Age-related macular degeneration and DNA methylation

Abstract

EpigenomicsVol. 5, No. 3 EditorialFree AccessAge-related macular degeneration and DNA methylationPaul N Baird & Lai WeiPaul N Baird* Author for correspondenceCentre for Eye Research Australia, University of Melbourne, Royal Victorian Eye & Ear Hospital, 32 Gisborne Street, East Melbourne, 3002 Victoria, Australia. Search for more papers by this authorEmail the corresponding author at pnb@unimelb.edu.au & Lai WeiLaboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA and Center for Human Immunology, Autoimmunity & Inflammation, NIH, Bethesda, MD 20892, USA and National Center for Complementary & Alternative Medicine, NIH, Bethesda, MD 20892, USASearch for more papers by this authorPublished Online:11 Jun 2013https://doi.org/10.2217/epi.13.19AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: age-related macular degenerationdiscordant twingenegenome-wideimmuneinterleukinmethylationAge-related macular degeneration (AMD) is a common, complex and progressive neurodegenerative disease detected in approximately one in seven (14%) Australians over the age of 50 years [1] and is a leading cause of blindness in the developed world. As populations rapidly age in developed countries, the number of affected individuals suffering from AMD will substantially increase [2]. The clinical presentation of AMD is diverse [3,4] with the early stages being characterized by the presence of drusen (extracellular deposits of protein and lipid materials found beneath the retina) and pigmentary disturbance. In the advanced stages of disease, AMD is usually classified as geographic atrophy (or ‘dry’ AMD), characterized by damage to the retinal pigment epithelium and photoreceptors, and eventually atrophy and central blindness, or choroidal neovascularization (or ‘wet’ AMD), where new blood vessels develop and leak under the retinal pigment epithelium, leading to loss of central vision.Genetic studies in AMD have been incredibly successful, identifying a number of genes significantly associated with disease. These include several genes involved in complement regulation (CFH,CFHR3, CFHR1, CFHR4, CFHR2, CFHR5,BF, C2 and C3) as well as noncomplement genes (LOC387715 [ARMS2], HTRA1 and APOE) [5]. In addition, these findings have been further consolidated through the AMD Gene Consortium, an international consortium bringing together genome-wide association study data on over 17,000 advanced AMD cases and 60,000 controls of European and Asian ancestry. In this study, previously identified AMD-associated genes were confirmed, and an additional seven novel genomic loci were identified to be significantly associated with AMD, including COL8A1/FILIP1L, IER3/DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9/MIR548A2 and B3GALTL genes [6]. These 19 gene associations are predicted to account for approximately half of the population attributable risk of this disease [6].While AMD may be considered almost as a poster child in the identification of significant genetic associations in a complex disease, there are still many gaps in our understanding of this disease. We still have limited knowledge as to which genetic variants are actually involved in disease etiology or how they are functionally involved. Currently, there is no specific genetic association able to differentiate the late disease clinical subtypes of either geographic atrophy or choroidal neovascularization disease, or which genetic changes might influence progression of the disease. Further complexities arise when a range of nongenetic risk factors associated with AMD, including aging, smoking, diet and inflammation, are considered. Again, the mode of action of how these factors may impact on AMD is unclear. Our ability to develop highly sensitive predictive testing for those most at risk, such as individuals with a family history of disease, or development of new personalized treatment therapies for AMD is, therefore, impaired. Thus, advice to patients can be incomplete.The finding of both genetic and environmental components begs the question as to whether there is a synergistic interaction between these factors in relation to disease and if so what kind of functional mechanism might be present to elicit this effect. For instance, varying risk associations have been reported between past and present smokers with AMD [7,8]. In addition, various dietary components, such as ω-3, vitamins, a Mediterranean diet and antioxidants, have been proposed to lead to altered risk of AMD [9–11]. Thus, the temporal nature of the smoking-induced effect as well as the variable uptake of nutrients may lead to a change in gene expression with a reversible or modifiable mechanism of action. Epigenetic regulation has been proposed as one means of providing such a mechanism, enabling cells to respond quickly to environmental changes, and providing a link between genes and the environment [12].Epigenetic regulation, including DNA methylation and histone modifications, represents the main mechanism by which gene expression patterns can be altered as a result of environmental stimulus without a change in DNA sequence. In order to overcome the need for the collection of an extensive array of patient samples to investigate the potential effect of methylation in AMD, it is possible to