Risk factors for progression of age-related macular degeneration

Abstract

Purpose: Age-related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare.

Recent findings: While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High-Density Lipoprotein Cholesterol (HDL-C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein.

Summary: Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice.

Keywords: age-related macular degeneration; epidemiology; genetics.

Figure 1

Hard druse on colour fundus photograph, as indicated with an arrow (left) and optical coherence tomography, as indicated with an arrow (right).

Figure 2

Large drusen on colour fundus photograph, as indicated with an arrow (left) and optical coherence tomography, as indicated with arrows (right).

Figure 3

Calcified druse on colour fundus photograph, as indicated with an arrow (left) and optical coherence tomography, as indicated with an arrow (right).

Figure 4

Reticular pseudodrusen on colour fundus photograph (left), near‐infrared photography (middle) and optical coherence tomography, as indicated with arrows (right).

Figure 5

Cuticular drusen on colour fundus photograph (left), fluorescein angiography (middle) and optical coherence tomography, as indicated with arrows (right).

Figure 6

Hyperpigmentation on top of a large druse on colour fundus photograph, as indicated with an arrow (left), hyperreflective foci (indicated with arrow) upon a drusenoid pigment epithelial detachment (indicated between dotted lines) on optical coherence tomography (right).

Figure 7

Overview of perilesional fundus autofluorescence patterns, from left to right: no pattern (a), focal pattern (b), banded pattern (c) and diffuse pattern (d).

Figure 8

No haemorrhaging or oedema on colour fundus photograph (left) identified quiescent choroidal neovascularisation (CNV)/subclinical choroidal neovascularisation (CNV) just below the pigment epithelium as shown between the dotted lines on optical coherence tomography angiography (middle) and a double layer sign showing an irregularly slightly elevated pigment epithelium as indicated between the arrows, at the site of the quiescent CNV/subclinical CNV (indicated between the dotted lines) on optical coherence tomography (right),

Figure 9

Incomplete retinal pigment epithelium atrophy and outer retina atrophy (iRORA) on optical coherence tomography as seen by irregular or interrupted RPE layer, indicated between dotted lines and a subsided outer plexiform layer and inner nuclear layer, indicated with an arrow (a), and an outer retinal tubulation on optical coherence tomography, as indicated with an arrow (b).