Clinical Study

Eye (2008) 22, 768–776; doi:10.1038/sj.eye.6702844; published online 11 May 2007

Age-related macular degeneration: a perspective on genetic studies

N Patel1, T Adewoyin1 and N V Chong1

1Laser and Retinal Research Unit, Kings College Hospital, London, UK

Correspondence: Victor Chong, Laser and Retinal Research Unit, Kings College Hospital, Denmark Hill, London SE5 9RS, UK. Tel: +44 20 3299 4548; Fax: +44 20 3299 3738; E-mail: victor@eretina.org

Received 22 November 2006; Accepted 19 March 2007; Published online 11 May 2007.

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Abstract

Aim

  

Age-related macular degeneration (AMD) is a common macular disease in the developed world and recent studies have shown that specific genes may be associated with it and may contribute to a higher risk of developing AMD.

Objective

  

Our objective was to review systematically recent publications related to the genetics of AMD and provide relevant information that would help both scientists and clinicians in advising patients.

Method

  

A systematic search was performed on PubMed, Medline, and National Library of Medicine as well as ARVO abstracts using key words relevant to the genetic associations of AMD.

Results

  

The most important genetic associations in AMD involved the complement factor H (CFH) gene, which showed that possession of the variant Y402H polymorphism significantly increases the risk for AMD. Protective genes have also been identified such as those on either factor B (BFor complement factor B (CFB)) or complement component 2 (C2) genes. The genes involved in inherited macular dystrophies such as ATP-binding cassette, subfamily A (ABC1), member 4 (ABCA4), vitelliform macular dystrophy (VMD2), tissue inhibitor of matrix metalloproteinase-3 (TIMP3), and EFEMP1have yielded some important information but further confirmatory work has yet to establish a clear association with AMD.

Conclusion

  

Patients with AMD possess specific genetic variants of the CFHgene, which put them at a higher risk of developing the disease. Other unaffected individuals may possess certain protective genetic variants, which could prevent them from developing AMD. Further research will no doubt shed light on other such mechanisms and these will be useful in identifying possible direct targets for drugs or indirectly through modulation of the genes responsible for disease presentation.

Keywords:

genetics, age-related macular degeneration, systemic review, complement factor H

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Introduction

Age-related macular degeneration (AMD) is a common macular disease affecting about 30% of adults aged 75 or older who have some signs of maculopathy, and about 6–8% of the individuals in this age group are afflicted with the advanced stages of this disease which causes the most severe visual loss.1 As the disease primarily impacts on central vision, it is the leading cause of blindness in people above 60 years of age and accounts for about 50% of blind registration.2, 3

A number of epidemiological studies have implicated AMD as an inherited disease showing that family members are at increased risk of the disease.4, 5 Results from twin and family-based studies have provided compelling evidence for a genetic basis for AMD.6, 7, 8 As it is a condition prevalent at old age, finding well-established family pedigrees is difficult. The inheritance is thought to be polygenic and environmental factors such as smoking, hypertension, and chronic inflammation are thought to play major roles in its pathogenesis. The emphasis on the genetic basis of AMD has increased in recent years. This systematic review was performed to look at the role of genes in AMD and to evaluate which particular genes play important roles in the inheritance of the disease so that accurate information can be displayed in a logical pattern for both clinicians and scientists. The information could be used to identify high-risk patients so that lifestyle behaviour such as smoking can be modified.

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Methods

A detailed search using, PubMed, MEDLINE (1985 to August 2006), and EMBASE (1985 to August 2006) was performed. Conference abstracts (sessions related to AMD genetics and Inherited Macular Dystrophies) in ARVO 1975 to 2006 were analysed in detail looking for relevant published articles in this field.

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Discussion

A number of studies including familial, twin-based, and other analyses have shown a strong genetic component in AMD. The work done by Seddon et al9 showed that prevalence among relatives was significantly higher compared to controls (23.7% vs 11.6%). Similar work by Klaver et al10 showed that the odds ratios for siblings and offsprings of AMD patients were higher compared to siblings of controls. Several independent groups have examined studies comparing concordance rates in monozygotic vs dizygotic twins.11, 12 These two larger studies showed that there is a substantial heritable component to AMD; however unique environmental factors also play an important role.

Researchers have carried out a number of linkage studies in an attempt to identify the genomic regions containing susceptibility loci for AMD. These studies were performed to evaluate whether genetic marker loci segregated independently of disease status within family pedigrees. In the last decade, the study of hereditary macular dystrophies such as Best's, Stargardt's, Sorsby's fundus, autosomal-dominant drusen- and peripherin/RDS-related dystrophy has provided some clues to the pathogenesis of AMD. Many investigators have proposed that inherited macular dystrophies could be potential models for AMD. Once positional loci and function of the various genes from some of these inherited macular diseases were confirmed, more specific analysis was performed on AMD patients. Tables 1 and 2 show the various candidate genes tested with negative findings in the former and positive findings in the latter.



