Common Variants in KLHL2 and C4orf50 Are Associated with Poorer Anti-VEGF Treatment Response in Age-Related Macular Degeneration

Abstract

Purpose : Response to anti-vascular endothelial growth factor(anti-VEGF) treatment in people with choroidal neovascularization (CNV) is variable. Candidate gene and genome-wide association studies (GWAS) of treatment response have produced inconsistent results. To better elucidate genetic factors underlying treatment response, we conducted a GWAS for one-year change in visual acuity in individuals with CNV treated with anti-VEGF therapy.

Methods : We studied 90 non-Hispanic whites with CNV (107 eyes) treated monthly for the first three months and as needed afterward and followed for at least one year at Bascom Palmer Eye Institute or Vanderbilt Eye Institute. Samples were genotyped using the Illumina CoreExome Array and imputed against the 1000 Genomes reference panel. All visual acuity values were transformed into Logarithm of the Minimum Angle Resolution(logMAR). Change in logMAR over one year(ΔlogMAR) was selected as the endpoint. Patients with positive values had worse vision and those with zero or negative values had stable or improving vision at one year. A linear mixed model evaluated the association of ΔlogMAR and single nucleotide polymorphism dosage, adjusted for age, sex, treatment [bevacizumab,ranibizumab or aflibercept], and correlation of paired eyes. A p-value less than 5x10^-8 was considered statistically significant. Institutional Review Boards approved the protocol at each institution.

Results : The sample was 58% female (n=52) and the mean age was 80 (range: 55-98). There were two regions on chromosome 4 with genome wide significant association, near C4orf50 and KLHL2. Each additional T allele at rs116641154 in C4orf50 was associated with a mean 0.4 increase in ΔlogMAR at one year (±0.07; p=3.16x10^-8), representing worsening visual acuity. A similar effect was observed in A allele carriers at rs79399888 in KLHL2. Participants with this allele had a mean 0.58 increase in ΔlogMAR at one year(±0.1; p=1.14X10^-9).

Conclusions : We identified two new loci associated with worse anti-VEGF treatment response evidences that mechanisms governing risk of AMD and response to treatment may be distinct. If confirmed by additional studies, these results could be used to identify individuals at risk of poorer treatment response, and these individuals could be prioritized for new treatments or altered therapeutic regimens.

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