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Role of genetic factors in the pathogenesis of exudative age-related macular degeneration
Taiwan Journal of Ophthalmology xxx (2014) 1e4
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Review article
Role of genetic factors in the pathogenesis of exudative age-related macular degeneration Peng Zhou a, b, Xiao-Xin Li a, c, * a
Key Laboratory of Vision Loss and Restoration, Ministry of Education of China, Beijing, People’s Republic of China Department of Ophthalmology, Parkway Health Hong Qiao Medical Center, Shanghai, People’s Republic of China c Department of Ophthalmology, Peking University People’s Hospital, Beijing, People’s Republic of China b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 March 2014 Accepted 21 March 2014 Available online xxx
Exudative age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness worldwide. Many recent genetic association studies on large caseecontrol cohorts have helped in drawing an outline of the pathogenesis of AMD. The majority of the associations observed in oxidative stress and lipid peroxidation (complement factor H or CFH), complement (CFH, C3, complement factor I, C2, complement factor B), and neovascularization (vascular endothelial growth factor A, high-temperature requirement factor A1) genes have been replicated in diverse populations worldwide. In this review, we have provided an overview on the genetic factors in the pathogenesis of AMD, and highlight their underlying molecular genetic mechanisms. Further comprehensive research is needed to verify this outline, to explore the treatment target, and to develop the effective primary and secondary prevention of AMD. Copyright Ó 2014, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: age-related macular degeneration complement lipid peroxidation neovascularization oxidative stress
1. Introduction 1.1. Age-related macular degeneration Age-related macular degeneration (AMD) is the leading cause of visual impairment in elderly individuals and is the most common cause of blindness in Western countries.1,2 Advanced AMD has two major subtypes, namely, geographic atrophy (also called advanced “dry” AMD) and choroidal neovascularization (CNV; also called exudative AMD or “wet” AMD). Exudative AMD affects 10e15% of patients with AMD and rapidly progresses to blindness if left untreated.3 1.2. Hypothesis of AMD pathogenesis In the early stages of AMD, the abnormal oxidative stress in retinal pigment epithelium (RPE) triggers the dysfunction or changes in the composition or permeability of Bruch’s membrane, leading to the formation of drusen. Drusen are small, yellowish
* Corresponding author. Department of Ophthalmology, Peking University People’s Hospital, Number 11, South Avenue of Xizhimen, Xicheng District, Beijing 100044, People’s Republic of China. E-mail address: [email protected] (X.-X. Li).
extracellular deposits of cellular debris, protein, lipid, carbohydrate, complement components, and anaphylatoxins. Local inflammatory and immune-mediated events play an important role in the development of drusen.4e8 In turn, the inflammation becomes chronic and increasingly amplified over decades as the outer macula becomes even more hypoxic. The complement system may play a central role in chronic inflammation. The inflammation triggers the production of vascular endothelial growth factor (VEGF), which was identified to play a major role in CNV in 1996.9,10 A previous study demonstrated that VEGF plays a role in the progression of CNV and enhancement of vascular permeability, both of which result in loss of vision.11 It stimulates dissociation of tight junction components, promotes vascular permeability, and endothelial cell growth.12,13 In the late stages of AMD, there is excessive recruitment of scar tissue that leads to irreversible destruction of photoreceptors (Fig. 1).
2. Role of genetic factors in the pathogenesis of AMD Recent large-sample genome-wide association studies (GWASs) confirmed previously reported AMD-associated genes, including complement factor H (CFH),14 high-temperature requirement factor A1 (HTRA1),14 age-related maculopathy susceptibility protein 2 (ARMS2),14 C3,14,15 VEGFA,14 etc. In this paper, the role of these genes in the pathogenesis of AMD is reviewed.
http://dx.doi.org/10.1016/j.tjo.2014.03.007 2211-5056/Copyright Ó 2014, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Zhou P, Li X-X, Role of genetic factors in the pathogenesis of exudative age-related macular degeneration, Taiwan Journal of Ophthalmology (2014), http://dx.doi.org/10.1016/j.tjo.2014.03.007
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P. Zhou, X.-X. Li / Taiwan Journal of Ophthalmology xxx (2014) 1e4
Fig. 1. Hypothesis of age-related macular degeneration pathogenesis. APOE ¼ apolipoprotein E; ARMS2 ¼ age-related maculopathy susceptibility protein 2; CFB ¼ complement factor B; CFH ¼ complement factor H; CFI ¼ complement factor I; HTRA1 ¼ high-temperature requirement factor A1; VEGFA ¼ vascular endothelial growth factor A.