Studies of Sorsby's fundus dystrophy and the identification of the gene mutation for a tissue inhibitor of matrix metalloproteinase-3 (TIMP3) has not correlated with AMD.13 The identification of the ATP-binding cassette, subfamily A (ABC1), member 4 (ABCA4) gene that encodes for a retinal rod/cone photoreceptor protein and its deletion results in Stargardt's macula dystrophy. Allikmets et al14 showed the presence of ABCA4 polymorphisms in 3.4% of their total screened patients compared to 0.95% of controls. It has also been suggested that heterozygotes for ABCA4 mutations were predisposed to AMD but these results have been disputed in later studies.14, 15 The role of ABCA4 remains uncertain in AMD and the possibility that this gene causes a small number of AMD cases cannot be excluded. The protein bestrophin and its gene mutation is responsible for vitelliform macular dystrophy (VMD2, Best's disease), an early onset, autosomal, dominant macular degeneration characterized by the deposition of lipofuscin-like material within and below the retinal pigment epithelium but studies have shown a small, non-significant correlation with AMD.16, 17

Malattia leventinese or Doyne honeycomb retinal dystrophy shares similar clinical and histological features to AMD and the gene (EFEMPI) responsible for the disease encodes for a member of the fibulin family (fibulin-3/SI-5/FBNL), a newly recognized group of extracellular matrix proteins.18 A recent study has shown that missense variations in the fibulin 5 gene were found in 1.7% of patients with AMD with many variations in other fibulin genes being found in these patients.19 This finding may be relevant to AMD pathogenesis as misfolding of the FBNL-5 protein may result in dysfunction at the extracellular matrix in Bruch's membrane. Reduced secretion of the mutant FBLN-5 protein seems to be important for AMD to develop in these patients.20 This could result in abnormal deposition as seen in drusen and consequent disinhibition of vascular endothelial growth factor (VEGF) resulting in CNV pathogenesis.21

The immune system has been implicated in pathogenesis of AMD for years from the work of Hageman and colleagues.22, 23, 24 Histological studies that have showed the presence of complement components both within drusen and along the RPE-choroid interface in AMD eyes.22 Its role in the pathogenesis of AMD has been confirmed recently by the identification of polymorphisms in the gene that encodes for complement factor H (CFH) in AMD patients. The complement system is part of the innate defence mechanism consisting of over 30 serum proteins involved as a cascade that results in the rapid delivery of activated enzymes which create micropores within foreign objects such as microbes resulting in cellular lysis and inflammation.

The CFH is part of the alternative pathway and it is specifically involved with the inhibition of the cascade in combination with other proteins. It is thought that for some reason in AMD patients, abnormal regulation of the complement cascade occurs at a local level within Bruch's membrane and adjacent retinal pigment epithelial cells resulting in uncontrolled compliment activation and consequent drusen formation.25 Recent studies has shown that the presence of the at-risk haplotype increased the risk of AMD 2.7-fold and accounted for 50% of the attributable risk of AMD in that group.26, 27 Another study has shown that individuals homozygous for the risk alleles (representing a tyrosine–histidine change at amino acid 402) have a 7.4-fold increased likelihood of AMD.28

These studies confirm an initial hypothesis, which established that chronic inflammation involving the complement pathway could contribute to disease progression. Using candidate gene screening, several different groups have found an association between the CFH gene and AMD in large numbers of patients.29, 30 Another study has shown that possession of the variant Y402H polymorphism significantly increases the risk for AMD with odds ratios between 2.45 and 5.57 and could explain approximately 43% of AMD in older adults.31 Table 3 shows a summary of the recent global papers on CFH and AMD containing the odds ratio and confidence intervals with each polymorphism.


A recent Japanese study showed that the CFH gene did not appear to be a primary hereditary contributor to AMD suggesting ethnic differences of AMD phenotypes.32 Most of the studies that showed significant findings consisted of Caucasian populations; however, in Chinese patients, results on AMD patients has shown that the frequency of the Y402H polymorphism is much lower in comparison and is associated with neovascular AMD.33 Gold et al34 examined two other factors involved in the complement cascade, factor B (BF) and complement component 2 (C2), for genetic variation in two independent cohorts. The results showed that 56% of the individuals who did not have AMD were in possession of the protective variant of either CFH, BF, or C2 gene compared to 74% with AMD who lacked the protective variant. As shown in Table 4, the figures from this study indicate that possession of the specific C2 and BF polymorphisms may have a protective effect against AMD. An absence of these variations on the C2/CFB genome may otherwise predispose patients to develop AMD. Other genes such as the LOC387715 on chromosome 10q26 are also thought to confer higher risks to developing CNV independent of the CFH gene.35, 36 This gene is located in an extensive region of linkage disequilibrium, which encompasses other genes that show association with AMD and it is postulated that the causative mutation could be in a neighbouring gene37 (Table 5). Interestingly, Schimdt et al38 have shown that genetic susceptibility (such as a coding change (Ala69Ser) on the LOC387715 gene) coupled with a modifiable lifestyle factor such as cigarette smoking could confer a significantly higher risk of AMD than either factor alone.



