038/eye.2015.203 · Cited by 38 · see citing works
Yamashiro, K., Mori, K., Honda, S., Kano, M., Yanagi, Y., Obana, A., Sakurada, Y., Sato, T., Nagai, Y., Hikichi, T., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-09632-0 · Cited by 35 · see citing works
Rasmussen, A., & Sander, B. (2014) · Current Opinion in Ophthalmology · doi:10.1097/icu.0000000000000050 · Cited by 35 · see citing works
Maugeri, A., Barchitta, M., Mazzone, M. G., Giuliano, F., & Agodi, A. (2018) · BioMed Research International · doi:10.1155/2018/7532507 · Cited by 34 · see citing works
“Particularly, the Comparison of AMD Treatments Trials (CATT) showed no significant effect of rs2230199 polymorphism on both visual and anatomical outcomes, after anti-VEGF therapy [118].”
BackgroundNagineni, C. N., Kommineni, V. K., Ganjbaksh, N., Nagineni, K. K., Hooks, J. J., & Detrick, B. (2015) · Aging and Disease · doi:10.14336/ad.2015.0323 · Cited by 35 · see citing works
Cobos, E., Recalde, S., Anter, J., Hernandez‐Sanchez, M., Barreales, C., Olavarrieta, L., Valverde-Megías, A., Suarez‐Figueroa, M., Cruz, F., Abraldes, M. J., et al. (2017) · Acta Ophthalmologica · doi:10.1111/aos.13519 · Cited by 33 · see citing works
Exploring the Use of Molecular Biomarkers for Precision Medicine in Age-Related Macular Degeneration
Lorés‐Motta, L., de Jong, E. K., & den Hollander, A. I. (2018) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-018-0332-1 · Cited by 32 · see citing works
“Notably, the two studies based on the IVAN and CATT clinical trials did not find any association for this variant, nor for any other variant investigated, despite their large sample sizes (n = 834 and n = 509, respectively) [71, 72].”
BackgroundAllingham, M. J., Mettu, P. S., & Cousins, S. W. (2021) · Ophthalmology Science · doi:10.1016/j.xops.2021.100095 · Cited by 32 · see citing works
Chen, G., Tzekov, R., Li, W., Jiang, F., Mao, S., & Tong, Y. (2015) · Scientific Reports · doi:10.1038/srep14517 · Cited by 31 · see citing works
Hata, M., Tsujikawa, A., Miyake, M., Yamashiro, K., Ooto, S., Oishi, A., Nakanishi, H., Takahashi, A., & Yoshimura, N. (2014) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-014-2688-1 · Cited by 31 · see citing works
“However, the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group found no associations of these genetic factors with anti-VEGF therapy response in AMD (mainly tAMD) [20].”
BackgroundTalks, J. S., Daïen, V., Finger, R. P., Eldem, B. M., Sakamoto, T., Cardillo, J. A., Mitchell, P., Wong, T. Y., & Korobelnik, J. (2019) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2019.02.008 · Cited by 30 · see citing works
SCHACHAT, A. P. (2013) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2013.04.009 · Cited by 31 · see citing works
Park, U. C., Shin, J. Y., McCarthy, L. C., Kim, S. J., Park, J., Chung, H., & Yu, H. G. (2014) · PubMed Central · Cited by 30 · see citing works
Singh, R. P., Wurzelmann, J. I., Ye, L., Henderson, L. S., Hossain, M. S., Trivedi, T., & Kelly, D. S. (2014) · Retina · doi:10.1097/iae.0000000000000179 · Cited by 30 · see citing works
“It should be noted that the results of Study 2, although inconsistent with those of the previous study, are consistent with the recent Comparison of AMD Treatments Trials report that evaluated a large, prospectively defined cohort of patients with neovascular AMD; that report found no association between AMD-risk geno…”
ResultPiermarocchi, S., Miotto, S., Colavito, D., Leon, A., & Segato, T. (2014) · Acta Ophthalmologica · doi:10.1111/aos.12587 · Cited by 29 · see citing works
“However, results regarding the role of genetics on response to antiVEGF are often conflicting (Smailhodzic et al. 2012; Hagstrom et al. 2013).”
