Elsevier

Survey of Ophthalmology

Volume 51, Issue 2, March–April 2006, Pages 137-152
Survey of Ophthalmology

Current Research
The Role of Inflammation in the Pathogenesis of Age-related Macular Degeneration

https://doi.org/10.1016/j.survophthal.2005.12.001Get rights and content

Abstract

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is a complex disease to study because of the potential role of demographic, environmental, and other systemic risk factors, such as age, sex, race, light exposure, diet, smoking, and underlying cardiovascular disease which may contribute to the pathogenesis of this disease. Recently, single nucleotide polymorphisms, DNA sequence variations found within the complement Factor H gene, have been found to be strongly associated with the development of AMD in Caucasians. One single nucleotide polymorphism, Tyr402His, was associated with approximately 50% of AMD cases. We review recent developments in the molecular biology of AMD, including single nucleotide polymorphisms within the Factor H gene, which may predispose individuals to the susceptibility of AMD as well as single nucleotide polymorphisms that may confer a protective effect. Taken together these findings help to provide new insights into the central issues surrounding the pathogenesis of AMD.

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)

  • A.E. Garrod

    The Incidence of Alkaptonuria: A study in chemical individuality

    Lancet

    (1902)
  • E. Giannakis et al.

    Multiple ligand binding sites on domain seven of human complement factor H

    Int Immunopharmacol

    (2001)
  • R.H. Guymer et al.

    HMG CoA reductase inhibitors (statins): do they have a role in age-related macular degeneration?

    Surv Ophthalmol

    (2005)
  • G.S. Hageman et al.

    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

    (2001)
  • J.R. Heckenlively et al.

    Association of antiretinal antibodies and cystoid macular edema in patients with retinitis pigmentosa

    Am J Ophthalmol

    (1999)
  • J. Jakobsdottir et al.

    Susceptibility genes for age-related maculopathy on chromosome 10q26

    Am J Hum Genet

    (2005)
  • L.V. Johnson et al.

    Complement activation and inflammatory processes in Drusen formation and age related macular degeneration

    Exp Eye Res

    (2001)
  • L.V. Johnson et al.

    A potential role for immune complex pathogenesis in drusen formation

    Exp Eye Res

    (2000)
  • M.M. Kini et al.

    Prevalence of senile cataract, diabetic retinopathy, senile macular degneration, and open-angle glaucoma in the Framingham eye study

    Am J Ophthalmol

    (1978)
  • C.C. Klaver et al.

    Genetic association of apolipoprotein E with age-related macular degeneration

    Am J Hum Genet

    (1998)
  • R. Klein et al.

    Early age-related maculopathy in the cardiovascular health study

    Ophthalmology

    (2003)
  • A.L. Kornzweig

    The eye in old age V. Diseases of the macula: a clinicopathologic study

    Am J Ophthalmol

    (1965)
  • I.M. MacDonald et al.

    Ocular genetics: current understanding

    Surv Ophthalmol

    (2004)
  • J. Majewski et al.

    Age-related macular degeneration—a genome scan in extended families

    Am J Hum Genet

    (2003)
  • S.M. Meyers et al.

    A twin study of age-related macular degeneration

    Am J Ophthalmol

    (1995)
  • ___: Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease...
  • ___: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons disease chromosomes....
  • ___: Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch...
  • R. Allikmets

    A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy

    Nat Genet

    (1997)
  • J.L. Anderson

    Infection, antibiotics, and atherothrombosis—end of the road or new beginnings?

    N Engl J Med

    (2005)
  • G. Ashwell et al.

    The dual role of sialic acid in the hepatic recognition and catabolism of serum glycoproteins

    Biochem Soc Symp

    (1974)
  • T.K. Blackmore et al.

    M protein of the group A Streptococcus binds to the seventh short consensus repeat of human complement factor H

    Infect Immun

    (1998)
  • D. Botstein et al.

    Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease

    Nat Genet

    (2003)
  • Botto M: Links between complement deficiency and apopthsis. Arthritis Res 3:207–10,...
  • G. Chaine et al.

    Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group

    Br J Ophthalmol

    (1998)
  • E. Cho et al.

    Prospective study of alcohol consumption and the risk of age-related macular degeneration

    Arch Ophthalmol

    (2000)
  • T.E. Clemons et al.

    Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19

    Ophthalmology

    (2005)
  • D. Colville et al.

    Visual impairment caused by retinal abnormalities in mesangiocapillary (membranoproliferative) glomerulonephritis type II (dense deposit disease)

    Am J Kidney Dis

    (2003)
  • N. Congdon et al.

    Causes and prevalence of visual impairment among adults in the United States

    Arch Ophthalmol

    (2004)
  • S.W. Cousins et al.

    Monocyte activation in patients with age-related macular degeneration: a biomarker of risk for choroidal neovascularization?

    Arch Ophthalmol

    (2004)
  • J.W. Crabb et al.

    Drusen proteome analysis: an approach to the etiology of age-related macular degeneration

    Proc Natl Acad Sci USA

    (2002)
  • S.P. Daiger

    Identifying retinal disease genes: how far have we come, how far do we have to go?

    Novartis Found Symp

    (2004)
  • B. Dasch et al.

    Inflammatory markers in age related maculopathy. Cross section anayysis from the Muenster Aging and Retina Study

    Arch Ophthalmol

    (2005)
  • J.C. Davies et al.

    Modifier genes in cystic fibrosis

    Pediatr Pulmonol

    (2005)
  • M.M. DeAngelis et al.

    Extremely discordant sib-pair study design to determine risk factors for neovascular age-related macular degeneration

    Arch Ophthalmol

    (2004)
  • P.J. Delves et al.

    The immune system. First of two parts

    N Engl J Med

    (2000)
  • P.J. Delves et al.

    The immune system. Second of two parts

    N Engl J Med

    (2000)
  • T.P. Dryja

    Gene-based approach to human gene-phenotype correlations

    Proc Natl Acad Sci USA

    (1997)
  • T.P. Dryja et al.

    Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa

    Invest Ophthalmol Vis Sci

    (1997)
  • T.P. Dryja et al.

    Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa

    N Engl J Med

    (1990)
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    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.

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