Research led by a team at the Radboud University Medical Center in Nijmegen, the Netherlands, have shown that the response to anti-VEGF medication may arise from a complexity of interactions, rather than a small defined number of common genetic variants. The clinical genetics research involved a genome-wide association study (GWAS) of 678 nAMD patients revealing a nominal association of an improved response to anti-VEGF with a single variant within the CCT3 gene. Rare variants showed significant association with a worse treatment outcome in the C10orf88 and UNC93B1 genes however, further validation will be required in larger cohorts to strengthen validity in a broader population.
It is estimated that up to 10% of nAMD patients receiving anti-VEGF treatment may suffer a decline in VA of at least 15 lines ETDRS score letters. Identifying such patients as early as possible is critical to optimizing clinical management. Identifying the specific factors that may be associated with non-response may provide valuable information to optimizing alternative treatment regimens, either available today or in the future. One strategy to identify such biomarkers of response is to use GWAS to identify pharmacogenomic signals that associate with either better or worse treatment outcomes with anti-VEGF therapies. In total, the study included 2,058 patients with nAMD, 678 patients in a discovery phase and 1,380 in a replication phase. In the discovery phase, genome-wide single variant association analyses were performed on the change in VA after 3-monthly anti-VEGF injections. This revealed 111 variants across 5 loci and, in the replication phase, these 5 loci were further analyzed to reveal a single variant of nominal significance associated with an improved outcome response. In addition, rare protein-altering variants in the C10ORF88 and UNC93B1 genes were found to associate with worse visual acuity response to anti-VEGF therapy. Patients carrying these rare variants in the C10orf88 and UNC93B1 genes lost a mean of 6 and 5 lines, respectively, on the ETDRS letter chart following treatment. In analyzing the results of the GWAS output, the researchers stated that “none of the previously identified genetic markers are individually strong determinants of overall functional treatment response. Furthermore, we also did not find an association for any of the 52 AMD-associated variants reported in the largest AMD GWAS performed so far”.
The researchers concluded that the multicenter GWAS data may indicate that the variability in how nAMD patients respond to anti-VEGF therapy is unlikely to be explained by large effects of common variants but that “rare genetic variants may have large effects on treatment outcome after 3 monthly anti-VEGF injections”. This is not unusual for many large GWAS and similar gene-based studies in which it can be very difficult to isolate a clear smoking gun. Unfortunately, biology tends to be significantly more complicated than is generally anticipated.