BackgroundMethodNguyen, V., Daïen, V., Guymer, R. H., Young, S. H., Hunyor, A. P., Fraser‐Bell, S., Hunt, A., Gillies, M. C., & Barthelmes, D. (2018) · Ophthalmology · doi:10.1016/j.ophtha.2018.08.023 · Cited by 28 · see citing works
Kikushima, W., Sakurada, Y., Yoneyama, S., Sugiyama, A., Tanabe, N., Kume, A., Mabuchi, F., & Iijima, H. (2017) · Scientific Reports · doi:10.1038/srep44020 · Cited by 28 · see citing works
Biomarkers as Predictive Factors of Anti-VEGF Response
Bobadilla, M., Pariente, A., Ana, I., Peláez, R., Pérez-Sala, Á., & Larráyoz, I. M. (2022) · Biomedicines · doi:10.3390/biomedicines10051003 · Cited by 26 · see citing works
Predictive Biomarkers of Age-Related Macular Degeneration Response to Anti-VEGF Treatment
Oca, A. I., Pérez-Sala, Á., Pariente, A., Ochoa, R., Velilla, S., Peláez, R., & Larráyoz, I. M. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11121329 · Cited by 25 · see citing works
Krishnan, R., Arora, R., Salvo, G. D., Stinghe, A., Severn, P. S., Pal, B., & Goverdhan, S. V. (2015) · Retina · doi:10.1097/iae.0000000000000714 · Cited by 25 · see citing works
Krohne, T. U., Muether, P. S., Stratmann, N. K., Holz, F. G., Kirchhof, B., Meyer, C. H., & Fauser, S. (2014) · Retina · doi:10.1097/iae.0000000000000265 · Cited by 26 · see citing works
“However, an analysis of the CATT study cohort of 1,149 patients with AMD treated with ranibizumab or bevacizumab detected no association of the CFH, ARMS2, HTRA1, and C3 risk alleles with either functional or morphologic treatment outcomes or the number of injections needed.(24) Thus, currently available data regardin…”
MethodHu, Z., Xie, P., Ding, Y., Yuan, D., & Liu, Q. (2014) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2014-305488 · Cited by 25 · see citing works
Hata, M., Tsujikawa, A., Miyake, M., Yamashiro, K., Ooto, S., Oishi, A., Nakata, I., Takahashi, A., & Yoshimura, N. (2014) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-014-2675-6 · Cited by 23 · see citing works
“Recent studies have revealed no associations of these genetic factors with anti-VEGF therapy response in patients with neovascular AMD [40].”
BackgroundMohamad, N. A., Ramachandran, V., Isa, H. M., Chan, Y. M., Ngah, N. F., Ching, S. M., Hoo, F. K., Sulaiman, W. A. W., Mat, L. N. I., & Mohamed, M. H. (2019) · Human Genomics · doi:10.1186/s40246-019-0197-3 · Cited by 21 · see citing works
Phan, L. T., Broadhead, G., Hong, T., & Chang, A. (2021) · Clinical ophthalmology · doi:10.2147/opth.s205147 · Cited by 23 · see citing works
“Analysis of data from the CATT clinical trials was unable to find any associations between SNPs of CFH, ARMS2, HTRA1 and C3 with treatment response across drugs or dosing regimens.(67) Similar results were obtained from analyzing data from the IVAN trials,(68) which also could not find associations in SNPs of CFH, FZD…”
ResultMaguire, M. G., Ying, G., Jaffe, G. J., Toth, C. A., Daniel, E., Grunwald, J. E., Martin, D. F., & Hagstrom, S. A. (2016) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2016.0669 · Cited by 21 · see citing works
Self-citationZhou, Y., Chen, C., Wang, Y.-X., Tong, Y., Fang, X., Li, L., & Wang, Z. (2017) · BMC Ophthalmology · doi:10.1186/s12886-017-0487-2 · Cited by 20 · see citing works
“Hagstrom (2013) [39] 251 81 123 47 285/217 43.”
