Archive for July 2015

Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a complex disorder triggered by a wide range of environmental and genetic risk factors.1-3 Numerous common variants are known markers of AMD including several complement pathway genes: complement factor H (CFH),4-8 complement factor I,9 complement component 2, complement factor B,7,10 and complement 3.11

We previously reported the association of a rare CFH variant with AMD, R1210C, which is the strongest genetic risk factor to date, with an odds ratio (OR) of 20.12,13 The R1210C variant is also known to be associated with inherited forms of atypical hemolytic uremic syndrome and primary glomerulonephritis.14-21 In addition to linking 2 clinically unrelated conditions, such as AMD and atypical hemolytic uremic syndrome,the R1210C finding suggests that compromised function of the factorH protein is involved in AMD pathogenesis as a causal factor and not merely as an associated factor.12

In that initial report, the R1210C rare variant was associated with an earlier age at diagnosis of advanced AMD.12 This variant is also significantly associated with progression from early or intermediate AMD to advanced stages in a multigene prediction model.22,23 However, the fundus phenotype typically related to the variant is still to be determined. This knowledge is needed to better understand the manifestations of this rare CFH mutation and to help detect and characterize this phenotype in clinical practice. Identification of such high-risk individuals will be important for screening, potential new therapeutic strategies, and personalized medicine. Therefore, the objective of this study, conducted from 2012 to 2014, was to determine specific fundus features of a white population carrying the CFH R1210C rare variant.

Full Paper: Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration
(461K PDF)


Progressive Atrophy in AMD Even With Treatment

Anti-VEGF therapies in many patients with wet age-related macular degeneration go on to develop atrophy. The speculation for causes of this are:

  1. Natural progression of underlying age-related macular degeneration driving the atrophy.
  2. Atrophy is associated with choroidal neovascularization.
  3. Atrophy is associated with anti-VEGF therapy independent of choroidal neovascularization.

No answers to these theories are yet available, so we should not change how we treat patients. We should, however, advise patients that treating wet age-related macular degeneration may not stop the progression of their underlying dry age-related macular degeneration.