Current ResearchThe Role of Inflammation in the Pathogenesis of Age-related Macular Degeneration
Introduction
Age-related macular degeneration (AMD) is an important disease to study not only because of its profound effects on vision of the elderly but also because of its potential association with other systemic disorders. It is the leading cause of visual impairment in the USA among persons 65 years of age and older. Although the clinical features of AMD were first described by Needelship in 1884 as a central choroidal atrophy,110 it was Haab in 1885 who used the term senile macular degeneration in describing the condition.1, 19, 55 The name senile is a misnomer because it does not involve senile dementia but age-related retinal changes, hence the more appropriate present-day term age-related macular degeneration, or AMD. The condition is now assuming greater importance in the USA due to the increasingly aging population, where it is estimated that legal blindness or low vision affects approximately 1 in 28 Americans over the age of 65 years.19, 43 By the year 2020, the number of individuals having AMD will increase by 50%.43
Although several lines of evidence, including twin and population-based aggregation studies63, 79, 80, 100, 117, 133 have implicated a hereditary component in the disorder, other contributing factors such as diet, smoking, obesity, and underlying vascular disease may also be important.1, 3, 15, 25, 67, 79, 82, 83, 135, 138, 144, 147, 152 The association between cardiovascular disease and AMD is inferred from the histological similarity of atherosclerotic deposits within arterial vessels to those of drusen, the hallmark of AMD, in the eye. Furthermore, a local inflammatory responses has been implicated in the etiology of both macular drusen70 and drusen-like deposits in arterial vessels.7, 97
Genetically, the condition is somewhat difficult to study because of its clinical variability and late onset, where most patients are not diagnosed with AMD until their mid 60s (mean age of diagnosis is 65.8 years139). Cohorts are often not available to study either because many potential subjects are deceased or they have not manifested the clinical features of AMD because of relatively young age at the time of the cohort study, but will develop the condition later in life.
Herein, we review recent molecular genetic findings regarding an increased risk for AMD associated with DNA sequence variants in the immune complement Factor H gene (HF1/CFH), a protein intimately involved in complement-mediated immune-inflammatory processes. The identification of genetic factors that predispose to the development of AMD, confer a protective effect, or provide a presymptomatic diagnosis may eventually play an important role in the clinical evaluation and in the management of this condition and is a central issue of this review. Excellent reviews concerning the diagnosis, treatment and other aspects of AMD already exist and are not the focus of this review.6, 26, 27, 39, 41, 54, 93, 115, 159
Section snippets
Epidemiology
In general terms, macular degenerations and/or macular dystrophies can be classified into the juvenile and age-related forms. With regard to the molecular genetics of the juvenile macular dystrophies, research over the last 10 years has contributed significantly to the understanding of these conditions.158 The clinical features and identification of many of the disease-causing genes have been identified (Fig. 1, Table 1). Functional studies and clinical treatment trials are presently being
Molecular Genetics of AMD
In 1866, 1 year after Andrew Johnson became the 17th president of the United States, Gregor Mendel published his findings on heredity in peas, setting the stage for the future of human genetics.99 Archibald Garrod in 1902 placed these concepts on solid ground when he first suggested that alkaptonuria, a recessive disease of childhood, originated from “a peculiarity of the parents, which may remain latent for generations.”45
Although oversimplified, genetic disorders may be classified as
Identification of the Factor H Gene Associated with AMD
Traditionally the identification of disease-causing genes was achieved by one of several techniques often taking years of laboratory research. For example, the gene responsible for Huntington disease was mapped early to chromosome 4, but took an additional 10 years to identify the disease-causing gene.2 Briefly, these techniques are classified as functional cloning, position cloning, candidate gene approach, or combinations of these techniques. Functional cloning requires the knowledge of an
Refine the “At Risk” Categories
According to Hageman there are at least eight SNPs within the Factor H gene that are associated with susceptibility or protectivity to AMD.56 Furthermore, the occurrence of two or more of these SNPs (haplotypes) increases or decreases the association of AMD. For example, the diplotype (both alleles) occurring in combination C at Y402H and T at IVS10 is purported to confer a 3.51 relative risk for AMD and the combination of T at IVS1 and A at I62V is associated with a protective effect (OR <1).
Summary
Modern molecular biological techniques such as genome-wide association studies using potentially thousands or millions of SNPs has made it technically feasible to identify a DNA sequence variant in Factor H that is associated with AMD in a high percentage of cases. An understanding of the function of Factor H allows for future studies aimed at unraveling the specific stages in the development of the condition including the contribution of inflammatory or immune mediated processes. Such studies
Method of Literature Search
PubMed (www.ncbi.nlm.gov/PubMed) was used as the primary literature search using the search words age-related macular degeneration, atherosclerosis, complement, drusen, Factor H gene, genetics, glomerulonephritis, inflammation, single nucleotide polymorphism. Additional citations were from the authors' possession as well as using general Internet searches (www.google.com). Last literature search was September 2005.
References (164)
- et al.
Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease
Am J Hum Genet
(2004) - et al.
Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies
Surv Ophthalmol
(2003) - et al.
A role for local inflammation in the formation of drusen in the aging eye
Am J Ophthalmol
(2002) - et al.
Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration
Exp Eye Res
(2004) - et al.
Risk factors in age-related maculopathy complicated by choroidal neovascularization
Ophthalmology
(1986) - et al.
Autosomal dominant Stargardt-like macular dystrophy
Surv Ophthalmol
(2001) - et al.
Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene
Surv Ophthalmol
(2003) - et al.
