Genetic Variants of Complement Factor H and a High-Fat Diet are Associated with the Pathogenesis of Age-Related Macular Degeneration

Jasmine Nguyen

Introduction. Age-related macular degeneration (AMD) is the leading cause of visual deficit in older populations in the developed world.1   There are two different types of AMD: a wet type and a dry type. The wet type is characterized by exudate with choroidal neovascularization while the dry type is characterized by the deposits of drusen within the retinal pigment epithelium (RPE).2 Both genetic and environmental factors play a role in the risk of developing AMD, however genetic factors play a larger role.3   Specifically smoking, higher dietary fat, and obesity play a larger role in the risk of developing AMD, while the Y402H variant of the CFH gene has also been supported to lead to a higher risk of AMD.1,3   Complement factor H (CFH) is involved in the inactivation of the alternate complement pathway.1 This high risk variant leads to chronic inflammation by inhibiting MP elimination during inflammation resolution that leads to vulnerability to uncontrolled complement activation.4   Furthermore this variant cannot inhibit the terminal complement pathway efficiently leading to more membrane attack complex in the choroid.5 Methods. Mice with either the wild genotype or the Y402H genotype were fed either a normal diet or a high fat, cholesterol enriched (HFC) diet and aged.1   In a separate experiment, mice with Cfh+/+, Cfh+/-, or Cfh -/- were either fed a normal diet or a HFC diet.2 The height of sub- RPE deposit was measured in each variation as well as RPE height itself.1,2   The presence of multinucleated cells was also measured to measure RPE damage.2 Results. It was found that the tallest deposits were found in mice with the Cfh +/- genotype fed a HFC diet and in mice with the Y402H genotypic variant.1,2 It is hypothesized that because Cfh -/- lacks the key activators of the complement cascade, it did not develop the pathology typical of AMD.1 Furthermore, in Cfh +/- mice, there is a much higher recruitment of mononuclear phagocytes (MNP), establishing a complement-mediated effector response in sub-RPE deposits present in comparison to Cfh -/- HFC mice.1   Conclusions. A deficiency in CFH or the high risk variant Y402H genotype is found to lead to a decrease in inactivation of the alternate complement pathway leading to a state of chronic inflammation due to decreased inactivation of the alternate complement cascade pathway that leads to the pathology characteristic of AMD when fed a HFC diet.1,5

  1. Landowski M, Kelly U, Klingeborn M, et al. Human complement factor H Y402H polymorphism causes an age- related macular degeneration phenotype and lipoprotein dysregulation in mice. Proc Natl Acad Sci U S A 2019;116(9):3703-3711. doi: 10.1073/pnas.1814014116 [doi].
  2. Toomey CB, Kelly U, Saban DR, Bowes Rickman C. Regulation of age-related macular degeneration-like pathology by complement factor H. Proc Natl Acad Sci U S A. 2015;112(23):3040. doi:10.1073/pnas.1424391112 [doi].
  3. Sobrin L, Seddon JM. Nature and nurture- genes and environment- predict onset and progression of macular degeneration. Progress in Retinal and Eye Research. 2014;40:1-15. doi:10.1016/j.preteyeres.2013.12.004.
  4. Calippe B, Augustin S, Beguier F, et al. Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation. Immunity. 2017;46(2):261-272. doi:10.1016/j.immuni.2017.01.006.
  5. Whitmore SS, Sohn EH, Chirco KR, et al. Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy. Progress in Retinal and Eye Research. 2015;45:1-6 doi:10.1016/j.preteyeres.2014.11.005.