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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. Peter J Francis (francisp{at}
  1. Casey Eye Institute, United States
    1. Sara C Hamon (shamon{at}
    1. Rockefeller University, United States
      1. Jurg Ott (jott{at}
      1. Rockefeller University, United States
        1. Richard G Weleber (weleberr{at}
        1. Ophthalmology & Molecular Medical Genetics, United States
          1. Michael L Klein (kleinm{at}
          1. Casey Eye Institute, United States


            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 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, totaling 3137 individuals were genotyped for SNPs in thirteen 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 nutritional supplements were investigated.

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

            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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