Association of Single-Nucleotide Polymorphisms in Age-Related Macular Degeneration With Pseudodrusen
Lin, L. Y., Zhou, Q., Hagstrom, S. A., et al. (2018) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2018.1231 · Cited by 19 · see citing works
Self-citationAnti-VEGF Drugs Influence Epigenetic Regulation and AMD-Specific Molecular Markers in ARPE-19 Cells
Hamid, M. A., Moustafa, M. T., Nashine, S., Costa, R. D., Schneider, K., Atilano, S. R., Kuppermann, B. D., & Kenney, M. C. (2021) · Cells · doi:10.3390/cells10040878 · Cited by 20 · see citing works
Genetics and age-related macular degeneration: a practical review for the clinician
Schwartz, S. G., Hampton, B. M., Kovach, J. L., & Brantley, M. A. (2016) · Clinical ophthalmology · doi:10.2147/opth.s109723 · Cited by 20 · see citing works
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Kozhevnikova, O. S., Фурсова, А. Ж., Derbeneva, A. S., Nikulich, I. F., Сергеевич, Т. М., Devyatkin, V. A., Rumyantseva, Y. V., Telegina, D. V., & Kolosova, N. G. (2022) · Biomedicines · doi:10.3390/biomedicines10071658 · Cited by 16 · see citing works
“However, a number of studies has been unable to replicate these findings, including multicenter randomized trials (CATT and IVAN), which reported that no statistically significant association was found between genetic variants and anti-VEGF responsiveness [25,26].”
ResultMaroñas, O., García‐Quintanilla, L., Luaces-Rodríguez, A., Fernández‐Ferreiro, A., Latorre-Pellicer, A., Abraldes, M. J., Lamas, M. J., & Carracedo, Á. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666190711105325 · Cited by 15 · see citing works
Zhang, J., Liu, Z., Hu, S., & Qi, J. (2021) · Ophthalmic Research · doi:10.1159/000508738 · Cited by 15 · see citing works
Hagstrom, S. A., Ying, G., Pauer, G. J. T., et al. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2014.02.025 · Cited by 14 · see citing works
Self-citationMedina, F. M. C., da Motta, A. A. L., Takahashi, W. Y., Carricondo, P. C., Motta, M. M. D. S., de Melo, M. B., & de Vasconcellos, J. P. C. (2015) · Ophthalmic Research · doi:10.1159/000439172 · Cited by 15 · see citing works
Complement Inhibition for Geographic Atrophy: A Tempting Target with Mixed Results
Lin, J. B., Halawa, O. A., Miller, J. W., & Vavvas, D. G. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10132890 · Cited by 14 · see citing works
“Given that there are reports that certain genotypes are associated with distinct responses to current AMD treatments, it may also be important to investigate whether patients with measurable complement dysregulation, whether due to underlying genetics or otherwise, may be more responsive to complement modulation [6,42…”
BackgroundValverde-Megías, A., Veganzones, S., Donate-López, J., Maestro-de-las-Casas, M. L., Megías-Fresno, A., & Garcia-Sanchez, J. (2017) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-017-3748-0 · Cited by 13 · see citing works
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Kubicka‐Trząska, A., Żuber-Łaskawiec, K., Dziedzina, S., Sanak, M., Romanowska‐Dixon, B., & Karska‐Basta, I. (2022) · Medicina · doi:10.3390/medicina58050658 · Cited by 14 · see citing works
Beykin, G., Grunin, M. A., Averbukh, E., Banin, E., Hemo, Y., & Chowers, I. (2015) · BMC Ophthalmology · doi:10.1186/s12886-015-0019-x · Cited by 13 · see citing works
“For example, the CATT trial and the IVAN trial concluded that the major risk alleles for AMD did not predict response to anti-VEGF therapy by one year of follow-up [18,31].”
BackgroundMethodResultInfluentialMedina, F. M. C., Motta, A. A. L. D., Takahashi, W. Y., Carricondo, P. C., Motta, M. M. D. S., Melo, M. B., & Vasconcellos, J. P. C. (2019) · Ophthalmic Research · doi:10.1159/000475995 · Cited by 12 · see citing works
AFLIBERCEPT AFTER RANIBIZUMAB INTRAVITREAL INJECTIONS IN EXUDATIVE AGE–RELATED MACULAR DEGENERATION
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Bakbak, B., Öztürk, B., Zamanı, A. G., Gönül, Ş., İyit, N., Gedik, Ş., & Yıldırım, M. S. (2015) · Current Eye Research · doi:10.3109/02713683.2015.1067325 · Cited by 12 · see citing works
“In the ‘‘Comparison of Age-Related Macular Degeneration Treatments Trials’’ (CATT) and the ‘‘Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularization’’ (IVAN) trials, no statistically significant association was found between genetic variants and anti-VEGF responsiveness.(24,25)…”
BackgroundGenetics and Age-Related Macular Degeneration: A Practical Review for Clinicians.
