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Masato Akiyama, Atsushi Takahashi, Yukihide Momozawa, Satoshi Arakawa, Fuyuki Miya, Yuji Oshima, Miho Yasuda, Shigeo Yoshida, Yasuo Yanagi, Koji Tanaka, Yuichiro Ogura, Kanji Takahashi, Kimihiko Fujisawa, Kazuaki Kadonosono, Tatsuro Ishibashi, Koh-hei Sonoda; Genome-wide association study for response to ranibizumab therapy in 919 individuals with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1426. doi: https://doi.org/.
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Although anti-vascular endothelial growth factor (VEGF) agents improved visual acuity in patients with exudative age-related macular degeneration (AMD), genetic factors associated with treatment outcomes have been largely unknown. To investigate genetic factors influencing visual outcome with ranibizumab therapy, we conducted a genome-wide association study (GWAS) and a replication study in a Japanese population.
Treatment response was determined based on the change in visual acuity at 3 months. We defined individuals who maintained or improved their best-corrected visual acuity (BCVA) as responders, and individuals whose BCVA worsened as non-responders. We performed a genome-wide association study (GWAS) in 434 individuals who were treated with intravitreal ranibizumab using 6,826,359 single nucleotide polymorphisms (SNPs). We selected 93 variants showing P < 1.0×10-4 in GWAS, and genotyped them in an independent set of 487 individuals with AMD.
Among the participants, 195 participants (21.2%) were defined as non-responders. In the combined analysis of GWAS and a replication study, we did not observe variants which showed genome-wide significant association. However, four SNPs showed suggestive levels of associations with the visual outcome (rs17822656, rs76150532, rs17296444, and rs75165563: Pcombined < 1.0×10-5). The frequencies of these SNPs were low in responders and were more than 2-fold higher in non-responders. The proportions of non-responders were 13.7%, 38.8%, 58.0%, and 80.0% in individuals with 0, 1, 2, and 3 or more risk alleles, respectively. Changes in BCVA at 3 months decreased linearly as the number of risk alleles increased (P = 1.67 × 10-12). The area under the curve using age, baseline best-corrected visual acuity, and history of previous treatment was 0.607, and improved significantly to 0.713 in combination with identified SNPs (P < 0.0001).
Although further evaluations are needed, our results suggest four candidate variants influencing response to ranibizumab therapy.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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