Apolipoprotein E (ApoE) genotype was studied initially for its association with Alzheimer disease due to the presence of increase amyloid β-peptides deposition in cerebral cortex.39 The role of ApoE has also been investigated extensively to understand the aetiology of AMD. This polymorphic protein plays an important role in lipid metabolism and central nervous system lipid homeostasis and the presence of lipid in drusen has prompted these studies. Souied et al40 showed a reduced prevalence of the ε4 allele in patients with exudative AMD as compared to a control sample and concluded that the ApoE gene is a genetic protective factor identified in AMD. Other studies have shown the presence of ApoE protein within AMD-associated deposits in the macula.41 Some studies have shown that ε4 allele could be protective, or at the very least, delaying the age of diagnosis of disease, whereas the ε2 allele appears to have a modifier effect by bringing forward the mean age of disease diagnosis.42, 43 There are other studies which did not find a significant association between AMD development and ApoE allele frequency.44, 45 Table 6 summarizes the findings of the odds ratios in AMD looking at ApoE2 and ApoE4 alleles in reference to ApoE3. The data shows that possession of ApoE4 may have a protective effect in comparison to ApoE2 with regard to development of AMD.


The role of inflammation and genetic predisposition reported in AMD may involve immune response gene such as human leucocyte antigen (HLA) polymorphisms that modulate susceptibility to AMD, HLA antigens are expressed both normally and in eyes affected with AMD and with intense HLA-DR immunoreactivity that has been demonstrated in both soft and hard drusens.46 Increased HLA class II immunoreactivity has been observed in the human retina affected with AMD and related to drusen formation.47 Genetic analysis of patients with AMD have revealed that there may be relevant positive and negative associations between HLA alleles and AMD, and these could influence the development of AMD through modulation of the choroidal immune function.48

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Conclusion

These studies have confirmed that some affected patients may possess specific genetic variants of the CFH gene, which put them at a higher risk of developing the disease. Other unaffected individuals may possess certain protective genetic variants, which could prevent them from developing AMD. Modifiable factors such as smoking and body mass index (BMI) are very important as they confer a higher risk of developing CNV in the presence of high-risk alleles.49 It is imperative to clarify that the mechanism of disease development can be difficult in complex diseases such as AMD, and these studies have helped in our understanding of pathological findings and genetic predispositions. From previous experience, screening has been important in prevention, early detection, and prompt treatment such as in diabetes. Using the same concept in AMD, we know that genetic factors play an important part as discussed previously and although mass screening in local populations is not indicated in AMD, there may be sufficient evidence to screen familial cases initially using genetic laboratory tests for the CFH, C2/BF, LOC, and ApoE polymorphisms. These tests are in fact inexpensive to perform and could be readily made available in local laboratories (actual costs for genotyping a DNA sample by Taqman assay could be as less as 28 pence. Identification of higher risk cases can then be used to inform patients of their potential risk of developing the disease and advised to implement changes in their lifestyle such as lowering BMI or cessation of smoking. It is important to note here that there may not be sufficient evidence yet to suggest that adjusting these modifiable risk factors will influence future risk of developing AMD in the presence of these genetic polymorphisms.

New treatments of neovascular AMD such as Ranibizumab and Pegaptanib have shown promising results so far.50, 51 It is feasible to assume that patients will respond differently to these new drugs due to inherent genetic influences which may need to be investigated further. These drugs were designed specifically as anti-VEGF therapy following extensive laboratory research. (VEGF) is an endothelial cell-specific mitogen that promotes angiogenesis and is a potent mediator of vascular permeability. Studies on diseases that involve inflammation and angiogenesis such as cancer, sarcoidosis, and more recently AMD have revealed VEGF polymorphisms that could put patients at higher or lower risks of developing the disease.52, 53, 54 Further research would no doubt shed light on other such mechanisms and these would be useful directly in identifying possible direct targets for drugs or indirectly through modulation of the genes responsible for disease presentation.

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Bringing age-related macular degeneration into focus

Nature Genetics News and Views (01 Jul 2008)