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Cited by 134Retinal Diseases and TreatmentsOcular Diseases and Behçet’s SyndromeComplement system in diseases

Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab

Open access
Lee, A Y, Raya, A K, Kymes, S M, Shiels, A, Brantley, M A·2009·British Journal of Ophthalmology
DOI 10.1136/bjo.2008.150995PMC PMC3490485
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Abstract

AIMS: To determine whether complement factor H (CFH) genotypes have a pharmacogenetic effect on the treatment of exudative age-related macular degeneration (AMD) with ranibizumab. METHODS: A retrospective study of 156 patients with exudative AMD treated with intravitreal ranibizumab monotherapy was conducted. AMD phenotypes were characterised by clinical examination, visual acuity, fundus photography, fluorescein angiography and injection timing. Patients received intravitreal ranibizumab injections as part of routine ophthalmological care and were followed for a minimum of 9 months. Each patient was genotyped for the single nucleotide polymorphism rs1061170 (Y402H) in the CFH gene. RESULTS: Baseline lesion size and angiographic type, as well as mean visual acuities at baseline, 6 months, and 9 months were similar among the three CFH genotypes. Over 9 months, patients with both risk alleles received approximately one more injection (p = 0.09). In a recurrent event analysis, patients homozygous for the CFH Y402H risk allele had a 37% significantly higher risk of requiring additional ranibizumab injections (p = 0.04). CONCLUSIONS: In this study cohort, the response to treatment of AMD with ranibizumab differed according to CFH genotype, suggesting that determining patients' CFH genotype may be helpful in the future in tailoring treatment for exudative AMD with intravitreal ranibizumab.

Integrity signals

Registry

Crossref · 10.1136/bjo.2008.150995

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 11 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Among the 156 genotyped patients, the CFH Y402H genotype distribution was 37 TT (24%), 71 TC (45%), and 48 CC (31%).

    “For the CFH Y402H polymorphism, 37 patients (24%) were TT, 71 (45%) were TC, and 48 (31%) were CC.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In a recurrent event analysis over nine months, the CC genotype was associated with a 37% higher risk of requiring an additional injection than the TT genotype (p = 0.04).

    “Furthermore patients with the homozygote variant (CC) were found to have a 37% significantly higher risk (p = 0.04) of needing another injection (Table 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    Post-treatment visual acuity at 6 months (p = 0.38) and 9 months (p = 0.70) did not differ significantly by CFH genotype.

    “The CFH genotypes were not found to significantly affect the post-treatment VA at 6 months (p = 0.38) or 9 months (p = 0.70) (Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    In a recurrent event analysis over nine months, the TC genotype showed a trend toward a 25% greater risk of requiring an additional injection compared with the TT genotype.

    “We found that, over a nine month period, patients with the heterozygote variant (TC) tended to have a 25% higher risk of needing another injection than patients with the TT genotype.”
    Quote in the paperSubstantial claim
  • Findingown data

    Over 9 months, those carrying two CFH risk alleles (CC) received about one additional injection compared with other patients (p = 0.09).

    “Over 9 months, patients with both risk alleles received approximately one more injection (p = 0.09).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 6
  • May combine two claims. 5
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The C risk allele was present in 54% of the cohort.

    “The prevalence of the C risk allele was 54%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Over 9 months, the mean number of injections differed among the three CFH genotypes only at a trend level, with the TT group receiving the fewest (p = 0.09).

    “However when the mean number of injections over the 9 month period was examined, we did observe a trend in the number of injections required over a 9 month period among the three genotypes, with the TT group receiving the fewest injections (p = 0.09).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Of 178 mouthwash samples collected, 156 (88%) yielded DNA of sufficient quality for genotyping.

    “Of the 178 mouthwash samples collected from the patients of nine retinal specialists, 156 (88%) produced sufficiently high quality DNA for genotypic analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    There was no difference in follow-up intervals between the TC and TT genotypes (HR = 1.00, p = 0.95) or between the CC and TT genotypes (HR = 1.03, p = 0.76).

    “When examining the intervals between follow-up appointments in the same manner, we found that there was no difference between how often patients with the TC genotype were seen in follow-up compared to patients with the TT genotype (HR: 1.00, p = 0.95) nor between how often patients with the CC genotype were seen in follow-up compared to patients with the TT genotype (HR: 1.03, p = 0.76).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Photodynamic therapy outcomes for exudative age-related macular degeneration are influenced by CFH Y402H genotype.

    “Further studies have shown an effect of CFH Y402H genotype on response of exudative AMD to photodynamic therapy.[10–12]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Goverdhan SV Hannan S Newsom RB An analysis of the CFH Y402H genotype in AMD patients and controls from the UK, response to PDT treatment Eye 2008 22 849 854 17464302 PMC5989925

      Not checked in the free run.

