To identify factors associated with ranibizumab responses in patients with exudative age-related macular degeneration (AMD), we performed a genome-wide association study (GWAS) and a replication study using a total of 919 exudative AMD patients treated with intravitreal ranibizumab in a Japanese population. In the combined analysis of GWAS and the replication study, no loci reached genome-wide significant level; however, we found four variants showed suggestive level of associations with visual loss at month three (rs17822656, rs76150532, rs17296444, and rs75165563: Pcombined < 1.0 × 10−5). Of the candidate genes within these loci, three were relevant to VEGF-related pathway (KCNMA1, SOCS2, and OTX2). The proportions of patients who worsened visual acuity were 13.7%, 38.8%, 58.0%, and 80.0% in patients with 0, 1, 2, and 3 or more identified risk variants, respectively. Changes in visual acuity decreased linearly as the number of risk variants increased (P = 1.67 × 10–12). The area under the curve using age, baseline visual acuity, and history of previous treatment was 0.607, and improved significantly to 0.713 in combination with identified variants (P < 0.0001). Although further study is needed to confirm their associations, our results offer candidate variants influencing response to ranibizumab therapy.
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We thank K. Ishikawa, T. Nakama, and Y. Kobayashi for practical advices. We are grateful to K. Kano, A. Yoshida, S. Shiose, A. Kuni, H. Yanagi, Y. Tanaka, K. Takeda, R. Obata, A. Kato, and A. Arisawa for samples and clinical data collection in collaborating hospitals. We would show our appreciation to Y. Kamatani for the statistical advice.
Conflict of interest
The authors declare that they have no conflict of interest.
The study was funded in part by the BioBank Japan project supported by Ministry of Education, Sports, Science and Technology and Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (Kakenhi 24249083).