2.1. Role of genetic factors in oxidative stress/lipid peroxidation stage Increased oxidative stress has been implicated in the pathogenesis of AMD.16,17 Owing to oxidative stress, proteins, lipids, and DNA can be damaged. When phospholipids in cell membranes undergo lipid peroxidation, malondialdehyde (MDA) and other reactive decomposition products are generated.18 Previous studies have reported that oxidative stress and lipid peroxidation-related genesdCFH and apolipoprotein E (APOE)dare associated with AMD. 2.1.1. CFH protects from oxidative stress The CFH is one of the first genes reported to be associated with AMD.19 Individuals with a CFH variant that substitutes a tyrosine for a histidine at position 402 have an increased likelihood of developing AMD by 4.6-folds if the variation is present on one allele and by 7.4folds if it is present on both alleles.19 Further CFH studies found that the CFH haplotype significantly increased the risk for AMD with odds ratios (ORs) between 2.45 and 5.57 and that a common variant likely explains approximately 43% of AMD in older adults.20e25 Recent research found that CFH is an innate defense protein against oxidative stress.17 Results from animal models lacking immunoglobulins showed that over 55% of peptides that bind to MDA could be attributed to CFH. Mapping of the binding site for MDA on CFH showed that it crossed the amino acid position 402, highlighted in the original genetic association studies and, most importantly, the H402 variant of CFH showed reduced MDA binding by up to 23% in the plasma of heterozygotes and up to 52% in homozygotes. Normal CFH then appears to protect against inflammation by inhibiting the complement pathway; however, once mutated, the CFH’s ability to control the inflammation associated with AMD appears to be lost. Functioning CFH is able to suppress the inflammatory response by mopping up the MDA adducts.17 2.1.2. APOE suppresses lipid peroxidation APOE is a lipid transport protein that acts as a ligand for the lowdensity lipoprotein (LDL) receptor, which is involved in the maintenance and repair of neuronal cell membranes. Variation at two single-nucleotide polymorphisms (SNPs) within the coding sequence of the APOE gene, rs429358 and rs7412, results in different isoforms reported to attenuate binding affinity to the LDL receptor. Three allelic variants derived from these SNPs commonly referred to as ε2, ε3, and ε4 are differentiated based on cysteine (Cys) and
arginine (Arg) residue interchanges at positions 112 (rs429358) and 158 (rs7412) in the amino acid. APOε2 has a much reduced binding affinity leading to lower total cholesterol levels with respect to APOε3 and APOε4, which reveal a higher binding affinity with higher total cholesterol levels.26 The APOE has been found to be associated with AMD. A pooled analysis of 15 studies demonstrated the associations between late AMD and APOε4 (OR ¼ 0.72 per haplotype) and APOε2 (OR ¼ 1.83 for homozygote carriers).27 APOE plays an important role in suppressing the oxidative stress and lipid peroxidation. APOE binds directly to 4-hydroxynonenal and has a protective effect against lipid peroxidation.28 A recent study found that lipid peroxidation is caused by a reduction of antioxidant activity with aging in APOE knockout mice.29 2.1.3. Role of genetic factors in chronic inflammation Oxidatively modified proteins are known to induce inflammatory responses and are recognized by innate immunity.30,31 The oxidation-specific epitopes are recognized as danger signals by innate immune receptors.32 Following a series of independent research papers in late 2005 suggesting a link between the body’s immune system and AMD, further investigations established the alternative complement system as a potentially critical player that may help scientists to join the dots between drusen, a fatty tissue characteristic of the disease, and the symptomatic degeneration of the macula. Understanding the links between the genetic susceptibility data and the clinical symptoms should provide a framework for a deeper understanding of AMD pathogenesis and consequently contribute to identifying new therapeutic targets to slow or halt vision loss associated with the disease. 2.1.4. CFH We have previously discussed that CFH protects from oxidative stress. Moreover, CFH plays an important role in the regulation of the alternative pathway. CFH binds C3b, and accelerates the decay of the alternative C3 convertase (C3bBb). It also acts as a cofactor for the inactivation of C3b by complement factor I (CFI).33,34 CFH binds to cell surfaces to regulate amplification of the alternative complement pathway resulting from spontaneous C3b deposition, which occurs on any surface in contact with blood.33,34 2.1.5. Complement C3 Complement C3 is the most abundant component of the complement pathway. Variations in the C3 gene are associated with AMD. A
