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Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN study

Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN study
Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN study
Purpose: to determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associations of response in nAMD and to test for novel associations.

Design: cohort study, combining information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-VEGF therapy for nAMD.

Participants: five hundred nine participants with nAMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial.

Methods: participants were classified as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). We computed the change in TRT from baseline to the latest time point for which OCT data were available (3, 6, 9, or 12 months). Eyes with changes in TRT greater than or equal to the 75th percentile or more were classified as responders, and those with changes less than or equal to the 25th percentile or lower were classified as non-responders. Three previously reported associations of response to VEGF inhibition in nAMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication. An additional 482 SNPs also were tested using a candidate gene approach. Associations were estimated as odds ratios (ORs) with confidence intervals (CIs).

Main outcome measures: the primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT.

Results: one hundred twenty-six participants were classified as responders and 128 were classified as nonresponders. The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99–2.36; P = 0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected P value was 0.84 (P = 0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene.

Conclusions: we estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of nAMD. No significant association or replication of previous associations were observed. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited.
2637-2643
Lotery, Andrew J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Cree, Angela J.
6724b71b-8828-4abb-971f-0856c2af555e
Downes, Susan M.
2c1e60a4-7a61-49e0-9f20-41db1db9afd7
Harding, Simon P.
10091207-4f52-491b-b069-98bb37444f5b
Rogers, Chris A.
1074c268-aced-471a-95fe-ad3e0067e605
Reeves, Barnaby C.
3d10eab6-24a5-41c7-8ecc-8b5ace0f25ff
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Chakravarthy, Usha
2c06cdaf-94c0-409a-8eff-2f624c120a5e
Lotery, Andrew J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Cree, Angela J.
6724b71b-8828-4abb-971f-0856c2af555e
Downes, Susan M.
2c1e60a4-7a61-49e0-9f20-41db1db9afd7
Harding, Simon P.
10091207-4f52-491b-b069-98bb37444f5b
Rogers, Chris A.
1074c268-aced-471a-95fe-ad3e0067e605
Reeves, Barnaby C.
3d10eab6-24a5-41c7-8ecc-8b5ace0f25ff
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Chakravarthy, Usha
2c06cdaf-94c0-409a-8eff-2f624c120a5e

Lotery, Andrew J., Gibson, Jane, Cree, Angela J., Downes, Susan M., Harding, Simon P., Rogers, Chris A., Reeves, Barnaby C., Ennis, Sarah and Chakravarthy, Usha (2013) Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN study. Ophthalmology, 120 (12), 2637-2643. (doi:10.1016/j.ophtha.2013.07.046). (PMID:24070809)

Record type: Article

Abstract

Purpose: to determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associations of response in nAMD and to test for novel associations.

Design: cohort study, combining information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-VEGF therapy for nAMD.

Participants: five hundred nine participants with nAMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial.

Methods: participants were classified as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). We computed the change in TRT from baseline to the latest time point for which OCT data were available (3, 6, 9, or 12 months). Eyes with changes in TRT greater than or equal to the 75th percentile or more were classified as responders, and those with changes less than or equal to the 25th percentile or lower were classified as non-responders. Three previously reported associations of response to VEGF inhibition in nAMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication. An additional 482 SNPs also were tested using a candidate gene approach. Associations were estimated as odds ratios (ORs) with confidence intervals (CIs).

Main outcome measures: the primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT.

Results: one hundred twenty-six participants were classified as responders and 128 were classified as nonresponders. The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99–2.36; P = 0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected P value was 0.84 (P = 0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene.

Conclusions: we estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of nAMD. No significant association or replication of previous associations were observed. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited.

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More information

e-pub ahead of print date: 23 September 2013
Published date: December 2013
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 358063
URI: http://eprints.soton.ac.uk/id/eprint/358063
PURE UUID: 7a227011-2c51-49d2-9504-c24c5ae104c2
ORCID for Andrew J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Angela J. Cree: ORCID iD orcid.org/0000-0002-1987-8900
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 04 Oct 2013 13:49
Last modified: 27 May 2022 01:38

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Contributors

Author: Jane Gibson ORCID iD
Author: Angela J. Cree ORCID iD
Author: Susan M. Downes
Author: Simon P. Harding
Author: Chris A. Rogers
Author: Barnaby C. Reeves
Author: Sarah Ennis ORCID iD
Author: Usha Chakravarthy

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