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

In the paper

“However, other studies report no association with the risk genotype.9,10”

What the sources say

• Supported

  The Results report no significant association between treatment response and any tested risk variant, including CFH Y402H. The Discussion likewise reports no statistically significant difference in CFH risk-genotype frequency between positive and negative responders to anti-VEGF treatment for wet AMD. (LLM, conf=0.94)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Genetic variation at this locus has been shown to confer a differential risk for CNV versus geographic atrophy.21”

What the sources say

• Supported

  The Results report that the T allele of ARMS2/HTRA1 rs10490924 was significantly more frequent in participants with CNV than in those with geographic atrophy (OR 1.37, 95% CI 1.21–1.54). This directly supports the cited claim of differential risk at the locus. (LLM, conf=0.95)

  cites [21] Sobrin, 2011, ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration, Am J Ophthalmol source

In the paper

“it has been proposed that the A69S polymorphism alters ARMS2 function and increases susceptibility of photoreceptor cells to oxidative damage and aging.22”

What the sources say

• Supported

  The Discussion links photoreceptors’ risk of oxidative damage to the proposal that the A69S substitution alters ARMS2 function and increases susceptibility to aging-associated degeneration of macular photoreceptors. The citing sentence accurately presents this as a proposal, not an established mechanism. (LLM, conf=0.94)

  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

In the paper

“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”

What the sources say

• Supported

  The cited Brantley paper concerns CFH genotype and visual response to bevacizumab, but the paper-scoped search returned no full-text snippets. A Semantic Scholar snippet from “Update on the role of genetics in the onset of age-related macular degeneration” describes an 86-patient bevacizumab study in which patients with the CFH CC risk genotype had worse visual outcomes than those with TC or TT genotypes; it identifies that study as reference 81. This supports the visual-outcomes part of the claim through a secondary citation, though it does not establish that Brantley reported a greater injection requirement. (LLM, conf=0.80)

  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
• Supported

  The cited Lee (2009) paper directly supports the injection part of the claim: patients homozygous for the CFH Y402H risk allele had a 37% higher risk of requiring additional ranibizumab injections (paper-scoped snippet, score 0.694). It does not support worse visual outcomes; the snippet reports similar mean visual acuities across genotypes. Because the citing sentence says “or required more injections,” attribution to this paper is reasonable. (LLM, conf=0.92)

  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
• ?Not checked — no full text of the sourcecites [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]
• Supported

  The cited Nischler et al. paper concerns CFH Y402H genotype and response to intravitreal bevacizumab in exudative AMD. Although paper-scoped Semantic Scholar searches returned no snippets, a review, “Personalized Medicine in Ophthalmology,” reports that patients with the CC risk genotype had worse visual-acuity outcomes after bevacizumab; its matching passage scored 0.858. The same passage describes more ranibizumab injections among CC patients, supporting the citing sentence’s broader summary of multiple reports. The review does not establish which result specifically came from Nischler et al., so confidence is limited. (LLM, conf=0.72)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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”

What the sources say

• Partly supported

  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)

  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

In the paper

“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.”

What the sources say

• Supported

  The Discussion (page unavailable) reports gains of 5.9 and 6.8 letters with as-needed bevacizumab and ranibizumab, respectively. It also reports differences from the corresponding monthly groups of 2.1 and 1.7 letters at one year, yielding the stated monthly gains of 8.0 and 8.5 letters. (LLM, conf=0.93)

  cites [1] 2011, Ranibizumab and bevacizumab for neovascular age-related macular degeneration, N Engl J Med source

In the paper

“It has been hypothesized that overexpression of HTRA1 may alter the integrity of Bruch’s membrane and favor the development of CNV.2”

What the sources say

• Supported

  Section 3.4.5 reports elevated HtrA1 expression in CNV components, and the following discussion proposes that HtrA1 protease activity may favor neovascularization by degrading extracellular matrix. Section 2.2 describes CNV vessels penetrating Bruch’s membrane. Together, these passages support the citing sentence’s explicitly hypothetical account; the paper does not present the mechanism as established. (LLM, conf=0.86)

  cites [2] Ding, 2009, Molecular pathology of age-related macular degeneration, Prog Retin Eye Res source

In the paper

“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”

What the sources say

• Supported

  Section 3.1 says that SNPs linked to several pathological processes have been associated with AMD. Sections 3.2, 3.4 and 3.6 describe variants in multiple genes and associations with early or intermediate, advanced, and neovascular AMD. Page numbers are not available in our copy. (LLM, conf=0.89)

  cites [2] Ding, 2009, Molecular pathology of age-related macular degeneration, Prog Retin Eye Res source
• Supported

  The Candidate Genes section describes variation in multiple genes statistically associated with AMD risk. Its Other Genes subsection reports an association with both early and advanced AMD for VEGFA variation, while the Complement Genes subsection identifies a C3 SNP associated with late-stage AMD. The indexed passages do not provide page numbers. (LLM, conf=0.91)

  cites [3] Deangelis, 2011, Genetics of age-related macular degeneration: current concepts, future directions, Semin Ophthalmol source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [2] Ding, 2009, Molecular pathology of age-related macular degeneration, Prog Retin Eye Res sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [3] Deangelis, 2011, Genetics of age-related macular degeneration: current concepts, future directions, Semin Ophthalmol sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [12] Schwartz, 2011, Pharmacogenetics and age-related macular degeneration, J Ophthalmol [serial online] sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [11] Kloeckener-Gruissem, 2011, Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD, Invest Ophthalmol Vis Sci source

In the paper

“The ARMS2 gene product has been localized to the mitochondrial outer membrane”

What the sources say

• Supported

  The Discussion states that LOC387715/ARMS2 protein localizes to the mitochondrial outer membrane in transfected mammalian cells. The Results describe mitochondrial colocalization and a proteinase K experiment consistent with outer-membrane localization. (LLM, conf=0.92)

  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

In the paper

“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).”

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“We cannot exclude the possibility that other SNPs that are less predictive of AMD risk may be associated with response to therapy.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“Patients were randomly assigned to one of the four treatment groups: (1) ranibizumab monthly; (2) bevacizumab monthly; (3) ranibizumab PRN; and (4) bevacizumab PRN.”

In the paper

“To account for multiple comparisons from multiple SNPs and multiple outcomes, we considered p≤0.01 as statistically significant.”

In the paper

“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.”

In the paper

“ARMS2 and HTRA1 both lie in the AMD susceptibility locus identified on chromosome 10q26 and are expressed in the retina.20”

What the sources say

• Not checked yetcites [20] Tong, 2010, LOC387715/HTRA1 gene polymorphisms and susceptibility to age-related macular degeneration: a HuGE review and meta-analysis, Mol Vis [serial online]

In the paper

“In addition, inflammation has been postulated to reduce response to anti-VEGF treatment.19”

What the sources say

• ?Not checked — no full text of the sourcecites [19] Bressler, 2009, Introduction: understanding the role of angiogenesis and antiangiogenic agents in age-related macular degeneration, Ophthalmology source

In the paper

“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.”

In the paper

“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).”

In the paper

“The SNP evaluated in HTRA1 is located in the promoter region and is predicted to increase expression levels of the gene.23”

What the sources say

• ?Not checked — no full text of the sourcecites [23] Dewan, 2006, HTRA1 promoter polymorphism in wet age-related macular degeneration, Science source