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Genetic risk factors in age-related macular degeneration: an increasing body of research suggests that genetic factors play a significant role in age-related macular degeneration. This article will consider the most important genes and the implications for practitioners when advising patients.


Age-related macular degeneration (AMD) is the leading cause of visual impairment in industrialised countries for people over 65 years of age. In the UK, the overall prevalence of the late form of AMD is 2.4% aged 50 years or more, increasing to 4.8% in those 65 years of age or more, and 12.2% in individuals greater than 80 years of age (see Figure I). (1-4) This equates to an estimated 513,000 individuals currently in the UK with AMD-related visual impairment eligible for registration as seriously visually impaired. With an ageing population, this figure is predicted to rise to 679,000 by 2020, (4) with a similar trend likely in many other countries.

In the last decade, research has revealed substantial evidence that genetic factors may be involved in AMD, (5-8) and play a significant role in the disease, in addition to other known risk factors such as smoking, (9-12) diet, (13-18), and exposure to sunlight. (19,20) A

number of genes have now been implicated as possible risk factors with the strongest evidence for genes involved in immune modulation and the complement system. (21-26) This article discusses genetic risk factors for AMD and considers the significance of these factors relative to other modifiable risk factors.


Many of the genes implicated as risk factors for AMD involve single nucleotide polymorphisms (SNPs) within genes, resulting in one amino acid within the protein being switched for another. Many of these substitutions result from 'missense mutations', that is the alteration of one DNA base within the coding region. Mutations, which give rise to the substitution of a similar amino acid within a protein, for example, valine for alanine, result in little protein modification. By contrast, other substitutions may be of greater consequence, resulting in various changes in protein function and interaction with other molecules. A further two types of substitution are less common but potentially have more serious effects than missense mutations. First, a codon is modified by base substitution from one coding for an amino acid such as glutamate, to a stop or termination codon ('null mutation' or 'nonsense mutation'); this type of mutation can result in a truncated protein with little natural function. Second, 'splice-site' mutations, where a substitution in a region of DNA which separates an exon from an intron can result in the incorporation of intron DNA into protein synthesis, resulting in proteins very different from their natural counterparts. These genetic changes often occur as natural variations within the human population and confer either increased risk or in some cases, protection against AMD. In contrast to SNP, copy number variation, the variation in the number of copies of a specific DNA sequence within the gene, appears to be less important in AMD, although a small number of such associations have been recently reported. (27) A summary of the major genes currently associated with AMD is given in Table 1 (page 40).

GENES INVOLVED IN AMD Complement system

Genes for the complement system protein factor H (CFH), (26,28-31) factor B (CFB), (32) and factor 3 (C3), (22,33) appear to exhibit the strongest associations with the risk of developing AMD. (34) A higher risk of wet AMD is associated with polymorphisms of the CFH gene. (26) A strong association between CFH and bilateral dry AMD has also been demonstrated. (34) By contrast, CFB is a component of the alternative pathway of complement activation and is involved in the proliferation of pre-activated B-lymphocytes. Genetic variants of the serpin peptidase inhibitor (SERPING1) gene, which regulates the activity of the complement proteins, have recently been shown to be associated with AMD. (23) The protein inhibits the first stage of the complement cascade thus regulating complement activation.

Membrane transport

The adenosine triphosphate (ATP)-binding cassette rim protein (ABCR) gene consisting of 50 exons, (35) is located on the short arm of chromosome 1 near to the centromere. (36,37) A large number of mutations of the ABCR gene have now been identified suggesting it is an especially variable gene.38 In early studies, however, there was little agreement concerning the importance of the ABCR gene in AMD. More recently, the presence of three significant mutations in ABCR was examined in eight cases of wet AMD with the analysis failing to identify the presence of disease-causing mutations. (39) However, ABCR mutations, which cause the protein to accumulate in the inner segment of rod cells also occur in patients with severe retinal dystrophies, including a small number of AMD cases. (40) ABCR may influence the active transport of a wide range of drugs, metabolites, peptides, and lipids with possible involvement in the transport of retinal derivatives, phospholipids, peptides, or other endogenous substrates across the disc membrane. Hence, disturbed transport across the membranes of retinal cells is one possible, albeit more rare route to AMD.

