Association of a Variant in VWA3A with Response to Anti-VEGF Treatment in Neovascular Age-Related Macular Degeneration

Abstract

Purpose : The effect of single candidate variants has been previously explored on neovascular age-related macular degeneration (nvAMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) treatment. However, few studies have performed an unbiased, genome-wide search for pharmacogenetic interactions. Additionally, population-specific variants may have been overlooked by previous multinational studies. Here, we performed a genome-wide association study for the response to anti-VEGF treatment on nvAMD patients from the Israeli population.

Methods : nvAMD patients from Hadassah-Hebrew University Medical Center (HMC) who underwent anti-VEGF treatment (n=186, female/male=114/72, average age±SEM=77.8±0.6) were genotyped on a whole exome chip containing ~500k variants by the International AMD Genetics Consortium. This chip was imputed using standard methods using both the Ashkenazi Genome Consortium and 1000 Genomes reference panels. Quality control was applied at the level of both patients and variants. Outcome measure was defined as delta visual acuity (deltaVA) in logMAR units, after 3 injections of anti-VEGF within a 3 month time period. Top principal components, age, and baseline VA were included in the analysis. Lead associated variants were genotyped in an independent validation set of nvAMD patients from HMC (n=108, female/male: 66/42, average age±SEM=79.6±0.76).

Results : Linear regression analysis on 5,353,842 variants revealed 5 exonic variants with an association P-value under 6x10^-5. Top variants were in the genes VWA3A (P=1.77X10^-6) and TESPA1 (P=3.24x10^-5). These variants were tested in the validation cohort. Among them, the minor allele of the variant in VWA3A was found to be significantly associated with worse response to treatment (P=0.02). The average deltaVA was -0.214 logMAR for individuals homozygotes for the major allele, 0.172 logMAR for heterozygotes, and 0.21 logMAR for individuals homozygotes for the minor allele.

Conclusions : This is the first genome-wide study on response to anti-VEGF in Israel. We found that a variant in the gene VWA3A is associated with worse response to anti-VEGF treatment in the Israeli population, both in our discovery and validation cohorts. Further studies on larger sample sizes and other populations are needed to confirm whether this genetic variant could be of clinical use in treatment decision making.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.