minimize at least one, if not both, sides of the gene × environment equation through the use of identical twins. Most twin studies typically compare identical or monozygotic (MZ) twins (who share 100% of their genes) with nonidentical or dizygotic twins (who share 50% of their genes) to dissect out genetic and environmental components of a disease or trait, as well as to undertake heritability analysis. It is well established that for genetically defined traits, MZ twins are more highly correlated than nonidentical or dizygotic twins and this also appears to be true for DNA methylation profiles [13]. In addition, the nonshared environmental components are minimized in MZ twins in their childhood, thus, diminishing the impact of these factors. The vast majority of MZ twins are concordant for disease but, in a small minority, it is possible to identify MZ twins that are discordant for a disease or trait. There are several plausible explanations to explain the occurrence of discordant twin pairs, one of which arises from an environmental trigger affecting one of the twins in utero, thereby providing an ideal starting point to establish whether methylation differences can be identified in such discordant twin pairs [14]. Alternatively, methylation changes may occur as a result of some aspect of the disease process itself. Identifying which of these scenarios is true is not easy but recently, we have gone some way to identifying methylation changes at the genome-wide level in AMD-discordant twin pairs. We were also able to confirm these changes in AMD-discordant sibling pairs and further verify these changes in case controls. In addition, a functional study on the promoter region of one of the genes identified, the IL17RC gene, showed immune alteration, demonstrating the role of epigenetics in AMD for the first time [15].The aged immune system is typically hyper-responsive to inflammatory stimuli and produces autoinflammatory T cells, causing tissue damage. We previously found an elevated level of IL-17 and IL-22 produced by Th17 cells, a subset of CD4+ helper T cells that cause tissue inflammation, in the serum of AMD patients [16]. Both IL-17 and IL-22 can induce demethylation of the IL17RC promoter and promote IL17RC expression [15]. The epigenetic DNA methylation changes, especially those found on the promoter of IL17RC, could, therefore, be due to a chronic Th17-mediated inflammatory response developed only in the diseased twin in response to their own living environment.Interestingly, while DNA from whole blood has been the most widely collected tissue to assess systemic changes in epidemiology investigations, there is ongoing concern regarding the effect of tissue-specific methylation and how representative methylation changes in blood would be of the tissue of choice. While there may be tissue-specific methylation patterns, it is very difficult to obtain retinal tissue, except through donation, and, thus, this caveat will always be present. However, the majority of cell populations in the blood (the red blood cells are removed before DNA extraction), including T cells, B cells, monocytes and natural killer cells (together called peripheral blood mononuclear cells), as well as myeloid cells, are all immune cells. Therefore, it is plausible to study the methylation changes in the blood if the disease is expected to involve changes to the immune system, as is the case in AMD, in which the dysregulation of the complement system has long been linked to its etiology.While we assessed the promoter region of the IL17RC gene at the epigenetic level, we also identified many other significant hypo- and hyper-methylated differences in approximately 1.5% of CpG sites within 231 gene promoters in the examined AMD twins. These genes were identified as belonging to different pathways, including 58 in immunological disease, 78 in gastrointestinal disorders, 55 in endocrine system disorders, 63 in metabolic diseases and 127 in genetic diseases [15]. Some of the genes identified have previously been implicated in eye disease, such as ELOV4.Interestingly, none of the differentially methylated genes identified in this study overlapped with the most significantly associated ‘top hits’ identified through the genome-wide association study of the AMD Gene Consortium [6]. Epigenetic studies may, therefore, provide a further wave of genes identified as being important in AMD etiology, potentially at different stages of disease. Certainly, the finding that a large number of genes were identified as significantly hypo- or hyper-methylated may represent ‘the tip of the iceberg’ in terms of identifying genetic modifications through differential methylation in AMD. The twins selected for this initial study were chosen based on disease discordance but there is no reason why such an approach could not be undertaken to explore the effect of environmental factors, such as smoking or nutritional influences, on epigenetics and their role in this age-related disease.The finding of epigenetic changes in AMD opens the door for the exploration of the role of environmental risk factors that may reduce or enhance the risk of AMD, allowing characterization of immune and other pathways important in this disease, identification of biomarkers and perhaps modification or enhancement of certain genes