Please cite this article in press as: Zhou P, Li X-X, Role of genetic factors in the pathogenesis of exudative age-related macular degeneration, Taiwan Journal of Ophthalmology (2014), http://dx.doi.org/10.1016/j.tjo.2014.03.007
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nonsynonymous C3 variation Arg80Gly (rs2230199) is associated with AMD.35e37 Another C3 variant (rs1047286) is also associated with AMD.20,36 Furthermore, some rare variants, such as p.Arg1210Cys38 and p.Pro314Leu,15 are associated with a high risk of AMD. C3 may have an important role in the pathogenesis of AMD. C3 messenger RNA can be detected in the neural retina, choroids, and RPE.7 Local C3a levels increase in the experimental model of wet AMD.39 Eliminating the C3 gene protects from CNV development after exposure to laser in C3 gene knockout mice.40 Furthermore, C3a may increase VEGF secretion40 and recruitment of monocytes by intercellular adhesion molecule 1 production. 2.1.6. CFI CFI is a serine protease that cleaves and inactivates C4b and C3b. A C>T transition (rs10033900) located downstream from the 30 untranslated region of the CFI gene has been shown to be associated with AMD.41,42 Recently, some rare variants in CFI, such as p.Gly119Arg43 and p.Pro50Ala,44 are associated with a high risk of advanced AMD. The effect of CFI variations on AMD formation may be due to a reduction in the degradation of C3b. A recent study found that plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b to a lesser extent than those from controls.43 2.1.7. Complement C2/complement factor B Complement component 2 (C2) and complement factor B (CFB) are described together because of similarities in structure, function, and genetic characteristics.34 The C2 gene, located on 6p21.33, encodes a serum glycoprotein that functions as part of the classical complement pathway, which is involved in innate immunity and inflammation.45 Two polymorphisms, rs9332739 G > C and rs547154 G > T, have been implicated in AMD. The C2 polymorphisms may be associated directly with AMD or indirectly through the high level of linkage disequilibrium that exists between C2 and CFB, which is located downstream on the same chromosome.20,46,47 The protective effect of C2/CFB variations may due to a reduction in formation of either classical or alternative pathway C3 convertase. Montes et al48 found that the CFB 32Q variant had up to four times less C3b binding affinity than the nonrisk 32R protein, with consequent reduction in C3 convertase formation. 2.2. Role of genetic factors in neovascularization 2.2.1. VEGF VEGF is a signal protein produced by cells and stimulates vasculogenesis and angiogenesis. VEGFA is the most important member of the VEGF family. VEGFA plays a particularly important role in the pathogenesis of wet AMD. Anti-VEGF therapies are the first-line treatment for AMD.49e51 Previous studies found that VEGF polymorphisms are associated with neovascular AMD. Previous studies on VEGF and AMD have yielded conflicting results. Some caseecontrol studies reported significant associations for VEGF polymorphisms,52e54 but the validity of these results remains unconfirmed.55 A recent collaborative GWAS, including 17,100 advanced AMD cases and 60,000 controls, found that the rs943080 variant in VEGFA is associated with increased risk of AMD.14 2.2.2. High-temperature requirement factor A1 and ARMS2 Numerous genetic association studies have shown that chromosome 10q26 is a major candidate region associated with the susceptibility of AMD.56 The linkage peak was refined to two neighboring genes, HTRA157e59 and ARMS2.20,60,61
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HTRA1 is a multifunctional serine protease. Overexpression of human HTRA1 in mouse eyes leads to CNV and polypoidal choroidal vasculopathy in mice.62 Further studies found that HTRA1 regulates angiogenesis through transforming growth factor-b family member growth differentiation factor 6.63 The function of ARMS2 has not yet been clearly demonstrated. Polymorphisms in ARMS2 and HTRA1 are strongly associated with AMD, whereas the strong linkage disequilibrium in the genomic region makes their effects indistinguishable in statistical analyses. Some experiments showed that ARMS2 localizes to the mitochondrial outer membrane.60 Other studies claimed that ARMS2 is mainly distributed in the cytosol.64 3. Conclusion The growing genetic evidence draws an outline of the pathogenesis of AMD. Further comprehensive research is needed to verify this outline, to explore the treatment target, and to develop the effective primary and secondary prevention of AMD. Conflicts of interest The authors declare no potential financial and nonfinancial conflicts of interest. Acknowledgments This study was supported by a grant (Grant No. 2011CB510200) from the National Basic Research Program of China (973 Program). References 1. de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355: 1474e1485. 2. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012;379:1728e1738. 3. Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 2008;115:116e126. 4. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20:705e732. 5. Dithmar S, Sharara NA, Curcio CA, Le NA, Zhang Y, Brown S, et al. Murine highfat diet and laser photochemical model of basal deposits in Bruch membrane. Arch Ophthalmol. 2001;119:1643e1649. 6. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227e7232. 7. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000;14:835e846. 8. Mullins RF, Aptsiauri N, Hageman GS. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond). 2001;15:390e395. 9. Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 1996;37:1929e1934. 10. Wells JA, Murthy R, Chibber R, Nunn A, Molinatti PA, Kohner EM, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br J Ophthalmol. 1996;80:363e366. 11. Ferrara N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med. 2010;16:1107e1111. 12. Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kud1a B. Vascular endothelial growth factor (VEGF)dpart 1: in physiology and pathophysiology. Endokrynol Pol. 2011;62:444e455. 13. Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov. 2012;11: 541e559. 14. Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, et al. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45: 433e439, 439e1ee2.
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Please cite this article in press as: Zhou P, Li X-X, Role of genetic factors in the pathogenesis of exudative age-related macular degeneration, Taiwan Journal of Ophthalmology (2014), http://dx.doi.org/10.1016/j.tjo.2014.03.007
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Review article
Role of genetic factors in the pathogenesis of exudative age-related macular degeneration Peng Zhou a, b, Xiao-Xin Li a, c, * a
Key Laboratory of Vision Loss and Restoration, Ministry of Education of China, Beijing, People’s Republic of China Department of Ophthalmology, Parkway Health Hong Qiao Medical Center, Shanghai, People’s Republic of China c Department of Ophthalmology, Peking University People’s Hospital, Beijing, People’s Republic of China b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 March 2014 Accepted 21 March 2014 Available online xxx
Exudative age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness worldwide. Many recent genetic association studies on large caseecontrol cohorts have helped in drawing an outline of the pathogenesis of AMD. The majority of the associations observed in oxidative stress and lipid peroxidation (complement factor H or CFH), complement (CFH, C3, complement factor I, C2, complement factor B), and neovascularization (vascular endothelial growth factor A, high-temperature requirement factor A1) genes have been replicated in diverse populations worldwide. In this review, we have provided an overview on the genetic factors in the pathogenesis of AMD, and highlight their underlying molecular genetic mechanisms. Further comprehensive research is needed to verify this outline, to explore the treatment target, and to develop the effective primary and secondary prevention of AMD. Copyright Ó 2014, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: age-related macular degeneration complement lipid peroxidation neovascularization oxidative stress
1. Introduction 1.1. Age-related macular degeneration Age-related macular degeneration (AMD) is the leading cause of visual impairment in elderly individuals and is the most common cause of blindness in Western countries.1,2 Advanced AMD has two major subtypes, namely, geographic atrophy (also called advanced “dry” AMD) and choroidal neovascularization (CNV; also called exudative AMD or “wet” AMD). Exudative AMD affects 10e15% of patients with AMD and rapidly progresses to blindness if left untreated.3 1.2. Hypothesis of AMD pathogenesis In the early stages of AMD, the abnormal oxidative stress in retinal pigment epithelium (RPE) triggers the dysfunction or changes in the composition or permeability of Bruch’s membrane, leading to the formation of drusen. Drusen are small, yellowish
* Corresponding author. Department of Ophthalmology, Peking University People’s Hospital, Number 11, South Avenue of Xizhimen, Xicheng District, Beijing 100044, People’s Republic of China. E-mail address: [email protected] (X.-X. Li).
