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

J Hum Genet. 2018 Oct;63(10):1083-1091. doi: 10.1038/s10038-018-0493-0. Epub 2018 Jul 27.

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.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Asian People
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Japan
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics*
  • Macular Degeneration* / drug therapy
  • Macular Degeneration* / genetics
  • Male
  • Middle Aged
  • Otx Transcription Factors / genetics*
  • Polymorphism, Genetic*
  • Ranibizumab / administration & dosage*
  • Suppressor of Cytokine Signaling Proteins / genetics*

Substances

  • KCNMA1 protein, human
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • OTX2 protein, human
  • Otx Transcription Factors
  • SOCS2 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • Ranibizumab