Blood vessels

A number of genes linked to the development of blood vessels or modulation of vascular processes have been implicated in AMD and these genes are interesting because of the involvement of neovascularisation in wet AMD.

Fibroblast growth factor 2 (FGF2) encodes a protein involved in various biological processes including cell division, the development of blood vessels, wound healing, and tumour growth. In a Spanish population, it has been shown that although the principal genetic risk factors are ARMS2 and CFH, FGF2 may also be associated with some cases of dry AMD. (41)

Rare forms of AMD, exhibiting an autosomal dominant pattern of inheritance, may be related to the fibulin-5 gene (FBLN5). Fibulin-5 is an excreted extracellular matrix protein and is expressed in basement membranes of epithelial cells and developing blood vessels. Screening of AMD patients has shown a statistically significant correlation between mutations of fibulin-5 and AMD. (42)

The activity of macrophages and endothelial cell activation may also be involved in AMD. (43) Selectin genes function as cell adhesion molecules on the surface of activated endothelial cells and platelets are involved in the interactions between platelets and white blood cells. A polymorphism of Selectin P (SELP) has been found to be statistically associated with dry AMD. (44) Platelet and leucocyte interactions promote thrombus formation and are active at the sites of inflammation but how these processes may contribute to dry AMD is unclear.

Lipid metabolism

Apolipoprotein E (APOE) is a lipid transport protein essential for the catabolism of triglyceride-rich lipoproteins. It transports lipoproteins, fat-soluble vitamins, and cholesterol to the lymph system and then to the blood. APOE has three major variants: e2, e3, and e4. These forms differ only slightly but are sufficient to alter the structure and function of the molecule. A pooled analysis of 15 studies found associations between APOE alleles e4 and e2 with late AMD but no interaction with gender or smoking behaviour. (44) By contrast, an association has been shown between possession of APOE allele e2 and early onset AMD in nonsmokers or previous smokers, but not in current smokers. (45) More recently, a meta-analysis of early onset AMD has suggested an association with APOE. (46)

The hepatic lipase (LIPC) gene codes for the enzyme hepatic triglyceride lipase, which is expressed in the liver and adrenal glands. The principle function of the enzyme is conversion of intermediate density lipoproteins (IDL) to low density lipoproteins (LDL). There may be an association between the proportion of different lipoproteins and AMD in that a specific genotype of LIPC has been linked with a reduced risk of both dry and wet forms of the disease. (47) Increased incidence of early AMD has also been observed in patients with elevated C-reactive protein, (48) which is associated with increased consumption of lard and solid fat. (49) High triglyceride levels, by contrast, are associated with a lower risk and, therefore, certain types of lipid could be protective against AMD. Hence, genes that affect lipid metabolism may alter the balance between different types of fat in the body thus influencing risk of AMD.


The most important genes implicated in AMD appear to be those involved in immune modulation and the complement system strongly suggesting that inflammatory processes are important in AMD. It has been concluded that changes in a small number of immune system-related genes together could account for 45% of the risk of developing AMD. (23) Genes associated with membrane transport, the vascular system, and with lipid metabolism are also involved. Of these, the vascular genes are of particular interest because of the neovascular aspects of wet AMD. In addition, a series of other genes of variable or unknown function could be involved in AMD and it is likely that many further genes will be identified in the future.

There are likely to be multiple pathways leading to the same ultimate pathology in AMD, namely a loss of retinal photoreceptors. Nevertheless, it is possible that carriers of high-risk genotypes may show detectable and specific visual changes before overt pathology is present. Feigle et alassessed the critical fusion frequency (CFF) in individuals with normal vision who were carriers of high-risk variants of genes associated with AMD. (50) CFF mediated by rods and cones was significantly reduced in those individuals with positive associations with AMD risk factor genes rather than gene variant-negative individuals, although CFF mediated by cones alone was unaffected.


