Elsevier

Ophthalmology

Volume 120, Issue 8, August 2013, Pages 1641-1648
Ophthalmology

Original article
Genetic Influences on the Outcome of Anti-Vascular Endothelial Growth Factor Treatment in Neovascular Age-related Macular Degeneration

Presented at: the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, Fort Lauderdale, Florida, May 2012.
https://doi.org/10.1016/j.ophtha.2013.01.014Get rights and content

Purpose

To determine the association of genetic variants in known age-related macular degeneration (AMD) risk-associated genes with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular AMD.

Participants

We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia.

Methods

Patients were treated with 3 initial monthly ranibizumab or bevacizumab injections followed by 9 months of “as required” injections based on clinician’s decision at each follow-up visit according to retreatment criteria. Seventeen single nucleotide polymorphisms (SNPs) in known AMD risk-associated genes including CFH (rs800292, rs3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6667243, and rs1853883), LOC387715/ARMS2 (rs3793917 and rs10490924), C3 (rs2230199 and rs1047286), C2 (rs547154), CFB (rs641153) and F13B (rs6003) were examined. Multivariate analysis was used to determine the role of each SNP in treatment outcome.

Main Outcome Measures

The influence of selected SNPs on mean change in visual acuity (VA) at 12 months.

Results

Mean baseline VA was 51±16.8 Early Treatment Diabetic Retinopathy Study letters. Overall, the mean change in VA from baseline was +3.2±14.9 letters at 12 months. The AA (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk) genotype at rs10490924 (A69S) in LOC387715/ARMS2 (P = 0.002) were each significantly associated with poorer VA outcome at 12 months after multiple correction. Mean ± standard deviation change in VA from baseline in patients with AA genotype at rs11200638 was –2.9±15.2 letters after 12 months compared with +5.1±14.1 letters in patients with AG or GG genotypes at this SNP. Patients with either of these genotypes were also significantly more likely to lose >15 letters after 12 months. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (r2 = 0.92). None of the other examined SNPs was associated with outcome.

Conclusions

The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/ARMS2 were associated with a poorer visual outcome for ranibizumab or bevacizumab treatment in neovascular AMD, suggesting strong pharmacogenetic associations with anti-VEGF treatment. This finding could aid in applying more individualized treatment regimens based on patients’ genotype to achieve optimal treatment response in AMD.

Financial Disclosure(s)

The authors have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Study Design and Eligibility

We prospectively recruited patients from the retina clinics of The Royal Victorian Eye and Ear Hospital (RVEEH) from 2006 to 2010 for this study. Approval was obtained from the human research and ethics committee of the RVEEH. Research adhered to the tenets of the Declaration of Helsinki, and all patients provided written informed consent before participation.

Patient Selection

Our study cohort comprised consecutive, treatment-naïve patients >50 years of age with active subfoveal choroidal neovascularization

Results

Two hundred twenty-four patients met the inclusion/exclusion criteria and were recruited into this study and monitored for 12 months. Mean age ± standard deviation SD) of the patients was 78±6.6 years and mean ± SD VA at baseline was 51±16.8 ETDRS letter scores (approximate Snellen equivalent of 20/100). Mean change ± SD in VA from baseline after 12 months was 3.2±14.9 letters, and the patients received on average 6.4±2.3 injections over 12 months. Of the patients, 24.8% had predominantly

Discussion

In this study, we have shown for the first time a strong genetic association for homozygote risk alleles at SNP rs11200638 (HTRA1 promoter SNP) and SNP rs10490924 (A69S) in the LOC387715/ARMS2 gene with poor outcome of intravitreal anti-VEGF injections in treatment-naïve patients with neovascular AMD. We also found a borderline association between homozygote risk alleles at SNP rs3793917 in the LOC387715/ARMS2 gene and poor response to this treatment.

The risk alleles rs10490924 and rs11200638

Acknowledgments

The authors are grateful to Professor Bob Augusteyn for helpful discussions.

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    Manuscript no. 2012-1122.

    Financial Disclosures: The authors have no proprietary or financial interest in any of the materials discussed in this article.

    Funded by the National Health and Medical Research Council (NHMRC) project grants 590205 and 1008979, an NHMRC– Clinical Research Excellence grant 529923 - Translational Clinical Research in Major Eye Diseases, NHMRC practitioner fellowship 529905 (R.H.G.), NHMRC Senior Research Fellowship 1028444 (P.N.B.), and the Macular Vision Loss Support Society of Australia. The Centre for Eye Research Australia (CERA) receives Operational Infrastructure Support from the Victorian Government. The sponsor or funding organizations had no role in the design or conduct of this research.

    Both authors Robyn H. Guymer and Paul N. Baird contributed equally to this article.

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