extracellular deposits of cellular debris, protein, lipid, carbohydrate, complement components, and anaphylatoxins. Local inflammatory and immune-mediated events play an important role in the development of drusen.4e8 In turn, the inflammation becomes chronic and increasingly amplified over decades as the outer macula becomes even more hypoxic. The complement system may play a central role in chronic inflammation. The inflammation triggers the production of vascular endothelial growth factor (VEGF), which was identified to play a major role in CNV in 1996.9,10 A previous study demonstrated that VEGF plays a role in the progression of CNV and enhancement of vascular permeability, both of which result in loss of vision.11 It stimulates dissociation of tight junction components, promotes vascular permeability, and endothelial cell growth.12,13 In the late stages of AMD, there is excessive recruitment of scar tissue that leads to irreversible destruction of photoreceptors (Fig. 1).
2. Role of genetic factors in the pathogenesis of AMD Recent large-sample genome-wide association studies (GWASs) confirmed previously reported AMD-associated genes, including complement factor H (CFH),14 high-temperature requirement factor A1 (HTRA1),14 age-related maculopathy susceptibility protein 2 (ARMS2),14 C3,14,15 VEGFA,14 etc. In this paper, the role of these genes in the pathogenesis of AMD is reviewed.
http://dx.doi.org/10.1016/j.tjo.2014.03.007 2211-5056/Copyright Ó 2014, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Zhou P, Li X-X, Role of genetic factors in the pathogenesis of exudative age-related macular degeneration, Taiwan Journal of Ophthalmology (2014), http://dx.doi.org/10.1016/j.tjo.2014.03.007
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Fig. 1. Hypothesis of age-related macular degeneration pathogenesis. APOE ¼ apolipoprotein E; ARMS2 ¼ age-related maculopathy susceptibility protein 2; CFB ¼ complement factor B; CFH ¼ complement factor H; CFI ¼ complement factor I; HTRA1 ¼ high-temperature requirement factor A1; VEGFA ¼ vascular endothelial growth factor A.
2.1. Role of genetic factors in oxidative stress/lipid peroxidation stage Increased oxidative stress has been implicated in the pathogenesis of AMD.16,17 Owing to oxidative stress, proteins, lipids, and DNA can be damaged. When phospholipids in cell membranes undergo lipid peroxidation, malondialdehyde (MDA) and other reactive decomposition products are generated.18 Previous studies have reported that oxidative stress and lipid peroxidation-related genesdCFH and apolipoprotein E (APOE)dare associated with AMD. 2.1.1. CFH protects from oxidative stress The CFH is one of the first genes reported to be associated with AMD.19 Individuals with a CFH variant that substitutes a tyrosine for a histidine at position 402 have an increased likelihood of developing AMD by 4.6-folds if the variation is present on one allele and by 7.4folds if it is present on both alleles.19 Further CFH studies found that the CFH haplotype significantly increased the risk for AMD with odds ratios (ORs) between 2.45 and 5.57 and that a common variant likely explains approximately 43% of AMD in older adults.20e25 Recent research found that CFH is an innate defense protein against oxidative stress.17 Results from animal models lacking immunoglobulins showed that over 55% of peptides that bind to MDA could be attributed to CFH. Mapping of the binding site for MDA on CFH showed that it crossed the amino acid position 402, highlighted in the original genetic association studies and, most importantly, the H402 variant of CFH showed reduced MDA binding by up to 23% in the plasma of heterozygotes and up to 52% in homozygotes. Normal CFH then appears to protect against inflammation by inhibiting the complement pathway; however, once mutated, the CFH’s ability to control the inflammation associated with AMD appears to be lost. Functioning CFH is able to suppress the inflammatory response by mopping up the MDA adducts.17 2.1.2. APOE suppresses lipid peroxidation APOE is a lipid transport protein that acts as a ligand for the lowdensity lipoprotein (LDL) receptor, which is involved in the maintenance and repair of neuronal cell membranes. Variation at two single-nucleotide polymorphisms (SNPs) within the coding sequence of the APOE gene, rs429358 and rs7412, results in different isoforms reported to attenuate binding affinity to the LDL receptor. Three allelic variants derived from these SNPs commonly referred to as ε2, ε3, and ε4 are differentiated based on cysteine (Cys) and