or gene pathways through pharmacoepigenetic interventions.Financial & competing interests disclosureFunding for this article was provided through the intramural research program of the National Eye Institute, the National Center for Complementary and Alternative Medicine and the National Health and Medical Research Council (NHMRC) Centre for Clinical Research Excellence #529923 – Translational Clinical Research in Major Eye Diseases and through an NHMRC Senior Research Fellowship 1028444 (PN Baird). The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Macular Degeneration Foundation. Eyes on the Future: a Clear Outlook on Age-Related Macular Degeneration. Deloitte Access Economics, Canberra, Australia (2011).Google Scholar2 Friedman DS, O’Colmain BJ, Muñoz B et al. Prevalence of age-related macular degeneration in the United States. Arch. Ophthalmol.122(4),564–572 (2004).Crossref, Medline, Google Scholar3 Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology104(1),7–21 (1997).Crossref, Medline, CAS, Google Scholar4 Klein R, Klein BE, Tomany SC, Moss SE. Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am. J. Epidemiol.156(7),589–598 (2002).Crossref, Medline, Google Scholar5 Baird PN, Hageman GS, Guymer RH. New era for personalized medicine: the diagnosis and management of age-related macular degeneration. Clin. Experiment. Ophthalmol.37(8),814–821 (2009).Crossref, Medline, Google Scholar6 Fritsche LG, Chen W, Schu M et al.; The AMD Gene Consortium. Seven new loci associated with age-related macular degeneration. Nat. Genet.45(4),433–439 (2013).Crossref, Medline, CAS, Google Scholar7 Smith W, Assink J, Klein R et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology108(4),697–704 (2001).Crossref, Medline, CAS, Google Scholar8 Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP. Smoking and age-related macular degeneration: a review of association. Eye (Lond.)19(9),935–944 (2005).Crossref, Medline, CAS, Google Scholar9 Kaushik S, Wang JJ, Flood V et al. Dietary glycemic index and the risk of age-related macular degeneration. Am. J. Clin. Nutr.88(4),1104–1110 (2008).Crossref, Medline, CAS, Google Scholar10 Mares JA, Voland RP, Sondel SA et al. Healthy lifestyles related to subsequent prevalence of age-related macular degeneration. Arch. Ophthalmol.129(4),470–480 (2011).Crossref, Medline, Google Scholar11 Tan JS, Wang JJ, Flood V, Rochtchina E, Smith W, Mitchell P. Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology115(2),334–341 (2008).Crossref, Medline, Google Scholar12 Hjelmeland LM. Dark matters in AMD genetics: epigenetics and stochasticity. Invest. Ophthalmol. Vis. Sci.52(3),1622–1631 (2011).Crossref, Medline, CAS, Google Scholar13 Kaminsky ZA, Tang T, Wang SC et al. DNA methylation profiles in monozygotic and dizygotic twins. Nat. Genet.41(2),240–245 (2009).Crossref, Medline, CAS, Google Scholar14 Gordon L, Joo JE, Powell JE et al. Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence. Genome Res.22(8),1395–1406 (2012).Crossref, Medline, CAS, Google Scholar15 Wei L, Liu B, Tuo J et al. Hypomethylation of the IL17RC promoter associates with age-related macular degeneration. Cell Rep.2(5),1151–1158 (2012).Crossref, Medline, CAS, Google Scholar16 Liu B, Wei L, Meyerle C et al. Complement component C5a promotes expression of IL-22 and IL-17 from human T cells and its implication in age-related macular degeneration. J. Transl. Med.9,1–12 (2011).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByDNA methylation plays important roles in retinal development and diseasesExperimental Eye Research, Vol. 211Adipose/Connective Tissue From Thyroid-Associated Ophthalmopathy Uncovers Interdependence Between Methylation and Disease Pathogenesis: A Genome-Wide Methylation Analysis8 September 2021 | Frontiers in Cell and Developmental Biology, Vol. 9Sleeping pattern and activities of daily living modulate protein expression in AMD1 June 2021 | PLOS ONE, Vol. 16, No. 6Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy8 November 2019 | Scientific Reports, Vol. 9, No. 1DNA Methylation and Uveal MelanomaChinese Medical Journal, Vol. 131, No. 7Comprehensive characterization of DNA methylation changes in Fuchs endothelial corneal dystrophy6 April 2017 | PLOS ONE, Vol. 12, No. 4Epigenetic modifications as potential therapeutic targets in age-related macular degeneration and diabetic retinopathyDrug Discovery Today, Vol. 19, No. 9Hypomethylation of the IL17RC Promoter in Peripheral Blood Leukocytes Is Not A Hallmark of Age-Related Macular DegenerationCell Reports, Vol. 5, No. 6 Vol. 5, No. 3 Follow us on social media for the latest updates Metrics History Published online 11 June 2013 Published in print June 2013 Information© Future Medicine LtdKeywordsage-related macular degenerationdiscordant twingenegenome-wideimmuneinterleukinmethylationFinancial & competing interests disclosureFunding for this article was provided through the intramural research program of the National Eye Institute, the National Center for Complementary and Alternative Medicine and the National Health and Medical Research Council (NHMRC) Centre for Clinical Research Excellence #529923 – Translational Clinical Research in Major Eye Diseases and through an NHMRC Senior Research Fellowship 1028444 (PN Baird). The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download