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Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss
  1. P J Francis1,
  2. S C Hamon2,
  3. J Ott3,
  4. R G Weleber1,
  5. M L Klein1
  1. 1
    Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA
  2. 2
    Rockefeller University, New York, USA
  3. 3
    Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
  1. Dr P Francis, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239–4197, USA; francisp{at}


Background: Age related macular degeneration (AMD) is a leading cause of blindness. AMD is a complex disorder caused by genetic and environmental factors in which single nucleotide polymorphisms (SNPs) in the genes CFH and LOC387715/HTRA1/ARMS2 have prognostic importance for progression to advanced AMD (with visual loss). CFH may also have a pharmacogenetic role by affecting treatment response to widely used nutritional supplements. This paper examines other AMD susceptibility genes to determine if these genotypes influenced disease progression and treatment response.

Methods: Three cohorts, totalling 3137 individuals, were genotyped for SNPs in 13 genes previously published to be associated with advanced AMD (other than CFH and LOC387715/ARMS2/HTRA1). Those genes found associated were then evaluated for their involvement in disease progression. Interactions between the genes and with AREDS (Age-Related Eye Disease Study) nutritional supplements were investigated.

Results: Positive independent associations were noted in SNPs in the genes C2 (p = 0.0001, odds ratio (OR) 0.35, 95% confidence interval (CI) 0.2 to 0.6), CFB (p = 0.0001, OR 0.35, 95% CI 0.2 to 0.6), C3 (p = 0.0001, OR 3.91, 95% CI 1.94 to 7.88), APOE (ϵ4, p = 0.01, OR 0.50, 95% CI 0.29 to 0.86) and VEGFA (p = 0.01, OR 2.23, 95% CI 1.06 to 4.68). C2/CFB and C3 were independently related to progression from early/intermediate to advanced AMD with OR 0.32 (95% CI 0.14 to 0.73) and 3.32 (95% CI 1.46 to 7.59), respectively. Gene–gene and pharmacogenetic interactions were not observed. No preferential associations were observed with geographic atrophy or choroidal neovascularisation.

Conclusion: This study provides insights into the genetic pathogenesis of AMD. Five genes have now been shown to be independently involved in progression from intermediate disease (before vision loss has occurred) to advanced disease in which blindness is frequent.

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  • Funding: This work is supported by grants from the National Institutes of Health (NIH) National Eye Institute R01-EY12203 (MLK); the Foundation Fighting Blindness, Owing Mills, MD (PJF, RGW); the Macular Degeneration Center Research Fund, Casey Eye Institute, Oregon Health & Science University, Portland (MLK, PJF), and Research to Prevent Blindness, New York, NY (unrestricted grant to Casey Eye Institute, Career Development Award to PJF) and China NSF grant no. 30730057 (JO).

  • Competing interests: None.

  • Patient consent: Obtained.