arginine (Arg) residue interchanges at positions 112 (rs429358) and 158 (rs7412) in the amino acid. APOε2 has a much reduced binding affinity leading to lower total cholesterol levels with respect to APOε3 and APOε4, which reveal a higher binding affinity with higher total cholesterol levels.26 The APOE has been found to be associated with AMD. A pooled analysis of 15 studies demonstrated the associations between late AMD and APOε4 (OR ¼ 0.72 per haplotype) and APOε2 (OR ¼ 1.83 for homozygote carriers).27 APOE plays an important role in suppressing the oxidative stress and lipid peroxidation. APOE binds directly to 4-hydroxynonenal and has a protective effect against lipid peroxidation.28 A recent study found that lipid peroxidation is caused by a reduction of antioxidant activity with aging in APOE knockout mice.29 2.1.3. Role of genetic factors in chronic inflammation Oxidatively modified proteins are known to induce inflammatory responses and are recognized by innate immunity.30,31 The oxidation-specific epitopes are recognized as danger signals by innate immune receptors.32 Following a series of independent research papers in late 2005 suggesting a link between the body’s immune system and AMD, further investigations established the alternative complement system as a potentially critical player that may help scientists to join the dots between drusen, a fatty tissue characteristic of the disease, and the symptomatic degeneration of the macula. Understanding the links between the genetic susceptibility data and the clinical symptoms should provide a framework for a deeper understanding of AMD pathogenesis and consequently contribute to identifying new therapeutic targets to slow or halt vision loss associated with the disease. 2.1.4. CFH We have previously discussed that CFH protects from oxidative stress. Moreover, CFH plays an important role in the regulation of the alternative pathway. CFH binds C3b, and accelerates the decay of the alternative C3 convertase (C3bBb). It also acts as a cofactor for the inactivation of C3b by complement factor I (CFI).33,34 CFH binds to cell surfaces to regulate amplification of the alternative complement pathway resulting from spontaneous C3b deposition, which occurs on any surface in contact with blood.33,34 2.1.5. Complement C3 Complement C3 is the most abundant component of the complement pathway. Variations in the C3 gene are associated with AMD. A
Please cite this article in press as: Zhou P, Li X-X, Role of genetic factors in the pathogenesis of exudative age-related macular degeneration, Taiwan Journal of Ophthalmology (2014), http://dx.doi.org/10.1016/j.tjo.2014.03.007
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nonsynonymous C3 variation Arg80Gly (rs2230199) is associated with AMD.35e37 Another C3 variant (rs1047286) is also associated with AMD.20,36 Furthermore, some rare variants, such as p.Arg1210Cys38 and p.Pro314Leu,15 are associated with a high risk of AMD. C3 may have an important role in the pathogenesis of AMD. C3 messenger RNA can be detected in the neural retina, choroids, and RPE.7 Local C3a levels increase in the experimental model of wet AMD.39 Eliminating the C3 gene protects from CNV development after exposure to laser in C3 gene knockout mice.40 Furthermore, C3a may increase VEGF secretion40 and recruitment of monocytes by intercellular adhesion molecule 1 production. 2.1.6. CFI CFI is a serine protease that cleaves and inactivates C4b and C3b. A C>T transition (rs10033900) located downstream from the 30 untranslated region of the CFI gene has been shown to be associated with AMD.41,42 Recently, some rare variants in CFI, such as p.Gly119Arg43 and p.Pro50Ala,44 are associated with a high risk of advanced AMD. The effect of CFI variations on AMD formation may be due to a reduction in the degradation of C3b. A recent study found that plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b to a lesser extent than those from controls.43 2.1.7. Complement C2/complement factor B Complement component 2 (C2) and complement factor B (CFB) are described together because of similarities in structure, function, and genetic characteristics.34 The C2 gene, located on 6p21.33, encodes a serum glycoprotein that functions as part of the classical complement pathway, which is involved in innate immunity and inflammation.45 Two polymorphisms, rs9332739 G > C and rs547154 G > T, have been implicated in AMD. The C2 polymorphisms may be associated directly with AMD or indirectly through the high level of linkage disequilibrium that exists between C2 and CFB, which is located downstream on the same chromosome.20,46,47 The protective effect of C2/CFB variations may due to a reduction in formation of either classical or alternative pathway C3 convertase. Montes et al48 found that the CFB 32Q variant had up to four times less C3b binding affinity than the nonrisk 32R protein, with consequent reduction in C3 convertase formation. 