Genetic Association Analysis of Anti-VEGF Treatment Response in Neovascular Age-Related Macular Degeneration

Abstract

Anti-VEGF treatment for neovascular age-related macular degeneration (nAMD) has been FDA-approved in 2004, and since then has helped tens of thousands of patients worldwide to preserve vision. Still, treatment responses vary widely, emphasizing the need for genetic biomarkers to robustly separate responders from non-responders. Here, we report the findings of an observational study compromising 179 treatment-naïve nAMD patients and their reaction to treatment after three monthly doses of anti-VEGF antibodies. We show that established criteria of treatment response such as visual acuity and central retinal thickness successfully divides our cohort into 128 responders and 51 non-responders. Nevertheless, retinal thickness around the fovea revealed significant reaction to treatment even in the formally categorized non-responders. To elucidate genetic effects underlying our criteria, we conducted an undirected genome-wide association study followed by a directed replication study of 30 previously reported genetic variants. Remarkably, both approaches failed to result in significant findings, suggesting study-specific effects were confounding the present and previous discovery studies. Of note, all studies so far are greatly underpowered, hampering interpretation of genetic findings. In consequence, we highlight the need for an extensive phenotyping study with sample sizes exceeding at least 15,000 to reliably assess anti-VEGF treatment responses in nAMD.

Latest Development on Genetics of Common Retinal Diseases

“…138 Genetic data, with big advancements in recent years particularly by GWAS, has been proven useful for clinical prediction, as well exemplified in a recent report of the association of 30 genetic variants with responses to anti-VEGF treatment in a big study cohort of over 15,000 study subjects. 139 In a study of GWAS variants in totally 2058 study subjects in discovery and validation cohorts, SNP rs12138564 in the chaperonin containing TCP1 subunit 3 (CCT3) gene has a mild association with anti-VEGF treatment outcome. 119 Accurate and informative prediction of risk, progression, and prognosis of AMD, PCV, and CSCR required individual information for the clinical management to be tailored made.…”

“…AI in recent years has been developed for the reliable and meticulous analysis of genetic data with clinical implications 138. Genetic data, with big advancements in recent years particularly by GWAS, has been proven useful for clinical prediction, as well exemplified in a recent report of the association of 30 genetic variants with responses to anti-VEGF treatment in a big study cohort of over 15,000 study subjects 139. In a study of GWAS variants in totally 2058 study subjects in discovery and validation cohorts, SNP rs12138564 in the chaperonin containing TCP1 subunit 3 ( CCT3 ) gene has a mild association with anti-VEGF treatment outcome 119…”

Construction of an Exudative Age-Related Macular Degeneration Diagnostic and Therapeutic Molecular Network Using Multi-Layer Network Analysis, a Fuzzy Logic Model, and Deep Learning Techniques: Are Retinal and Brain Neurodegenerative Disorders Related?

“…At this point, the procedure of reviewing recent studies, data extraction, and classifications were performed in order to identify metabolites [276][277][278][279] and single-nucleotide polymorphisms (SNPs) [101,[280][281][282][283][284][285][286][287][288][289][290][291][292][293] relevant to nAMD disease. As a result, 317 SNPs (Supplementary Table S11) and 115 metabolites (Supplementary Table S12) that are effective in the development of nAMD were identified.…”

Influence of Genetic Polymorphisms on the Short-Term Response to Ranibizumab in Patients With Neovascular Age-Related Macular Degeneration

“… 9 On the other hand, variants of NRP1 and HTRA1/ARMS genes have been associated with poor or no response to anti-VEGF treatment, 18 , 19 but the evidence either is substandard or does not support this association because other studies failed to replicate it. 20 , 21 There is a lack of agreement in the pharmacogenetic studies of nAMD response to anti-VEGF treatment, because different periods have been studied such as one, three, 22 , 23 four, 24 five 25 or six 26 months when it comes to short-term response and 12 to 24 months to long-term response. 27 , 28 This makes it difficult for results comparison, particularly, in short-term analysis of the response.…”