Nguyen, J., Brantley, & Schwartz, S. G. (2024) · Frontiers in Bioscience-Scholar · doi:10.31083/j.fbs1601003 · Cited by 12 · see citing works
“However, two large, multicenter randomized clinical trials could not replicate these findings [36,37].”
BackgroundVeloso, C. E. D. R., de Almeida, L. N. F., & Nehemy, M. B. (2014) · Revista do Colégio Brasileiro de Cirurgiões · doi:10.1590/0100-69912014006002 · Cited by 11 · see citing works
Genetic Risk Evaluation in Wet Age-Related Macular Degeneration Treatment Response
Chaudhary, V., Brent, M., Lam, W.-C., Devenyi, R., Teichman, J., Mak, M., Barbosa, J., Kaur, H., Carter, R., & Farrokhyar, F. (2016) · Ophthalmologica · doi:10.1159/000446819 · Cited by 10 · see citing works
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Pharmacogenetics and nutritional supplementation in age-related macular degeneration
Schwartz, S., Hampton, B., & Kovach, J. (2015) · Clinical Ophthalmology · doi:10.2147/opth.s84155 · Cited by 9 · see citing works
Vofo, B. N., Beykin, G., Levy, J., & Chowers, I. (2021) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2021-319054 · Cited by 9 · see citing works
Ätiologie und Pathogenese der altersabhängigen Makuladegeneration
Herrmann, P., Holz, F. G., & Issa, P. C. (2013) · Der Ophthalmologe · doi:10.1007/s00347-012-2779-5 · Cited by 9 · see citing works
Told, R., Palkovits, S., Boltz, A., Schmidl, D., Napora, K. J., Werkmeister, R. M., Haslacher, H., Frantal, S., Popa‐Cherecheanu, A., Schmetterer, L. F., et al. (2014) · Acta Ophthalmologica · doi:10.1111/aos.12433 · Cited by 9 · see citing works
“This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. doi: 10.1111/aos.12433”
MethodResultInfluentialSimonett, J. M., Sohrab, M. A., Pacheco, J. A., Armstrong, L. L., Rzhetskaya, M., Smith, M. E., Hayes, M. G., & Fawzi, A. A. (2015) · Scientific Reports · doi:10.1038/srep12875 · Cited by 8 · see citing works
- Authors
- Hagstrom, S. A., Ying, G.-S., Pauer, G. J. T., Sturgill-Short, G. M., Huang, J., Callanan, D. G., Kim, I. K., Klein, M. L., Maguire, M. G., & Martin, D. F.
- Affiliations
- Cleveland Clinic (US)
- University of Pennsylvania (US)
- Texas Retina Associates (United States) (US)
- Massachusetts Eye and Ear Infirmary (US)
- Oregon Health & Science University (US)
- Corresponding author
- Hagstrom, Stephanie A.
- ORCID
- Venue
- Ophthalmology
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 120
- Issue
- 3
- Pages
- 593-599
- ISSN
- 0161-6420 (ISSN-L)
- PMC
- PMC3633658
- OpenAlex
- W2162946426
- Semantic Scholar
- 6bb1df2e038b945fd63d4609450bb54fbb03b99d
- Cited by
- 142
- References
- 28
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 12 · 2020: 9 · 2019: 6 · 2018: 12 · 2017: 16 · 2016: 13 · 2015: 22 · 2014: 23 · 2013: 13
- FWCI
- 23.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Ophthalmology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000439)
- National Eye Institute (U10EY017825, U10EY017826, U10EY017823, U10EY017828)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related macular degeneration, neovascular AMD, pharmacogenetics, single nucleotide polymorphisms, ranibizumab, bevacizumab, complement factor H, ARMS2, HTRA1, complement C3, treatment response, visual acuity, anti-VEGF therapy, epistasis, pro re nata dosing
- MeSH terms
- Bevacizumab, Ranibizumab, High-Temperature Requirement A Serine Peptidase 1, Aged, Aged, 80 and over, Complement C3, Female, Fluorescein Angiography, Gene Frequency, Genotype, Humans, Macular Degeneration, Male, Pharmacogenetics, Prospective Studies, Proteins, Serine Endopeptidases, Visual Acuity, Complement Factor H, Angiogenesis Inhibitors, Polymorphism, Single Nucleotide, Tomography, Optical Coherence, Vascular Endothelial Growth Factor A, Antibodies, Monoclonal, Humanized
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