2.2. Role of genetic factors in neovascularization 2.2.1. VEGF VEGF is a signal protein produced by cells and stimulates vasculogenesis and angiogenesis. VEGFA is the most important member of the VEGF family. VEGFA plays a particularly important role in the pathogenesis of wet AMD. Anti-VEGF therapies are the first-line treatment for AMD.49e51 Previous studies found that VEGF polymorphisms are associated with neovascular AMD. Previous studies on VEGF and AMD have yielded conflicting results. Some caseecontrol studies reported significant associations for VEGF polymorphisms,52e54 but the validity of these results remains unconfirmed.55 A recent collaborative GWAS, including 17,100 advanced AMD cases and 60,000 controls, found that the rs943080 variant in VEGFA is associated with increased risk of AMD.14 2.2.2. High-temperature requirement factor A1 and ARMS2 Numerous genetic association studies have shown that chromosome 10q26 is a major candidate region associated with the susceptibility of AMD.56 The linkage peak was refined to two neighboring genes, HTRA157e59 and ARMS2.20,60,61
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HTRA1 is a multifunctional serine protease. Overexpression of human HTRA1 in mouse eyes leads to CNV and polypoidal choroidal vasculopathy in mice.62 Further studies found that HTRA1 regulates angiogenesis through transforming growth factor-b family member growth differentiation factor 6.63 The function of ARMS2 has not yet been clearly demonstrated. Polymorphisms in ARMS2 and HTRA1 are strongly associated with AMD, whereas the strong linkage disequilibrium in the genomic region makes their effects indistinguishable in statistical analyses. Some experiments showed that ARMS2 localizes to the mitochondrial outer membrane.60 Other studies claimed that ARMS2 is mainly distributed in the cytosol.64 3. Conclusion The growing genetic evidence draws an outline of the pathogenesis of AMD. Further comprehensive research is needed to verify this outline, to explore the treatment target, and to develop the effective primary and secondary prevention of AMD. Conflicts of interest The authors declare no potential financial and nonfinancial conflicts of interest. Acknowledgments This study was supported by a grant (Grant No. 2011CB510200) from the National Basic Research Program of China (973 Program). References 1. de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355: 1474e1485. 2. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012;379:1728e1738. 3. Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 2008;115:116e126. 4. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20:705e732. 5. Dithmar S, Sharara NA, Curcio CA, Le NA, Zhang Y, Brown S, et al. Murine highfat diet and laser photochemical model of basal deposits in Bruch membrane. Arch Ophthalmol. 2001;119:1643e1649. 6. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227e7232. 7. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000;14:835e846. 8. Mullins RF, Aptsiauri N, Hageman GS. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond). 2001;15:390e395. 9. Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 1996;37:1929e1934. 10. Wells JA, Murthy R, Chibber R, Nunn A, Molinatti PA, Kohner EM, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br J Ophthalmol. 1996;80:363e366. 11. Ferrara N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med. 2010;16:1107e1111. 12. Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kud1a B. Vascular endothelial growth factor (VEGF)dpart 1: in physiology and pathophysiology. Endokrynol Pol. 2011;62:444e455. 13. Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov. 2012;11: 541e559. 14. Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, et al. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45: 433e439, 439e1ee2.
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Please cite this article in press as: Zhou P, Li X-X, Role of genetic factors in the pathogenesis of exudative age-related macular degeneration, Taiwan Journal of Ophthalmology (2014), http://dx.doi.org/10.1016/j.tjo.2014.03.007