Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration

Masato Akiyama, Atsushi Takahashi, Yukihide Momozawa, Satoshi Arakawa, Fuyuki Miya, Tatsuhiko Tsunoda, Kyota Ashikawa, Yuji Oshima, Miho Yasuda, Shigeo Yoshida, Hiroshi Enaida, Xue Tan, Yasuo Yanagi, Tsutomu Yasukawa, Yuichiro Ogura, Yoshimi Nagai, Kanji Takahashi, Kimihiko Fujisawa, Maiko Inoue, Akira Arakawa & 6 others Koji Tanaka, Mitsuko Yuzawa, Kazuaki Kadonosono, Koh Hei Sonoda, Tatsuro Ishibashi, Michiaki Kubo

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1083-1091
Number of pages9
JournalJournal of Human Genetics
Volume63
Issue number10
DOIs
Publication statusPublished - 01-10-2018

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Genome-Wide Association Study
Macular Degeneration
Visual Acuity
Therapeutics
Vascular Endothelial Growth Factor A
Area Under Curve
Genome
Ranibizumab
Population
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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Akiyama, Masato ; Takahashi, Atsushi ; Momozawa, Yukihide ; Arakawa, Satoshi ; Miya, Fuyuki ; Tsunoda, Tatsuhiko ; Ashikawa, Kyota ; Oshima, Yuji ; Yasuda, Miho ; Yoshida, Shigeo ; Enaida, Hiroshi ; Tan, Xue ; Yanagi, Yasuo ; Yasukawa, Tsutomu ; Ogura, Yuichiro ; Nagai, Yoshimi ; Takahashi, Kanji ; Fujisawa, Kimihiko ; Inoue, Maiko ; Arakawa, Akira ; Tanaka, Koji ; Yuzawa, Mitsuko ; Kadonosono, Kazuaki ; Sonoda, Koh Hei ; Ishibashi, Tatsuro ; Kubo, Michiaki. / Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration. In: Journal of Human Genetics. 2018 ; Vol. 63, No. 10. pp. 1083-1091.
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abstract = "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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Akiyama, M, Takahashi, A, Momozawa, Y, Arakawa, S, Miya, F, Tsunoda, T, Ashikawa, K, Oshima, Y, Yasuda, M, Yoshida, S, Enaida, H, Tan, X, Yanagi, Y, Yasukawa, T, Ogura, Y, Nagai, Y, Takahashi, K, Fujisawa, K, Inoue, M, Arakawa, A, Tanaka, K, Yuzawa, M, Kadonosono, K, Sonoda, KH, Ishibashi, T & Kubo, M 2018, 'Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration', Journal of Human Genetics, vol. 63, no. 10, pp. 1083-1091. https://doi.org/10.1038/s10038-018-0493-0

Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration. / Akiyama, Masato; Takahashi, Atsushi; Momozawa, Yukihide; Arakawa, Satoshi; Miya, Fuyuki; Tsunoda, Tatsuhiko; Ashikawa, Kyota; Oshima, Yuji; Yasuda, Miho; Yoshida, Shigeo; Enaida, Hiroshi; Tan, Xue; Yanagi, Yasuo; Yasukawa, Tsutomu; Ogura, Yuichiro; Nagai, Yoshimi; Takahashi, Kanji; Fujisawa, Kimihiko; Inoue, Maiko; Arakawa, Akira; Tanaka, Koji; Yuzawa, Mitsuko; Kadonosono, Kazuaki; Sonoda, Koh Hei; Ishibashi, Tatsuro; Kubo, Michiaki.

In: Journal of Human Genetics, Vol. 63, No. 10, 01.10.2018, p. 1083-1091.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration

AU - Akiyama, Masato

AU - Takahashi, Atsushi

AU - Momozawa, Yukihide

AU - Arakawa, Satoshi

AU - Miya, Fuyuki

AU - Tsunoda, Tatsuhiko

AU - Ashikawa, Kyota

AU - Oshima, Yuji

AU - Yasuda, Miho

AU - Yoshida, Shigeo

AU - Enaida, Hiroshi

AU - Tan, Xue

AU - Yanagi, Yasuo

AU - Yasukawa, Tsutomu

AU - Ogura, Yuichiro

AU - Nagai, Yoshimi

AU - Takahashi, Kanji

AU - Fujisawa, Kimihiko

AU - Inoue, Maiko

AU - Arakawa, Akira

AU - Tanaka, Koji

AU - Yuzawa, Mitsuko

AU - Kadonosono, Kazuaki

AU - Sonoda, Koh Hei

AU - Ishibashi, Tatsuro

AU - Kubo, Michiaki

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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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