    • cites [11] Seitsonen SP Jarvela IE Meri S The effect of complement factor H Y402H polymorphism on the outcome of photodynamic therapy in age-related macular degeneration Eur J Ophthalmol 2007 17 943 949 18050121

      Not checked in the free run.

    • cites [12] Brantley MA Edelstein SL King JM Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy Eye 2008 epub. PMC5531276 18292785

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The current study used stricter inclusion criteria, a longer follow-up, and adjustment for variable follow-up duration compared with the earlier bevacizumab study.

    “First, the current study had more stringent inclusion criteria, a longer follow up period, and controlled for variability in the length of follow-up.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the Age Related Eye Disease Study, zinc supplementation response may be predicted by CFH Y402H genotype.

    “Analyzing data from the Age Related Eye Disease Study (AREDS), Klein et al. recently demonstrated that CFH Y402H genotypes may be predictive of treatment response to zinc supplementation.[9]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Klein ML Francis PJ Rosner B CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration Ophthalmology 2008 115 1019 1025 18423869

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    After intravitreal bevacizumab, visual acuity improvement was lower in CC genotype patients than in those with TC or TT genotypes.

    “Recently, we reported that patients with the CC genotype (two CFH Y402H variant alleles) demonstrated less visual acuity improvement with intravitreal injections of the anti-vascular endothelial growth factor (anti-VEGF) agent bevacizumab than patients with the TC and TT genotypes.[13]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Brantley MA Fang AM King JM Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab Ophthalmology 2007 114 2168 2173 18054635

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    The difference in visual acuity outcomes between the current ranibizumab study and the previous bevacizumab study may be due to more stringent inclusion criteria, longer follow-up, controlling for follow-up variability, and better baseline visual acuity.

    “Several factors may account for this difference. First, the current study had more stringent inclusion criteria, a longer follow up period, and controlled for variability in the length of follow-up.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Patient follow-up was inconsistent, making the 6-month and 9-month cohorts non-identical.

    “The follow-up of patients was not consistent, and thus the cohorts at 6 and 9 months were not identical.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The recurrent event analysis, being a survival analysis, is robust to variable follow-up and censored data.

    “While this could influence the results of the visual acuity outcomes, the recurrent event analysis is a type of survival analysis and thus is robust to variable follow-up and censored data.”
    Quote in the paperSubstantial claim
11 of 11

  • The paper relies on this without support.

    The number of ranibizumab injections a patient requires is a valid measure of treatment response or need for treatment.

    “a conditional approach by Cox regression analysis for modeling recurrent events was built with time between injections after the first 70 days as the outcome and genotypes as the main effect.”
    “patients homozygous for the CFH Y402H risk allele had a 37% significantly higher risk of requiring additional ranibizumab injections”
1 of 1

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?

  • Increased 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”

    From Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT) (2013) · cites this paper as [5]

    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

  • Reports 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”

    From Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT) (2013) · cites this paper as [5]

    Experimental — accuracy not yet measured

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Related

Authors
Lee, A. Y., Raya, A. K., Kymes, S. M., Shiels, A., & Brantley, M. A.
Affiliations
Washington University in St. Louis (US)
ORCID
Venue
British Journal of Ophthalmology
Publisher
BMJ
Published
2008-12-17
Volume
93
Issue
5
Pages
610-613
ISSN
0007-1161 (ISSN-L)
DOI
10.1136/bjo.2008.150995
PMC
PMC3490485
OpenAlex
W2132467155
Cited by
134
References
15
Citations by year
2026: 1 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 10 · 2016: 8 · 2015: 7 · 2014: 11 · 2013: 25 · 2012: 22
FWCI
9.79
Type
journal article
Language
en
Open access
Locations
  • British Journal of Ophthalmology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Genentech
  • National Eye Institute (5P30EY02687, P30EY002687, EY012284, R01EY012284)
  • National Center for Research Resources (T32RR023255, UL1RR024992)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Keywords
complement factor H, CFH Y402H polymorphism, rs1061170, neovascular age-related macular degeneration, ranibizumab, pharmacogenetics, intravitreal injection frequency, treatment response, anti-VEGF therapy, complement system
MeSH terms
Ranibizumab, Aged, Aged, 80 and over, Antibodies, Monoclonal, Female, Genotype, Humans, Macular Degeneration, Male, Retrospective Studies, Visual Acuity, Treatment Outcome, Complement Factor H, Angiogenesis Inhibitors, Antibodies, Monoclonal, Humanized

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