Duration 5min, Q&A 3min
Pharmacogenetic Studies in AMD
Objective/Purpose Age-related macular degeneration (AMD) is the most common cause of irreversible loss of vision amongst the elderly in Australia. Treatment of the neovascular or 'wet' AMD is now through the use of various anti-VEGF monoclonal antibodies. While 30-50% of patients improve and maintain their vision, 10-25% of patients continue to lose vision and the remainder remain stable with no improvement in vision following treatment. A genetic involvement behind this varied treatment responses has been proposed but association of known AMD risk genes with treatment outcome has so far proved inconsistent. We undertook a genome wide association study (GWAS) to explore the role of other genetic variants in treatment response.
Materials/Patients A total of 378 patients were recruited from private ophthalmology rooms and the Medical Retina Clinic at the Royal Victorian Eye and Ear Hospital, Melbourne. At baseline, a number of imaging and clinical measures were obtained including best-correct visual acuity (BCVA), fluorescein angiography (FA), colour fundus photography, age, gender, smoking status, treatment delay between first symptoms and first treatment, lesion types, injection number, and ocular coherence tomography (OCT) characteristics. A blood sample was obtained for genomic DNA analysis.
Methods Change in BCVA was collected at 3, 6 and 12 months from each patient after lucentis injection. Individuals of European descent showing a consistent change in BCVA at each time point with either a gain or loss of 5 letters or more as defined by an Early Treatment Diabetic Retinopathy Study (ETDRS) letter score were included in a pooled genome wide association study (GWAS). An Illumina HumanOmni5-Quad Beadchip was used to identify genetic variants responsible for treatment response.
Results Following GWAS, 100,000 SNPs were significant at p=0.05 or less. Significant association (p<5x10-8) was identified for 29 SNPs and 104 showed suggestive association (p<1x10-7). A number of biologically interesting genes were identified involved in cell signalling, cell adhesion and extracellular matrix genes. In addition, several genes in the VEGF pathway were also associated as well as an important pharmagene involved in multidrug resistance. Our previous finding of association at the ARMS2/HTRA1 locus was also identified, adding confidence to the pooled findings reported here.
Conclusions We have identified a number of biologically plausible genes including several in the VEGF pathway itself, a gene involved in drug response as well as signalling and extracellular matrix genes. We are currently undertaking technical replication on these top hits to validate these findings.
[ Keyword ]
AMD / lucentis / anti-VEGF / pharmacogenetic
[ Conflict of Interest ]