Autosomal dominant macular dystrophy in a large Canadian family
Can J Ophthalmol
(2003) Risk factors for age-related macular degeneration
Prog Retin Eye Res
(2001)Age-related macular degeneration 1969-2004: a 35-year personal perspective
Am J Ophthalmol
(2005)
The Incidence of Alkaptonuria: A study in chemical individuality
Lancet
Multiple ligand binding sites on domain seven of human complement factor H
Int Immunopharmacol
HMG CoA reductase inhibitors (statins): do they have a role in age-related macular degeneration?
Surv Ophthalmol
An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruchs membrane interface in aging and age-related macular degeneration
Prog Retin Eye Res
Association of antiretinal antibodies and cystoid macular edema in patients with retinitis pigmentosa
Am J Ophthalmol
Susceptibility genes for age-related maculopathy on chromosome 10q26
Am J Hum Genet
Complement activation and inflammatory processes in Drusen formation and age related macular degeneration
Exp Eye Res
A potential role for immune complex pathogenesis in drusen formation
Exp Eye Res
Prevalence of senile cataract, diabetic retinopathy, senile macular degneration, and open-angle glaucoma in the Framingham eye study
Am J Ophthalmol
Genetic association of apolipoprotein E with age-related macular degeneration
Am J Hum Genet
Early age-related maculopathy in the cardiovascular health study
Ophthalmology
The eye in old age V. Diseases of the macula: a clinicopathologic study
Am J Ophthalmol
Ocular genetics: current understanding
Surv Ophthalmol
Age-related macular degeneration—a genome scan in extended families
Am J Hum Genet
A twin study of age-related macular degeneration
Am J Ophthalmol
A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy
Nat Genet
Infection, antibiotics, and atherothrombosis—end of the road or new beginnings?
N Engl J Med
The dual role of sialic acid in the hepatic recognition and catabolism of serum glycoproteins
Biochem Soc Symp
M protein of the group A Streptococcus binds to the seventh short consensus repeat of human complement factor H
Infect Immun
Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease
Nat Genet
Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group
Br J Ophthalmol
Prospective study of alcohol consumption and the risk of age-related macular degeneration
Arch Ophthalmol
Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19
Ophthalmology
Visual impairment caused by retinal abnormalities in mesangiocapillary (membranoproliferative) glomerulonephritis type II (dense deposit disease)
Am J Kidney Dis
Causes and prevalence of visual impairment among adults in the United States
Arch Ophthalmol
Monocyte activation in patients with age-related macular degeneration: a biomarker of risk for choroidal neovascularization?
Arch Ophthalmol
Drusen proteome analysis: an approach to the etiology of age-related macular degeneration
Proc Natl Acad Sci USA
Identifying retinal disease genes: how far have we come, how far do we have to go?
Novartis Found Symp
Inflammatory markers in age related maculopathy. Cross section anayysis from the Muenster Aging and Retina Study
Arch Ophthalmol
Modifier genes in cystic fibrosis
Pediatr Pulmonol
Extremely discordant sib-pair study design to determine risk factors for neovascular age-related macular degeneration
Arch Ophthalmol
The immune system. First of two parts
N Engl J Med
The immune system. Second of two parts
N Engl J Med
Gene-based approach to human gene-phenotype correlations
Proc Natl Acad Sci USA
Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa
Invest Ophthalmol Vis Sci
Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa
N Engl J Med
Cited by (436)
Association between glycemic status and age-related macular degeneration: A nationwide population-based cohort study
2023, Diabetes and MetabolismBioengineering approaches for modelling retinal pathologies of the outer blood-retinal barrier
2022, Progress in Retinal and Eye ResearchSystemic dendrimer nanotherapies for targeted suppression of choroidal inflammation and neovascularization in age-related macular degeneration
2021, Journal of Controlled ReleaseCitation Excerpt :Worldwide prevalence is expected to reach more than 288 million by 2040, and thus the societal cost of the treatment is expected to increase significantly [5]. Although the precise molecular mechanisms underlying the progression of this heterogenous disease are not well understood [2,6], oxidative stress and inflammation followed by neovascularization are implicated in human AMD [7–10]. Many clinical and preclinical studies underscore the active involvement of microglia/macrophages (mi/ma) in disease progression and choroidal neovascular (CNV) growth [7,11–16].
Progress in developing rodent models of age-related macular degeneration (AMD)
2021, Experimental Eye ResearchCitation Excerpt :Diminished CD46 and CD59 expressions were also seen in the RPE during early AMD, and further decreased in atrophic AMD, implying that complement deposition may be due to the lack of negative regulation (Ebrahimi et al., 2013). Analysis of drusen proteomics demonstrates the presence of C-reactive protein, C3a, C5a, C5b-9, amyloid beta protein, vitronectin and alpha-1 antitrypsin (Donoso et al., 2006; Mullins et al., 2000; Nozaki et al., 2006; Wang et al., 2010), which confirms the link between inflammation and AMD. In AMD patients, retinal microglia also become reactive in response to RPE degeneration (Gupta et al., 2003).
Impairing Gasdermin D-mediated pyroptosis is protective against retinal degeneration
2023, Journal of Neuroinflammation
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. This manuscript is dedicated to Alston Callahan, MD, (1911–2005) and to Charles D. Kelman, MD, (1930–2004) two of the co-founders of the International Retinal Research Foundation. Dr. Callahan contributed directly to this manuscript and his help is greatly appreciated. The manuscript was supported, in part, by the Henry and Corinne Bower Laboratory, the Eye Research Institute, and the Elizabeth C. King Trust. The support of L. Stanley Mauger is greatly appreciated. Sandra Blackwood and Thomas Perski provided helpful discussions.