Thesis Abstract - Hautamäki Asta


Genetic and Structural Variations Associated with the Activity of Exudative Age-Related Macular Degeneration Lesion


Age-related macular degeneration (AMD) is the leading cause of visual impairment in developed countries. Geographic atrophy and exudative AMD, the advanced forms of AMD account for the majority of visual impairment. No evidence-based medical treatment exists for geographic atrophy, but the choroidal neovascularization (CNV) forming exudative AMD lesion can be targeted with therapy. Vascular endothelial growth factor (VEGF) has a crucial role in ocular neovessel formation. VEGF-inhibitors form the mainstay of present-day treatment of exudative AMD. Although response to anti-VEGF agents is usually good, marked individual variations exist in treatment outcomes. The reasons behind the variations are largely unknown.


The aim of this study was to identify factors that predict treatment response during anti-VEGF therapy and affect activity of exudative AMD lesion. We analyzed the effects of CNV lesion characteristics, the effects of potential genetic predictors: variants of interleukin-8 (IL-8), VEGF, and erythropoietin genes, the effects of well-known risk factors for AMD: tobacco smoking, risk variants of complement factor H (CFH), ARMS2, and complement component 3 (C3) genes, and the variations in anterior chamber protein concentration (flare). Initial treatment response after the first injections of anti-VEGF agent bevacizumab was analyzed retrospectively in a material of 96 patients. Long-term treatment response and flare was studied in a prospective two-year follow-up of 50 patients treated with bevacizumab. Association of the genetic variant of IL-8 with earlier onset of exudative AMD was analyzed retrospectively using the medical records of 301 patients with exudative AMD, 72 patients with dry AMD, and 119 control subjects.

The IL-8 (rs4073) promoter polymorphism has been associated with regulation of the production of IL-8, a potent mediator of inflammation and neovascularization. It was the only genetic factor in the analyses that had an association with the initial anatomic treatment response. It also had a marked cumulative effect on the long-term anatomic response together with the risk variants of VEGF and CFH genes. CNV lesion characteristics affected both functional and anatomic outcomes of initial treatment, but were less important in predicting long-term response. In the long term follow-up also the genetic variant of ARMS2 was associated with functional outcome. Flare reflected poorly the lesion activity and did not predict treatment response. However, the fellow eyes that developed exudative AMD later had higher flare values at the beginning of follow-up compared with the eyes that remained free of exudative AMD features. An association was also found between the variant of IL-8 and age of onset of exudative AMD. These findings support the hypothesis that IL-8 has a role in the process leading to CNV growth in exudative AMD and in the regulation of activity of exudative AMD lesion during anti-VEGF treatment.

Dissertationes Scholae Doctoralis ad Sanitatem investigandam Universitatis Helsinkiensis - URN:ISSN:2342-317X