Several studies have proposed additional lifestyle changes to reduce the lifetime risk of AMD that should be considered in patients with a high genetic risk. Higher red meat intake has been positively associated with early AMD whereas consumption of chicken may be negatively associated with AMD. (51) There is considerable evidence that the incidence of AMD also varies with both ethnicity and geographical location which could be attributed in part to varying diet. The risk of AMD varies among Americans of different Asian origin, (52) with 5.4% of Asian Americans having dry AMD and 0.49% wet AMD. Chinese and Pakistani Americans have a significantly increased risk of dry AMD compared with non-Hispanic whites. By contrast, Japanese Americans have a 29% decreased risk of dry AMD compared to the general US population. (53) There is no significant difference in the risk of wet AMD in Asian Americans of any ethnicity compared with white Americans. Outside of the US, a Japanese study found that the prevalence of early AMD in individuals greater than 35 years of age was 3.5%, and of late AMD 0.5%. (53) In rural China, prevalence of wet and dry AMD is 1.45% and 1.55%, respectively. (54) An overview of epidemiological studies from around the world suggests that prevalence of early AMD is similar in the white, black, and Hispanic populations, but that whites have a greater prevalence of late AMD. (55) Hence, prevalence studies provide considerable evidence that environmental, and lifestyle differences among populations, as well as genetic variation are likely to be involved in determining the risk of AMD.


Modifiable risk factors for AMD should be discussed with patients whose lifestyle and/or family history place them in an elevated risk category for the disease. Protective modifications include: cessation of smoking, wearing sunglasses under conditions of elevated light intensity, and dietary modifications. Interactions between different genes and the environment play a prominent role in the development of AMD and are likely to be continuing areas of future research.

Course code: C-41832 Deadline: September 5, 2015


To be able to explain to patients about the genetic risk factors in AMD (Group 1.2.4)

To be able to advise patients at risk of developing AMD (Group 2.2.1)

To understand the risk factors in AMD (Group 6.1.9)


To be able to explain to patients about the genetic risk factors in AMD (Group 1.2.4)

To understand the role of genetics and the risk of developing AMD (Group 8.1.5)

Maryam Mousavi is an optometrist with a research interest in retinal pathology. Before qualifying in the UK, she was a registered optician working in Vancouver, Canada.

Table 1

Genes associated
with age-
related macular

Gene                   Function               Link with AMD

Apolipoprotein E       Lipid transport        Early onset

ATP-binding cassette   Membrane transport     Wet AMD
rim protein (ABCR)

Age-related            Unknown                Wet AMD; less with
maculopathy                                   dry AMD
protein 2 (ARMS2)

ATP synthase           Produces ATP from      Implicated in dry
(MT-ATP6)              ADP                    AMD

Complement Factor H    Inhibition of          Bilateral wet AMD
(CFH)                  inflammatory

Complement Factor B    Component of           AMD
(CFB)                  alternative pathway

Complement Factor 3    Mediates               Wet AMD
(C3)                   inflammatory

DNA excision repair    Promotes complex       Unclear
protein (ERCC6)        formation at repair

Fibroblast growth      Diverse biological     Dry AMD
Factor 2 (FGF2)        functions

Fibulin 5 (FBLN5)      Polymerisation of      AMD

Hepatic lipase         Converts IDL to LDL    Reduced risk of wet
(LIPC)                                        and dry AMD

Lysyl oxidase-like 1   Connective tissue      Wet AMD
(LOXYL1)               development

Selectin P (SELP)      Platelet/leucocyte     Dry AMD

Serpin peptidase       Regulates complement   AMD
inhibitor (SERPING1)   activation

Serum peptidase        Regulates cell         Bilateral wet AMD
inhibitor (HTRA1)      growth

Transferrin (TF)       Iron binding protein   AMD in smokers

Voltage-dependent      L-type calcium         AMD
calcium channel 3      channel protein
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Author:Mousavi, Maryam
Publication:Optometry Today
Article Type:Report
Date:Aug 8, 2015
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