ANO2 Genetic Variants and Anti-VEGF Treatment Response in Neovascular AMD: A Pharmacogenetic Substudy of VIEW 1 and VIEW 2

• Published in: Investigative ophthalmology & visual science Vol. 65; no. 8; p. 17
• Main Authors: Guymer, Robyn H., Silva, Rufino, Ghadessi, Mercedeh, Leal, Sergio, Gashaw, Isabella, Damask, Amy, Paulding, Charles, Rittenhouse, Kay D.
• Format: Journal Article
• Language: English
• Published: United States 01.07.2024
• Subjects: Aged; Aged, 80 and over; Angiogenesis Inhibitors - therapeutic use; Anoctamins - genetics; Female; Genome-Wide Association Study; Genotype; Humans; Intravitreal Injections; Male; Pharmacogenetics; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Ranibizumab - therapeutic use; Receptors, Vascular Endothelial Growth Factor - genetics; Recombinant Fusion Proteins - therapeutic use; Treatment Outcome; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics; Visual Acuity - physiology; Wet Macular Degeneration - drug therapy; Wet Macular Degeneration - genetics
• ISSN: 1552-5783; 1552-5783
• DOI: 10.1167/iovs.65.8.17

This analysis investigated potential associations between gene variants and clinical end points in the VIEW 1 and 2 randomized clinical trials of intravitreal aflibercept and ranibizumab in neovascular age-related macular degeneration (AMD). A genome-wide association analysis was conducted in a subgroup of patients from VIEW 1 and 2 consenting to the optional pharmacogenetic analysis. Data were pooled from 780 samples from patients representative of the overall VIEW 1 and 2 populations. After Bonferroni correction for multiplicity and statistical adjustment for baseline risk factors, no significant associations were found between previously identified prognostic AMD gene variants and treatment response according to key prespecified VIEW 1 and 2 end points. Genome-wide, there were no significant genetic associations in patients experiencing gains of ≥15 Early Treatment of Diabetic Retinopathy Study letters after 1 or 2 years of treatment. A cluster of variants in ANO2 (encoding anoctamin 2, a calcium-activated chloride channel expressed on photoreceptor cells) on chromosome 12 reached the level of significance for loss of ≥5 letters after 1 year of treatment (P < 5 × 10-8), with the ANO2 rs2110166 SNP demonstrating highly significant association (P = 1.99 × 10-8). Carriers of the ANO2 rs2110166 TT genotype showed a robust increase in visual acuity versus baseline compared with a small decrease in those with the TC genotype. None of the potential prognostic candidate genes were associated with the clinical end points for treated patients. Preliminary analyses suggest an association of ANO2 with retinal function, with a potential impact on vision of approximately one line over at least the first year. Further investigation of the function of ANO2 in retinal pathophysiology is merited.